English

• 1. Introduction

  Polyamines are a type of aliphatic compounds that contain multiple amino groups and are a class of compounds that carry important physiological functions in plants and animals [1–4]. The polyamines that promote normal physiological activities in living organisms are called biogenic amines, including spermine, spermidine, putrescine, etc. As the first discovered biogenic amine, spermine phosphate was extracted from human semen by Van Leeuwenhoek in 1678 [5]. Since then, biogenic amines such as putrescine, spermidine, 1,3-diaminopropane, homospermidine, norethindrone and norethindrone have been identified in various bacterial algae [6,7]. Different polyamine concentrations in the body are closely related to the physiological activities of the organism. Some polyamines are involved in the synthesis of nucleic acids and also play a role in cell growth, such as spermidine, which stimulates DNA synthesis [8]. The amount of polyamines in living organisms is usually at the millimolar level, where most of them are bound to different polyanions, including nucleic acids, proteins, phospholipids, etc. [9–12].

  Macrocyclic polyamines are an important member of the polyamine family, and are vital in the development of coordination chemistry due to their chemical and biological properties and their coordination with transition metals [13–15]. Especially, the armed macrocyclic polyamines by adding pendant side chains to unsaturated nitrogen donor atoms, such as 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), have endowed them to the gold standard contrast agents in the filed of magnetic resonance imaging (MRI). Several reviews have been published with special focus on the synthesis, metal chelation and bioactive applications of macrocyclic compounds [16–18]. However, the latest advances of macrocyclic polyamines on medicinal applications has rarely been reported [13,18–20]. The purpose of this article is to understand the medical applications of macrocyclic polyamines from some new perspectives. Focusing on the original strategies designed and implemented over the past decade to explore the functionalization and biological evaluation of cyclic polyamines in medicine, including anti-cancer, antimicrobial infection therapy, and diagnostic therapies. Our research perspectives include: (ⅰ) Iron chelators used for anti-tumor and antibacterial activities; (ⅱ) Zinc chelators for metallo-β-lactamases (MBLs) inhibitors; (ⅲ) Cellular ATP depletion for anti-tumor treatment; (ⅳ) Non-viral vectors used for gene therapy; (ⅴ) Artificial nucleases for DNA/RNA synthesis inhibitors; (ⅵ) Radiopharmaceuticals for therapeutic diagnosis. In addition, we also discussed the cleavage and protection of DNA by macrocyclic polyamines. The current review will understand the application of macrocyclic polyamine in medicine from some new perspectives, which is helpful to further design new structures and thus achieve better drug activity.

  2. Structure and function of macrocyclic polyamine

  2.1 Basic structure and variations

  Macrocyclic polyamines are a class of nitrogen-containing heterocyclic compounds, and its history goes back to the 1960's [21–23]. It forms the cyclic counterpart of simple units such as ethylenediamine, diethylenetriamine and triethylenetetramine. Some common types of representative macrocyclic polyamines include 1,4,7-triazacyclononane (TACN or [9]aneN₃), 1,5,9-triazacyclododecane (TACD or [12]aneN₃), 1,4,7,10-tetraazacyclododecane (Cyclen or [12]aneN₄) and 1,4,8,11-tetraazacyclotetradecane (Cyclam or [14]aneN₄) (Fig. 1A). The molecular structure of protonated polyamine macrocycles is well regulated to recognize selectively different objects ranging from simple metal ions to biologically relevant species such as ATP, RNA, DNA and even short peptides [18,19]. With the rapid development of fundamental coordination chemistry and diagnostic medicine, researchers extensively study and apply functionalization of parent macrocycles. This is based on the presence of available free secondary amine functional groups in the macrocycles [24,25]. Of particular importance are the armed macrocyclic polyamines, including 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraethanol (DOTE), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO₃A), ((1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis(methylene))tetraphosphonicacid (DOTP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(puridine-2-ylmethyl) (DOTPy), and derivatives based on these structures (Fig. 1B). Additionally, there are some variants derived from basic structure of macrocyclic polyamine, such as oxa- or thiocycloamines, spermine, short peptides and porphyrin (Fig. 1C). Upon similarity with cyclic polyamine, these variants gain new properties beyond their anticipated due to unique coordination with metal ions.

  Figure 1

  

  Figure 1.  Structures of representative (A) parent and (B) armed macrocyclic polyamines, and (C) some variants.

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  2.2 Physicochemical properties

  Since conformational constraints in cyclic polyamines, the lone pairs of nitrogen can overlap to produce higher electron densities in the large ring cavities compared to the common linear polyamines or crown ethers [13]. The proton affinity (pKa) at the initial stage is unusually higher than the ordinary secondary amines. For instance, the pKa value for spermidine is 10.53 ± 0.19, while that of the cyclic derivative (1,5,9-triazacyclotridecane) is up to 11.40 ± 0.19. In addition, once protons are bound into the recirculation cavity, those amines that are not protonated no longer have an electron cloud present, which leads to very weak proton affinity at later stages. Compared the protonation constants K_i of cyclam with the corresponding linear derivative 2,3,2-tetramine as shown in Fig. S1 (Supporting information), the subsequent logK₃ and logK₄ are significantly reduced when two protons have incorporated into cyclam cavity [26]. In fact, many macrocyclic polyamines are known as "proton sponges" because of their strong proton binding and buffering capability [27,28]. As many pathological tissues or cells (e.g., tumors or inflammation) have a lower pH than physiological values [29], which can offer a favorable condition for the protonation of macrocyclic polyamines. High affinity of protonated polyamines bound to drug molecules for negatively charged cell membranes and nuclei, achieving drug cellular uptake and nuclear accumulation.

  Another important property of macrocyclic polyamine is their metal complexation, which has been used mostly as a chelating agent for transition metal ions in basic coordination chemistry research in early 1970's [30,31]. They show an excellent ability to bind various of metals and to undergo marked conformational changes during binding in many cases [16]. In terms of entropy factor, as the number of chelating rings increases, so does the stability of the complex due to increasing entropy (ΔS), as shown from EDA-Zn(Ⅱ) (logK = 10.79) to cyclen-Zn(Ⅱ) (logK = 15.41) [32]. Moreover, in the absence of any other conformational constraints, the optimal size adaptation of metal ions and macrocyclic cavity gives the highest stability of the complexes, such as Zn(Ⅱ) ion may be more suitable for cyclam (logK = 15.5 for cyclam-Zn(Ⅱ)) cavity than cyclen (logK = 15.41 for cyclen-Zn(Ⅱ)) [33]. Although cyclam usually form stable complexes with metals, the most stable macrocyclic complex is generated always from its armed derivatives, e.g., TETA (logK = 16.3 for TETA-Zn(Ⅱ)) [34]. This is because the freedom to fix the substituted donor to the most favorable ligand site is limited. The evolution of chelating stability with structural changes is shown in Fig. S2 (Supporting information).

  3. Molecular design based on macrocyclic polyamine and application

  3.1 Iron chelators for antitumor and antimicrobial activities

  Metal ions are vital to organisms, and in particular iron and zinc ions, the main metal ions found in humans, are arguably the best-studied. Imbalances in metal ion levels have been linked to many diseases, including diabetes, neurodegenerative diseases, and cancer [35–37]. Iron is the base metal of most living organisms as it acts in numerous cellular processes [38]. For example, iron is integral to protein cofactors like heme and iron-sulfur clusters [39]. In addition, since tumor cells require more iron compared to normal cells, surplus iron could potentially accelerate DNA synthesis in tumor cells [40]. Iron chelation acts as an anti-tumor agent through two different mechanisms. Firstly, iron consumption is used to limit the interference of iron in many cellular processes that are crucial for cell proliferation [40]. The second mechanism of action is to generate toxic free radicals within tumor cells by forming complexes that increase the redox potential of iron, ultimately leading to cell damage and death [41]. Certain clinically available iron chelators have some drawbacks in terms of their effectiveness in iron removal and are also associated with side effects [42]. There is a significant need for the development of new chelating agents to manage toxicity from metal overload, especially in specific organs [43].

  Traditional iron chelators like desferrioxamine (DFO) and diethylene triamine pentaacetic acid (DTPA) are extensively utilized as agents to deplete iron in antitumor therapy (Fig. 2A). DFO, a metabolite of Streptomyces precociousus with many carboxyamido acid groups, has been shown to exhibit inhibitory and antiproliferative activity against tumor cells, such as leukaemia, bladder and hepatocellular carcinoma, based on the effective induction of apoptosis, probably due to ribonucleotide reduction (RR) inhibition caused by iron depletion [44–46]. In contrast, DTPA is an iron chelator that cannot permeate cell membranes, exerting antiproliferative effects by chelating the extracellular iron pool [47]. Polycarbamate chelators have come into the limelight as potential antitumor agents due to the fact that DTPA shows potent iron depletion and biological activity. Chong et al. reported the synthesis and assessment of a series of polyaminocarboxylates NETA, NE3TA and NE3TA-Bn, and their bifunctional versions C-NETA, C-NE3TA, and N-NE3TA (Fig. 2B) [48]. The parent structure NETA has the same coordination group as DTPA, with both macrocyclic and acyclic portions. Compared to DTPA, NETA showed significantly enhanced cytotoxicity in HeLa and HT29 cells with IC₅₀ of 30.8 ± 4.0 and 7.3 ± 1.5 µmol/L, respectively. The analogues, NE3TA, NE3TA-Bn and N-NE3TA, presented more effective antiproliferative activity in both cell lines, with IC₅₀ values ranging from 4.4 ± 0.9 µmol/L to 8.4 ± 0.4 µmol/L for HeLa cell and from 2.6 ± 0.2 µmol/L to 6.8 ± 0.4 µmol/L for HT29 cell, respectively. The introduction of benzyl substituent remarkably increased cytotoxicity probably due to the lipophilic group improved the membrane permeability. Subsequently, a number of bifunctional ligands were synthesized containing a nitro group that could be used to target iron depletion therapy (IDT) by binding to a tumor-targeting peptide or antibody, which could be further transformed into either an amino (NH₂) or an isothiocyanate (NCS) moiety. The results of cytotoxicity measurements indicated that substitution of NE3TA and NE3TA-Bn by nitro did not reduce cytotoxic activity, whereas introduction of nitro into the NETA backbone led to a significant reduction in antiproliferative activity. Fluorescent group N-(7-nitrobenz-2-oxa-1,3-diazole) (NBD) was conjugated with C-NE3TA to form C-NE3TA-NBD, and the following fluorescent cellular uptake study indicated that C-NE3TA was uptaken into HT29 cancer cells (Fig. 2C). Similarly, Wang et al. designed and synthesized a bifunctional ligand p-NO₂-PhPr-NE3TA based on C-NETA, in which the nitro group can be further converted to amino NH₂ to form p-NH₂-PhPr-NE3TA (Fig. 2D) [49]. Both bifunctional chelators showed excellent antiproliferative activity in HepG2 cells with IC₅₀ of 1.4 ± 0.1 µmol/L and 1.5 ± 0.1 µmol/L, respectively, much higher than DTPA (38.3 ± 1.4 µmol/L) and DFO (> 100 µmol/L). The high activity of the bifunctional ligands could be attributed to p-nitrophenyl propyl on the side arm, in which the presence of long chains reduced the potential spatial blockage in the formation of iron complexes.

  Figure 2

  

  Figure 2.  (A) Structures and antiproliferative activities against cancer cells of classic hydrophilic iron chelators DFO, DTPA. (B) Anti-tumor cell activity of NETA, NE3TA and NE3TA-Bn and their respective derivatives (C-NETA, C-NE3TA and N-NE3TA) (C) Fluorescence images of HT29 cells with C-NE3TA-NBD incubation. (D) Anti-tumor cell activity of p-NO₂-PhPr-NE3TA and p-NH₂-PhPr-NE3TA.

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  Hydroxypyridone (HOPO) is an excellent bidentate chelator known for its strong affinity for Fe(Ⅲ) [50]. Three prototypical HOPOs, including 3-hydroxy-2-pyridinone (3,2-HOPO), 1-hydroxy-2-pyridinone (1,2-HOPO) and 3-hydroxy-4-pyridinone (3,4-HOPO), consist of the two neighboring oxygen atoms as oxygen donor sites that can form chelate rings with iron ions (Fig. S3 in Supporting information). Many studies have been published on HOPO derivatives based on nitrogen heterocyclic platforms as iron chelators [51–53].

  Based on the excellent performance of NETA and its bifunctional version C-NETA in Fe(Ⅲ) ion chelation mentioned above, Wang et al. synthesized two triazamacrocyclic hydroxypyridinone derivatives HE-NO₂A and HP-NO₂A by the introduction of HOPO groups as metal chelators, and further investigations involved testing these compounds for their potential in anticancer therapy targeting iron metabolism in human liver cancer (Fig. 3) [49]. The cytotoxicities of both chelators were determined using hepatocellular carcinoma cells (HepG2), and with DFO and DTPA as controls. The IC₅₀ of HE-NO₂A was 6.9 ± 0.9 µmol/L, which was much lower than those of DTPA (38.3 ± 1.4 µmol/L) and DFO (> 100 µmol/L). The ability of HE-NO₂A to chelate Fe (Ⅲ) ion might be derived from the TACN platform with two acetate branched chains and hydroxypyridinone. HOPOs are known to bind Fe(Ⅲ) ion efficiently, while the cantilever on the TACN platform maintains the high stability of the complex. These together with the rigid structure of TACN that allow the geometry of the metal-binding donor moiety to be controlled, and significantly influence the stability of the metal complexes formed [51]. HP-NO₂A with a longer chain between TACN platform and hydroxypyridinone moiety compared to HE-NO₂A, which could reduce the potential spatial site block in the Fe(Ⅲ) ion chelation process and lead to enhanced cytotoxicity (4.5 ± 0.2 µmol/L). To further improve the ability of macrocyclic polyamines and HOPO complexes in iron chelation, two new chelators HP-TACD and HP-TACN that all amine group substituted by 3,4-HOPO were designed and synthesized (Fig. 3) [54]. The reason for choosing 3,4-HOPO for functionalization is the relatively high pKa values compared to the other HOPO derivatives. Thus, the 3,4-HOPO demonstrate robust chelating ability with Fe(Ⅲ) at physiological pH, while remains quite stable under physiological conditions. HP-TACD and HP-TACN showed excellent antiproliferative activity in HepG2 cells based on the MTT assay results, with IC₅₀ value of for 18 µmol/L and 27 µmol/L, respectively. Both chelating agents showed little cytotoxicity to normal cells.

  Figure 3

  

  Figure 3.  Representative structures of macrocyclic polyamines and 3,2-HOPO chelators linked by alkyl chain.

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  Among the HOPO family, 3,4-HOPO is recognized as the most potent Fe(Ⅲ) chelator [55]. Furthermore, several chelators with hexadentate coordinating atoms derived from this group are well-regarded for their antimicrobial properties. Hider et al. reported that hydroxypyridone hexadentate capped dendrimer chelating agents have been shown to have high affinity and significant antibacterial activity towards Fe(Ⅲ) [56]. However, the opposite effect was observed: the Fe(Ⅲ) complex formed by the synthesized hexadentate 3,4-HOPO chelating agent was recognized and absorbed by Escherichia coli, providing the necessary iron ions for its growth and actually promoting its growth. This underscores the need for a thorough understanding of how the structure of these chelators relates to their biological function [57]. Therefore, synthetic chelators must avoid recognition and uptake by pathogens, as it could promote their growth. Fe³⁺/Fe²⁺ oxidation-reduction can catalyze a wide range of biological reactions, making it an ideal target for preventing microbial growth through chelation. Therefore, chelating agents designed for potent chelation of Fe³⁺ can compete with the high affinity iron uptake system of pathogens (including iron carriers) and supplement the activity of antibacterial compounds. Studies on the binding of certain 1,2-HOPO-based chelators with siderocalin have revealed that the interaction is very weak. It suggests that the class of coordinating groups is unlikely to undermine this defense strategy and may instead enhance it [58].

  Workman et al. reported the initial instances of hexadentate chelators derived from 1,2-HOPO with biostatic properties (Fig. 4A) [59]. They suggest that these 1,2-HOPO chelators may be more advantageous than the 3,4-HOPO isomers, although they are expected to be weaker Fe(Ⅲ) chelators [55]. For instance, the lower pKa of the hydroxyl group in 1,2-HOPO might reduce its ability to penetrate host cells, thus offering advantages in terms of patient safety. TACN-Me-3-HOPO appeared to be the best microbial growth inhibitor within the range of microorganisms tested. The optical density plot reflects the effect of sub-MIC concentration on microbial growth (Fig. 4B). Without the addition of TACN-Me-3-HOPO, K. pneumoniae DSM-30104 exhibited a lag phase before entering exponential growth. In the case of adding TACN-Me-3-HOPO, the lag period is longer and the growth rate is significantly reduced. TACN-Me-1,2-HOPO also shows promising chelating properties, but it does not match the effectiveness of TACN-Me-3-HOPO. On the contrary, TACN-EtNHCO-1,2-HOPO and TACN-CO-1,2-HOPO seem to be the least effective chelators in the series. The efficacy of the chelator TACN-Me-1,2-HOPO, with the HOPO moiety connected to the TACN core through a methylene group, contrasts with the inefficacy of TACN-CO-1,2-HOPO, in which the linker is a carbonyl group. It highlights the importance of optimizing the linker for improving chelator performance. The outcomes observed with TACN-Me-1,2-HOPO and TACN-CO-1,2-HOPO suggested that using a different macrocyclic scaffold, rather than the tris(2-aminoethyl)amine core to enhance chelation, did not lead to improved biological activity [60].

  Figure 4

  

  Figure 4.  Structures of TACN and 1,2-HOPO chelators applied in microbial growth inhibition. Copied with permission [59]. Copyright 2016, Elsevier.

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  3.2 Zinc chelators for metallo-β-lactamases inhibitors

  β-Lactam antibiotics are widely utilized for treating a broad spectrum of bacterial infections due to their high efficacy and low toxicity [61]. However, the expression of β-lactamases inactivates β-lactams mainly by hydrolysis mechanism [62]. Among them, class B enzymes use Zn(Ⅱ) ions to activate nucleophilic water molecules to open the ring for metal-β-lactamases (MBL), which facilitate the hydrolysis of a wide range of antibiotics, such as NDM, VIM and IMP [63]. Due to resistance to β-lactamases, carbapenem antibiotics such as imipenem and meropenem are considered to be the last line of defense. However, due to the emergence of extended-spectrum β-lactamases, carbapenem β-lactam antibiotics will also become resistant [64]. Thus, there is an urgent need to construct clinically effective and low-toxicity MBL inhibitors. MBLs rely on zinc(Ⅱ) ions in the active site to hydrolyze β-lactams and are zinc ion-dependent enzymes. The presence of a metal chelator has an important effect and the Zn(Ⅱ) chelators can competitively bind Zn(Ⅱ) at the active site of MBLs to reduce their activity [65].

  Somboro et al. explored the ability of NOTA and DOTA as Zn(Ⅱ) chelators to recover the activity of carbapenems against MBLs-producing bacteria [66]. Both chelators restored meropenem (MEM) activity to minimum inhibitory concentration (MIC) as low as 0.06 mg/L. NOTA is a good chelator of copper and gallium, while the size of zinc is between copper and gallium [67,68], so superior activity of NOTA can be expected. In the assays determining the MIC of carbapenem and chelating agent combinations, the optimal concentration of NOTA was found to be 4 mg/L, whereas DOTA required a concentration at least eight times higher. TACN is a homologous cyclic compound in the NOTA and DOTA series that does not contain the carboxylic acid cantilever portion and has a much lower molecular weight. Based on these results, the ability of MEM to restore resistance to carbapenem-resistant Enterobacteriaceae (CRE) activity was assessed, and the results showed that the MIC was reduced to a low of 0.03 mg/L in the presence of TACN [69]. In the presence of 8 mg/L TACN, the minimum bactericidal concentration (MBC) of meropenem (MEM) was assessed. The study revealed that, for the reference and clinical CRE strains, the ratios of MBC to MIC varied between 1-fold and 4-fold. However, MTT assay results indicated that HepG2 cell viability decreased as TACN concentration increased, although its IC₅₀ value was much higher than the MIC value. The authors still investigated the cytotoxicity of TACN and measured the oxidative parameters in HepG2 cells [70] and the apoptotic index of Hek293 cells [71], respectively, demonstrating the safe hepatic and renal toxicity of TACN.

  By comparing the optimal concentration of NOTA and TACN as potential MBL inhibitors, the carboxylic acid cantilever was considered to provide the ability to assist in metal chelation. Thus, a 1,4,7-triazacyclononane-1-glutaric acid-4,7-acetic acid (NODAGA), with an extra carboxylic acid, was evaluated as a metal chelator and was able to reduce the MIC of the NDM-1 producing E. coli strain to 0.125 mg/L at 4 mg/L NODAGA (Fig. 5A) [72]. Although the armed chelators have shown promising activity in restoring the pharmacological activity of MEM, it has to be acknowledged that their strong polarity is extremely incompatible with the physicochemical properties of carbapenems and will lead them to stay forever in in vitro studies. Subsequently, NODAGA was modified by N-methylated amino acids, which increased its lipophilicity by linking the peptide chains and made it more accessible to bacterial cells. NODAGA-4 and NODAGA-8 showed activity only at 16 mg/L, presumably because the linkage of the peptide chains resulted in a greater spatial barrier, which affected the activity.

  Figure 5

  

  Figure 5.  Structures of (A) NODAGA and its short peptide derivatives (B) NOTE dithiocarbamate.

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  Inspired by the discovery of captopril, where replacing the carboxyl group with a sulfhydryl group significantly enhanced Zn(Ⅱ) ion binding [73,74]. NOTA dithiocarbamate, as a class of novel sulfur-containing macrocyclic polyamine analogue, was synthesized and assessed as MBLs inhibitors (Fig. 5B) [75]. The results from MIC testing of the inhibitor and MEM indicated that NOTA dithiocarbamate could act as an antibiotic adjuvant to combat antibiotic resistance associated with NDM-1-MBLs and to restore the activity of carbapenem-MEM against Gram-negative pathogens resistant to carbapenems. NOTA dithiocarbamate restores MEM to < 0.03 µg/mL in the presence of resistant strains of bacteria. More importantly, fluorescence microscopy images confirmed the compound's low toxicity to mammalian cells. Additionally, it showed no hemolytic activity at a concentration of 1000 mg/mL. Thus, it was demonstrated that NOTE dithiocarbamate is demonstrated to be a potential adjunctive antibiotic combination therapy drug to address the recent clinical emergence of MBL.

  3.3 Cellular ATP depletion for antitumor

  Cancer treatment can be regulated by the biochemical metabolism of cells [76]. Unlike normally differentiated cells, the majority of cancer cells rely on aerobic glycolysis, a phenomenon known as the Warburg effect [77]. ATP is highly enriched in tumor cells (1-10 × 10⁻³ mol/L) due to excess glycolysis [78]. Therefore, it is feasible to exploit the metabolic dependence of cancer cells to treat cancer. Reduced intracellular ATP levels are effective in increasing the chemosensitivity of cancer cells and thus the efficacy of chemotherapeutic agents.

  Macrocyclic polyamines function as catalysts for ATP hydrolysis, and the affinity was first observed by Dietrich in 1981 [79]. The ability of different macrocyclic polyamines to mimic ATP-ase action on ATP depends on ring size [80–82]. Therefore, it is promising to explore the potential application of macrocyclic polyamines to achieve antitumor activity by binding ATP.

  The earliest application of the macrocyclic polyamine ATP depletion capacity to the antitumor field was reported by Frydman et al. in 2004 [83], which originated from a report that the acacia macrocyclic alkaloids, budmunchiamines, could exhibit cytotoxicity against tumor cells [84]. In this study, five macrocyclic polyamines of varying sizes associated with the budmunchamine alkaloid family were synthesized and tested for their efficacy against two human prostate cancer cell lines in culture (Fig. 6). The size of the macrocyclic polyamines and the introduction of methylation are known to have an effect on their ATP hydrolysis rate. Although the degree of protonation of macrocyclic polyamines has a significant effect on the rate of ATP degradation, the authors probably considered that the substitution would increase the spatial site resistance during catalysis, which was found to be extremely sensitive to spatial site resistance in previous studies, and therefore the nitrogen atoms on the synthesized macrocyclic polyamines were secondary amines [80]. The results of ATP-catalyzed hydrolysis experiments indicated that the [13]-membered macrocycle exhibited the lowest release of inorganic phosphate from ATP, whereas the [20]-membered macrocycle demonstrated the highest release of inorganic phosphate.

  Figure 6

  

  Figure 6.  Inhibitory effects of [13]-, [16]-, [17]-, [18]- and [20]-membered macrocyclic polyamines on DuPro and PC-3 cell line.

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  The [18]-, [17]-, and [16]-membered macrocycles were also shown to release inorganic phosphate from ATP effectively. Both human prostate cancer cell lines DuPro and PC-3 were sensitive to macrocyclic polyamines with ID₅₀ values ranging from 500 nmol/L to 1.8 µmol/L, and the best activity was achieved by [16]-membered and [17]-membered compounds, with ID₅₀ less than 1 µmol/L. The results of macrocyclic polyamine uptake in DuPro cells showed that the initial uptake of [20]-membered macrocycles was slow, reaching high concentrations in cells only after five days. This explained the lower antitumor activity of the best-performing [20]-membered macrocycles in the ATP hydrolysis assay. Experimental evidence suggests that the reduction in cellular ATP levels caused by macrocycles could be associated with their cytotoxic effects.

  ATP binding and depletion capacity of macrocyclic polyamine is also widely applied in the design of tyrosine kinase inhibitor (TKI). Epidermal growth factor receptor (EGFR), a human epidermal growth factor receiver (HER) family kinase, is an important drug target for the regulation of several malignancies [85–88]. Studies have shown that EGFR is overexpressed in 20%-40% of solid tumors, including breast cancer, ovarian cancer, prostate cancer and colon cancer [89]. A typical feature of EGFR is the presence of structural domains used to catalyze tyrosine phosphorylation on substrate proteins [90]. Thus, cancer prevention and treatment can be achieved by blocking extracellular EGFR binding sites and intracellularly by inhibiting tyrosine kinase activity. Various macrocyclic polyamines have been reported to bind in the ATP pocket as potent Mer tyrosine kinase (MerTK)-specific inhibitor [91–93].

  Recently, our group identified a set of promising EGFR TKI by incorporating macrocyclic polyamines in the 4-anilinoquinazoline structure [94]. The anilinoquinazoline portion will bind to the EGFR structural domain, while the macrocyclic polyamine portion can trap and hydrolyze ATP molecules. It effectively induces apoptosis in cancer cells by additionally obstructing ATP binding to the EGFR hydrophobic cavity, thereby blocking the signaling pathway (Fig. 7A). Evaluate the antiproliferative activity of these compounds against A549 and A431 cell lines with abnormally high EGFR expression using MTT assay. The most promising results were achieved with Lapa-Gefi-Cyclen, exhibiting IC₅₀ values of 0.958 µmol/L against A431 cells and 3.4 µmol/L against A549 cells. These values were substantially lower compared to the control, Gefitinib, which had IC₅₀ values of 2.47 µmol/L and 11.08 µmol/L for A431 and A549 cells, respectively. Cellular ATP depletion studies revealed that Lapa-Gefi-Cyclen needed just 2 µmol/L to reduce intracellular ATP to 0.1 µmol/L within 72 hours. In contrast, Lapa-Gefi-TACN required 8 µmol/L to produce a comparable level of inhibition (Fig. 7B). In vivo antitumor experiment of Lapa-Gefi-Cyclen was evaluated by the A549 xenografts mouse model, exhibiting a tumor growth inhibition value of 44.2% (Fig. 7C). In the design, thus the ATP depletion ability of macrocyclic polyamines played a significant role in antitumor activity. Additionally, we also found that Lapa-Gefi-Cyclen and Lapa-Gefi-TACN showed the excellent dual inhibition against EGFR^WT (IC₅₀ 1.4 ± 0.2 µmol/L for Lapa-Gefi-Cyclen; 0.3 ± 0.1 µmol/L for Lapa-Gefi-TACN) and HER2 (IC₅₀ 2.1 ± 0.6 µmol/L for Lapa-Gefi-Cyclen; 9.6 ± 0.4 µmol/L for Lapa-Gefi-TACN) in kinase assays. We speculate that this is attributed to the unique substituent 3-chloro-4-((3-fluorobenzyl)oxy)phenyl moiety reported previously for Lapatinib [95].

  Figure 7

  

  Figure 7.  (A) Structures, antiproliferative activities and in vitro kinase inhibitory activity of 4-anilinoquinazoline incorporated with macrocyclic polyamines, Lapa-Gefi-TACN and Lapa-Gefi-Cyclen. (B) ATP levels in A549 cells after 72 h of co-incubation with compounds. (C) Representative photographs of tumors after treatment by Lapa-Gefi-Cyclen, and H&E staining images. Copied with permission [94]. Copyright 2018, American Chemical Society.

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  The mechanism of blocking or restricting the entry of drugs into the site of action is of great significance in the drug treatment of tumors. One mechanism involves the increased expression of ATP-binding cassette (ABC) transporter family proteins, which are crucial in developing multidrug resistance (MDR). These proteins include MDR1 (P-glycoprotein), multidrug resistance proteins (MRPs), and brain cancer resistance proteins (BCRPs) [96]. These proteins can act as cell membrane pumps to remove drugs from cancer cells. Many cancer treatment drugs are affected by it and their efficacy decreases in the treatment of various types of tumors, especially chemotherapy drugs such as vinblastine, vincristine, doxorubicin, erythromycin, and paclitaxel [97]. Thus, cellular ATP depletion is associated with inhibition of tumor cell growth and the emergence of drug resistance in multi-drug resistant cells [78,98,99]. Liu et al. designed a supramolecular hydrogel to combine 10-hydroxycamptothecin (HCPT) and macrocyclic polyamines with self-assembling peptides (Fig. 8A) [100]. Combining macrocyclic polyamines with HCPT enhanced the anticancer effects of the agents by hydrolyzing ATP, thereby reversing cancer drug resistance. Notably, the authors achieved subcellular drug delivery by introducing macrocyclic polyamines to release the drug in the nucleus, which is mainly attributed to the protonation properties of macrocyclic polyamines in tumor cells, making them more affinity to the cell membrane and nucleus. Cellular ATP depletion experiments showed HCPT-FFFK-cyclen nanofibers displayed the best ATP depletion capacity among the A549 and CEM/C1 cells, and also exhibited the best inhibition activity in A549, HeLa, MCF-7 and CEM/C1 cell lines compared to the control groups. These results demonstrated that the introduction of macrocyclic polyamines has led to a reversal of tumor drug resistance. The authors also performed cellular uptake and in vitro DNA damage experiments, showing that HCPT-FFFK-cyclen nanofibers not only enhanced drug uptake but also enriched in the nucleus and significantly enhanced DNA-induced damage. Two other small-molecule anti-cancer drugs, Chlorambucil [101] and Lonidamine [102], were also prepared to supramolecular nanomedicine, CRB-FFFK-Cyclen and LND-GFFYK-Cyclen, bearing short peptide and cyclen in the same way (Figs. 8B and C). These systems exhibited significant drug stability, cellular uptake and antitumor activity.

  Figure 8

  

  Figure 8.  Inhibitory effects of (A) HCPT-FFFK-Cyclen. Copied with permission [100]. Copyright 2020, Elsevier. (B) CRB-FFFK-Cyclen. Copied with permission [101]. Copyright 2021, Royal Society of Chemistry. (C) LND-GFFYK-Cyclen in different tumor cell lines. Copied with permission [102]. Copyright 2022, Ivyspring International.

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  3.4 Non-viral vector for gene therapy

  Gene therapy can be used to treat inherited and acquired diseases, which by transporting exogenous genes (DNA or RNA) to cells to achieve therapeutic purposes by compensating or repairing defective or abnormal genes [103].

  During delivery, unprotected nucleic acids might face repulsion from negatively charged cell membranes and could be prone to degradation by extracellular or intracellular nucleases [104]. Therefore, gene vectors with high transfection efficiency are key to gene therapy [105]. Among this, cellular uptake and endosomal escape capacity are the main factors affecting the transfection efficiency of carrier. A common strategy to enhance endosome escape involves imparting pH buffering capacity to the complex and promoting the "proton sponge" effect, which induces swelling and rupture of the endosome [106]. Macrocyclic polyamines have the unique ring-like and nitrogen-rich structure, which make it easier to trap protons, exhibit cationic properties, and increase affinity for cell membranes. Also, the wide range of pKa values allows them to exhibit a "proton sponge" effect, enhancing endosomal escape. In the past decade, a number of polycationic and amphipathic carriers conjugated with macrocyclic polyamines have been successfully investigated.

  Yu group developed a series of cationic polymers based on cyclen and liposomes as potential non-viral gene delivery carriers, demonstrating robust DNA binding capacity and efficient transfection outcomes. The detailed structure-activity relationship (SAR) study focused on the type and length of hydrophobic chains, including single- and double tails [107–111], pH-sensitive imidazole moiety [112], rigid aromatic backbone [113], bola-type lipids [114], distributed hydroxyl chain [115], dioleyl tails [111] and biotin-modified tails [116]. The findings indicated that structures featuring double hydrophobic oleyl moieties and rigid-containing tails displayed markedly superior transfection efficiency and reduced cytotoxicity in comparison to other variants (Fig. 9A). Due to their tendency to form micelles, single tailed fatty chains are more toxic and less efficient than double tailed fatty chains. The presence of a rigid tail makes the lamellar more stable (Fig. 9B) [117]. Following this, they adopted a ring-opening polymerization approach to fabricate amphiphilic polymers using small cationic lipids derived from cyclen. The method allowed for the integration of advantages from both liposomes and polymers. (Fig. 9C) [118]. The synthetic lipopolymer presented stronger DNA binding ability, transfection efficiency and serum tolerance than the liposomes. Under optimized conditions, the transfection efficiency was 14.2 times higher than that for 25 kDa bPEI.

  Figure 9

  

  Figure 9.  (A) Hydrophobic derivatives of cyclen as cationic liposomes. (B) Schematic diagram of cationic lipid assembly of single tailed and double tailed aliphatic chains. Copied with permission [117]. Copyright 2013, American Chemical Society. (C) Amphiphilic polymers based on cyclen liposomes as non-viral gene vectors.

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  Recently, Yu et al. explored a variety of Zn(Ⅱ)-containing polymers and liposomes as novel non-viral DNA vectors based on the strong coordination ability of macrocyclic polyamines [119–122]. Despite demonstrating slightly lower DNA binding capacity than their polycation counterparts, the Zn(Ⅱ)-polycations demonstrated the enhanced DNA release, increased serum tolerance, and improved gene transfection efficiency. This is also reflected in their recent report, a fluorinated polymer based on cyclen [123]. More importantly, zinc-containing liposomes can improve liposome safety and induce more efficient endosomal escape due to their enhanced buffering capacity at acidic pH compared to zinc-free liposomes.

  Guo and Zhou et al. also developed a multifunctional polymer utilizing zinc(Ⅱ)-coordinated cyclen as a high-performance DNA vector (Fig. 10A) [124]. The transfection experiments with Zn-PCD and Zn-PCA highlighted the pivotal influence of the hydrophilic-hydrophobic balance of functional moieties on transfection efficiency. In ADSC stem cells, the optimal Zn-PCD complex demonstrated a significant 160-fold increase in transfection efficiency compared to PEI25k, all while exhibiting minimal cytotoxicity after 48 h of incubation (Fig. 10B), and it also achieved outstanding transfection efficiency in 293F suspension cells, significantly outperforming both PEI2.5k and PEI25k (Fig. 10C). The author proposes that the synergistic effect of the functional part and PEI2.5K is the key to its significant effect, effectively surmounting key obstacles in the gene transfection process.

  Figure 10

  

  Figure 10.  (A) Zn(Ⅱ)-cyclen multifunctional complex Zn-PCD and Zn-PCA. (B) Gluciferase transfection efficiency (a and c) and cytotoxicity (b and d) of Zn-PCA and Zn-PCD in 3T3 and PC3 cells, respectively. (C) EGFP transfection efficiency of Zn-PCD in suspension cells 293F. Copied with permission [124]. Copyright 2021, American Chemical Society.

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  In 2023, Lu group developed a series of new dual responsive nanoparticle systems by combining [12]aneN₃, prodrug camptothecin (CPT), and 4-nitrobenzyl ester through alkyl chains [125]. A plasmid used for co delivery of camptothecin (CPT) and TNF related apoptosis inducing ligand (pTRAIL) DNA in cancer treatment. The NPs composed of CNN2, pDNA, and DOPE were further co assembled with amphiphilic polymers (TTPs) linked to ROS responsive thiooxanes to obtain CNN2-DT/pDNA nanoparticles (Fig. 11A). In vitro release experiments showed that CNN2-DT/pDNA NPs can smoothly release CPT and pDNA from NPs in the presence of a mixture of nitroreductase (NTR) and H₂O₂. Showing a dual response of ROS/NTR in NPs (Fig. 11B). In HeLa cells, CNN2-D/pTRAIL and CNN2-DT/pTRAIL NPs exhibit higher growth inhibition than single drug carriers alone. This indicates that the combination of CPT and pTRAIL achieves enhanced anti-tumor activity (Fig. 11C). In vivo experiments have shown that CNN2-DT/pTRAIL NPs effectively accumulate in tumor tissues by prolonging blood circulation and EPR effect, and have a strong inhibitory effect on tumors with a high tumor inhibition rate (60%) (Fig. 11D). The co delivery system of prodrugs and genes has the advantage of spatially and temporally controlled release. Provided a new strategy for [12]aneN₃ in cancer synergistic therapy.

  Figure 11

  

  Figure 11.  (A) Chemical structures of CNN2 and TPP. (B) Release of pDNA from CNN2-DT/pDNA NPs in PBS with H₂O₂ or NTR, H₂O₂, and NTR. (C) Viability of HeLa cells after incubation with different treatments. (D) Tumors weight of the mice after tail vein injection of different treatments on day 15 from each group and tumor growth inhibition (TGI) rate after tail vein injection of different treatments. Copied with permission [125]. Copyright 2023, Royal Society of Chemistry.

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  In addition, they used the macrocyclic polyamine [12]aneN₃ as the positive unit and utilized the structural tunability of non-viral gene vectors to introduce single photon, two-photon, aggregation induced, near-infrared fluorescence imaging units, esterase and glutathione stimulation response units, as well as bile acid and biotin targeting units. They designed and synthesized a series of multifunctional non-viral gene vectors, and reviewed their synthesis and properties as multifunctional non-viral gene vectors [126]. The research on small molecule macrocyclic polyamine derivatives with fluorescence localization function will not be further discussed [127–129].

  Our group has been committed to the exploration of non-viral gene vectors based on macrocyclic polyamines. The efforts mainly focused on the design and modification of the molecular skeleton, including chitosan, amino acid polymer, block copolymer and even polyphosphazene. We synthesized a class of chitosan gene carriers ground with macrocyclic polyamines (Cs-g-MCPA) by grafting cyclodextrin and TACN onto chitosan at different sites (Fig. S4A in Supporting information) [130]. The Cs-g-MCPA polymers were engineered to provide protonated amino/imino groups, boosting their DNA binding capacity. In vitro transfection assays revealed significantly higher transfection efficiency compared to chitosan, with relatively low cytotoxicity. The introduction of amine groups into copolymers is widely recognized as a source of cytotoxicity. These groups can bind to the plasma membrane and may also interact unfavorably with cellular components and proteins that carry negative charges [131,132], and breaking down the cationic group into shorter segments is a key strategy for reducing cytotoxicity in hybrid polymers [133]. In the case, thus the introduction of small and cyclic polyamines may be good candidates as efficient grafters to reduce cytotoxicity of the polymers. Further, we attempted to covalently graft phosphoacylcholine (PC) onto Cs-g-MCPA vectors for better solubility and hemocompatibility in physiological pH conditions [134]. PC is abundant in the outer leaflet of red blood cell membranes' lipid bilayer, primarily in the form of phospholipids [135]. Therefore, it is hoped that the introduction of PC can increase the permeability of membrane of the vector and achieve high gene transfection efficiency. AFM imaging revealed the aggregation of PC-g(6)-Cs-g(2)-cyclen into uniform particles, driven by the interaction between its cyclen core and PC headgroup. Furthermore, it effectively enclosed pDNA within nanoparticles of approximately 100 nm in diameter, driven by the electrostatic attraction between the polymer's positively charged groups and the pDNA's negatively charged groups (Fig. S4B in Supporting information). In subsequent in vitro transfection assay performed in 293T cells, PC-g(6)-Cs-g(2)-Cyclen exhibited superior transfection efficiency and low cytotoxicity (Figs. S4C and D in Supporting information), thanks to its robust DNA binding affinity, excellent water solubility, and membrane-mimetic structure.

  The widespread utilization of chitosan-based gene vectors may face limitations stemming from their inadequate solubility in physiological solutions and elevated viscosity at concentrations necessary for in vivo delivery. We thus designed a kind of aspartic acid/lysine copolymer as backbone grafted with cyclen (cyclen-pAL) for efficient gene delivery (Fig. S5A in Supporting information) [136]. The incorporation of the lysine moiety was intended to enhance DNA binding or improve cell-penetrating ability. However, it is well-established that copolymers containing cationic groups frequently exhibit cytotoxicity, largely attributed to their interactions with negatively charged cellular components, proteins, or the lipid bilayer of the plasma membrane. The carboxyl group in aspartic acid contributes to the partial neutralization of the positive charges of lysine, helping to achieve a balance between transfection efficiency and cytotoxicity. A neutral succinimide moiety in p(SI)L was used as a control for comparison with cyclen-pAL, revealing lower cell viability at the same concentration, confirming earlier observations (Fig. S5B in Supporting information). In in vitro gene transfection assays, the increased transfection efficiency of cyclen-pAL was obtained compared with that of unmodified copolymer pAL due to the presence of cyclen (Figs. S5C-E in Supporting information).

  Another interesting attempt by us was to use poly(organo)phosphazenes as a molecular framework for non-viral gene vectors [137]. Following the pioneering research by Hennink's group, which demonstrated that poly(2-dimethylaminoethylamine)phosphazene efficiently transfected COS-7 cells in vitro with reduced harm compared to alternative polymeric transfection agents, researchers have synthesized and tested various derivatives of polyphosphazenes for gene delivery applications [138]. We designed and synthesized a class of polyphosphazenes that incorporate cyclic polyamines and imidazole groups as gene vectors (Fig. S6A in Supporting information). Polyamine, well known for its proton sponge properties, has been thoroughly investigated as a material for DNA delivery. Its appeal lies in the effective buffering capacity, strong affinity for binding DNA, and comparatively high transfection efficiency, as highlighted in numerous prior studies. The morphology assay revealed that Im-PPZ-cyclen can condense pDNA into multiple globules, each having a diameter of 98 ± 8.3 nm and a height of 9.01 ± 0.06 nm, from its supercoiled DNA form (Fig. S6B in Supporting information). Of the different poly(organo)phosphazene polymers studied, Im-PPZ-Im demonstrated the highest cell viability in HeLa cells, outperforming both Im-PPZ-cyclen and cyclen-PPZ-cyclen (Fig. S6C in Supporting information). It indicates that the amount of grafted amino groups has a significant impact on the cytotoxicity of the poly(organo)phase gene vector gene vector.

  In the assessment of the transfection efficiency of the Im-PPZ-cyclen/DNA complex in 293T cells, as determined by measuring pEGFP-N3 gene expression, a bell-shaped relationship was observed between transfection efficiency and the concentration of Im-PPZ-cyclen (Fig. S6D in Supporting information). The trend is consistent with the findings reported for other poly(organo)phosphazenes [139,140]. The peak transfection efficiency was attained at an Im-PPZ-cyclen/DNA weight ratio of 5:1.

  In addition to the extensively used macromolecules mentioned above as non-viral gene vectors, certain low-molecular-weight polyamines exhibit unique functional characteristics owing to their interactions with DNA. The properties of water solubility, metal coordination, and full protonation at physiological pH could be usefully explored in gene delivery from a new perspective. Our group reported a simple cyclic and rigid polyamine as efficient nucleic acid condensation agent induced DNA to compressed nanoparticles at 50 ℃ (Fig. S7A in Supporting information) [141]. The acetyl-modified polyamines showed an excellent ability to condense DNA than those of ethyl-modified analogues and linear amines (Fig. S7B in Supporting information). This was attributed to an "external hydrogen bond building" mechanism that involved oxygen atom in acetyl moiety as hydrogen bond acceptor (Fig. S7C in Supporting information) [142]. We also found that cyclen-actyl-Zn²⁺ complex gave an increased DNA condensing rate compared to the corresponding ligand without Zn²⁺. Thus, Zn²⁺ acceleration to condensation could be achieved through "pretreating" plasmid, this is, from supercoiled plasmid to open circular DNA (Fig. S7D in Supporting information). Although the role of small-molecular condensing agents in protecting DNA is still up for debate, the investigation of structural design and mechanism understanding should be of value for the development in non-viral gene vectors.

  3.5 Artificial nucleases for DNA/RNA synthesis inhibitors

  The prospect of genome manipulation regulated by small molecules has long been a subject of considerable fascination, largely owing to its potential implications in drug development and medicine [143]. Like natural enzymes, artificial nucleases interact with DNA and hydrolyze it, is expected to be effective chemotherapeutic agents [144]. Extensive research has focused on the exploration of macrocyclic polyamines as potential artificial nucleases [17,24]. Spiccia et al. gave a comprehensive review of macrocyclic metal complexes for metalloenzyme mimicry, including TACN, cyclen and their derivatives in 2015 [145]. Here we reviewed and appraised the latest advances in novel macrocyclic polyamine complexes after that as promising DNA/RNA-targeting anticancer agents for cancer treatment.

  Kulak et al. reported a Cu(Ⅱ)-cyclen complex conjugated with different amount of 9, 10-anthraquinone (AQ) as intercalators [146]. In addition to efficiently condensing and aggregating DNA, macrocyclic polyamines have shown promise in various applications, including their ability to hinder DNA and RNA synthesis, resulting in high cellular uptake and cytotoxicity against tumor cell lines (Fig. 12A). The complex Cu(Ⅱ)L₃ with 1, 4-AQ ligands exhibited greater effectiveness against A549 cells (IC₅₀ = 96.9 µmol/L) compared to the mono-AQ complexes Cu(Ⅱ)L₂ (IC₅₀ = 28.3 µmol/L) and Cu(Ⅱ)L₁ (IC₅₀ = 109.4 µmol/L). The p-substituted complex Cu(Ⅱ)L₄ and the tri-substituted complex Cu(Ⅱ)L₅ showed even higher activity (IC₅₀ = 1.3 µmol/L and 1.4 µmol/L, respectively), correlating with their inhibition of DNA and RNA synthesis. In the normal cells, although Cu(Ⅱ)L₄ and Cu(Ⅱ)L₅ showed the concerned cytotoxicity (IC₅₀ = 13.4 µmol/L and 8.1 µmol/L) against normal human dermal fibroblasts (NHDF), the slight selectivity for the cancer cell can be observed. AFM images in Fig. 12B showed the plasmid DNA can be linearized by Cu(Ⅱ)L₄ complex at 3.1 µmol/L. Interestingly, the regioisomers Cu(Ⅱ)L₃ and Cu(Ⅱ)L₄ exhibited comparable efficiency in DNA aggregation, yet they demonstrated significant differences in their abilities to inhibit DNA synthesis and their cytotoxic properties. The authors used molecular modeling to further elucidate the possible mechanism (Fig. 12C). Conformational energy calculations indicated that Cu(Ⅱ)L₃ and Cu(Ⅱ)L₄ exhibited similar profiles in the minor and major grooves, given the precision of the force field employed. However, the bisintercalative binding mode observed for Cu(Ⅱ)L₄ could be attained in G-rich sequences adopting an A-DNA conformation. The feature likely underlies the heightened cytotoxicity of Cu(Ⅱ)L₄, as well as its effectiveness in inhibiting DNA and RNA synthesis, along with its propensity for DNA aggregation. This work indicated multi-substituted AQ cyclen Cu(Ⅱ) complexes exhibited modest DNA binding affinities compared to mono-substituted species, remarkable effects on the DNA configuration, and high cytotoxicity of tumor cell lines. The rationale behind the selective toxicity of these bisintercalators lies in their capacity to discriminate between different DNA sequences.

  Figure 12

  

  Figure 12.  (A) Structural design of AQ-based Cu(Ⅱ) complexes, anti-proliferation activities to A549 and cytotoxicity to NHDF cell lines. (B) AFM plot of plasmid pSP73 DNA linearised in the presence of 1.56 µmol/L (left) and 3.13 µmol/L (right) of Cu(Ⅱ)L₄. (C) Schematic diagram of Cu(Ⅱ)L₄ binding to DNA. Copied with permission [146]. Copyright 2018, American Chemical Society.

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  Xu and co-worker synthesized a series of 4-benzyloxy-benzyl-1,4,7-triazacyclononane (btacn) and metal complexes as DNA synthesis interferents [147]. The IC₅₀ of Cu(Ⅱ) complexes (Cu(btan)Cl₂ and [Cu(btan)₂]·(ClO₄)₂) was around 3 µmol/L, demonstrating superior anti-proliferation effect in liver cancer cells (HepG-2) compared to other cells (Fig. 13A). The liver plays a crucial role in regulating copper balance, as copper serves not only as a component of various biological enzymes but also actively participates in the enzymatic processes within tissue cells. Therefore, the authors suggested that Cu(Ⅱ) complexes could potentially serve as a substitute for copper in HepG-2 cells. Simultaneously, these complexes showed reduced cytotoxicity towards normal cells like HUVEC. In the control experiments, the Zn(Ⅱ) complex Zn(btan)Cl₂ showed minimal DNA binding affinity and did not exhibit noticeable cytotoxic effects. This could be attributed to the Zn(Ⅱ) ion's reduced capacity as a catalytic center to interfere with DNA synthesis or cause DNA strand breaks compared to the Cu(Ⅱ) ion complex. However, a Zn(Ⅱ) cyclen complex conjugated with two L-tryptophan Zn(Ⅱ)-Cyclen-(Trp)₂ was prepared by Datta et al., showing the IC₅₀ value of 25 µmol/L towards U-87 MG cells comparable to that of 20.68 µmol/L for cisplatin (Fig. 13B) [148]. Similarly, Zhang group recently reported a cryptolepine-cyclen Zn(Ⅱ) complex, namely Zn(BQTC), and evaluated DNA damage–induced antitumor activity [149]. The antiproliferative activities of Zn(BQTC) against A549 and A549R (cisplatin-resistant) cell lines exhibited IC₅₀ values of 11.59 µmol/L and 0.01 µmol/L, respectively (Fig. 13C). Results from A549R cells showed that Zn(BQTC) was 7010 times more potent than cisplatin (IC₅₀ = 70.10 µmol/L). Additionally, Zn(BQTC) demonstrated markedly low cytotoxicity in normal HL-7702 cells (> 100 µmol/L). Both the cases above indicated that Zn(Ⅱ) complexes also provided considerable antiproliferative activities against tumor cell lines, which was attributed to the suitable ligands to interact with DNA or the improving cell membrane permeability [150,151]. Furthermore, compounds incorporating cobalt have been the subject of extensive research for their anticancer properties for more than two decades [152]. Cobalt, a vital trace element in animals, plays a crucial role in numerous biologically significant processes. Suntharalingam et al. prepared a Co(Ⅲ)-cyclam complex conjugated with naproxen (anti-inflammatory nonsteroidal drug), to evaluate its anti-cancer activity [153]. Cytotoxicity assay by MTT method showed that Co(Ⅲ)-cyclam exhibited better antiproliferative efficiency against HMLER (IC₅₀ = 0.43 µmol/L) and HMLER-shEcad (IC₅₀ = 0.11 µmol/L) cells than those of salinoycin, respectively (Fig. 13D). Interestingly, the given compound presented significant inhibitory to the formation of three-dimensional tumor-like mammospheres in single-cell suspensions and reduced their viability to a greater extent than vinorelbine, cisplatin and paclitaxel that clinically used breast cancer drugs (Fig. 13E).

  Figure 13

  

  Figure 13.  Structures and inhibitory effects of (A) btan metal complexes, (B) Zn(Ⅱ)-cyclen-(Trp)₂, (C) Zn(BQTC) and (D) Co(Ⅲ)-cyclam on the growth of different cancer cell lines. (E) Bright-field images of HMLER-shEcad mammospheres. Copied with permission [153]. Copyright 2016, Wiley-VCH Verlag.

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  Another interesting application of macrocyclic polyamine complexes is in boron neutron capture therapy (BNCT) [154]. Polyamines are essential for a wide range of cellular functions, contributing significantly to DNA replication and protein synthesis among other vital processes, thus playing an indispensable role in cellular functions [3,11].

  The surge in polyamine concentrations within cancer cells is intricately linked to the stimulation of cell proliferation. The phenomenon is governed by the enhanced activity of the polyamine transport system (PTS) and biosynthesis pathways [155]. Consequently, polyamine derivatives have emerged as viable candidates for delivering boron-containing drugs into cancer cells. Aoki et al. firstly preapred a series of boron-containing ligands based on polyamines, such as tacn, cyclen and 15-membered pentaamine [15]aneN₅, and evaluated the cytotoxicity of their Zn(Ⅱ) complexes against HeLa S3, A549 and IMR-90 cell lines [156]. For tacn and cyclen ligands, the cytotoxicity of p-form complexes was higher than the corresponding m-form. In the case of [15]aneN₅, however, o-form Zn(Ⅱ) complex showed moderate antiproliferation activity against cancer (HeLa S3 and A549) and normal (IMR-90) cell lines. Among them, para-substituted 15-membered pentaamine complex (Zn-[15]aneN₅-m-boron) exhibited the highest cytotoxicity with IC₅₀ values of 71 µmol/L for HeLa S3 and 32 µmol/L for IMR-90, respectively (Fig. S8A in Supporting information). Subsequently, they further synthesized some dimers containing different polyamines and phenylboronic acid ester, and supposed that the interaction of these di-Zn(Ⅱ) complexes with DNA would be strong than that of the mono-Zn(Ⅱ) complex (Fig. S8B in Supporting information). The cytotoxicity results of di-Zn(Ⅱ) complexes were consistent with the hypothesis above [157].

  3.6 DNA protection or cleavage? Gene delivery or artificial nucleases?

  It is easy to think of a paradox from the successful cases above: Are these macrocyclic polyamines used to deliver therapetic genes by protecting DNA, or inhibit DNA synthese as aritifical nucleases? It is certain that Cu(Ⅱ), Co(Ⅲ) and some lanthanide metal complexes of polyamine mostly served as DNA cleavage agents or Topoisomerase inhibitors due to the strong redox activity. The macrocyclic polyamine complexes based on these metal ions cause the hydrolysis of phosphodiester bond and even oxidative cleavage of ribsome when interacting with DNA molecules [146,147,153]. In the present of Zn(Ⅱ) ion, many well-designed polyamine derivatives discussed above also showed the significant antiproliferation activity to various cancer or normal cell lines by DNA/RNA synthese inhibition. For gene delivery, however, Zn(Ⅱ)-containing non-viral DNA vectors displayed better nucleic acid release, serum tolerance and gene transfection efficiency than the corresponding free ligands. Although the ligands used for gene delivery are mainly cationic polymers or liposomes rather than DNA intercalators, damage of the polyamine Zn(Ⅱ) complex as core to nucleic acid should be considered. Moreover, specific metal-free macrocyclic polyamine ligands have shown remarkable cytotoxicity against human tumor cell lines by effectively inhibiting topoisomerases. Xu group synthesized a series of Naphthalimide-cyclam conjugates with long lipophilic chains, and cytotoxicity assay indicated that these metal-free compounds based on polyamine showed more potent antiproliferative activity against A549, HeLa and HCT116 cell lines than the drug amonafide as positive control (Fig. 14A) [158]. The authors considered that the active ligand can form multiple H-bonds with both enzyme and DNA by molecular modeling (Figs. 14B and C).

  Figure 14

  

  Figure 14.  (A) Structures and antiproliferation activities of Naphthalimides-cyclam. (B) Binding mode for naphthalimides-cyclam (R₂ = n - C₈H₁₇) with topo Ⅰ/DNA (PDB ID: 1K4T) and (C) topo Ⅱ/DNA (PDB ID: 4G0V) complexes. Copied with permission [158]. Copyright 2015, Elsevier.

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  Our group also tried to explore the ability of polyamine derivatives in the absence of metal ion to bind and cleave DNA. Importantly, the similar mechanism of metal-free ligands to damage nucleic acid was identified in different cases (Fig. S9A in Supporting information). Initially, in the structure of polyamine-modified aspartic acid, protonated polyamines facilitate the formation of pairs between polyamine cations and phosphate anions through hydrogen bonding and electrostatic interactions. Consequently, the positively charged phosphorus becomes susceptible to attack by ungrafted nucleophilic groups within the PASP framework. Consequently, phosphodiester breakage occurs via the transphosphorylation pathway (Fig. S9B in Supporting information) [159]. When bis-(2-benzimidazolyl-methyl)amine (IDB) as a polyamine variant was grafted to the PASP, the conjugate can effectively induce DNA cleavage in the absence of metal ion at a relatively low concentration. The similar transphosphorylation pathway may occur in the process of DNA cleavage (Fig. S9C in Supporting information). The electropositive phosphorus is prone to attack by nearby nucleophilic groups, including ungrafted carboxyl groups within the skeleton, thereby facilitating the transphosphorylation reaction [160].

  In previous studies, the researchers tended to attach importance to the three characteristics of polyamines: (ⅰ) "proton sponges" feature due to their strong proton binding and buffering capability, which was applied in response to the microenvironment of tumor tissue [161]; (ⅱ) electropositivity after protonation that facilitates to cellular uptake and nuclear accumulation [127,146]; (ⅲ) metal chelating ability to improve gene transfection efficiency and apply in magnetic resonance imaging (MRI). While it is widely recognized that polyamines, particularly in their cyclic forms, exhibit stable and sometimes selective interactions with phosphate groups (e.g., ATP binding), its combination to DNA phosphate skeleton is easily neglected. The formation of hydrogen bonds between N-H and P-O depends on the electrostatic interaction between polyamines and phosphates [83]. The stabilized transition state significantly reduces the charge density surrounding the phosphate group. Consequently, the phosphorus becomes vulnerable to attack by neighboring nucleophilic groups, such as hydroxyl and carboxyl groups, as well as by "activated" water molecules, which can be facilitated by a metal complex. It will be more likely to occur when a DNA intercalator is incorporated into polyamine because it is closer to the phosphate group. For the design of non-viral gene vectors, therefore, DNA-binding molecules with rigid structure should be avoid to minimize the damage to DNA. Besides, Zn(Ⅱ) complex of macrocyclic polyamine can activate water molecule to form nucleophilic hydroxyl group, resulting in the ability to break DNA phosphodiester bonds [148,149]. The design of using Zn(Ⅱ) complex to promote cell uptake and gene transfection efficiency should be carefully considered. The issue about whether DNA is protected or broken by macrocyclic polyamines or even its metal complexes needs to be further explored and verified as new research work emerges.

  3.7 Radiopharmaceutical for theranostics

  Theranotics is a combination of therapeutic markers and diagnostic tools for simultaneous or continuous treatment and visualization [162]. One of the rapid developments in therapeutic diagnostics is the use of radionuclides in the chemical scaffolding of drugs. Such developed drugs are further called "therapeutic diagnostic radiopharmaceuticals", also known as "radiothermal diagnostics" [163]. When radionuclides are bound to chelators, they emit radioactive particles capable of inducing tissue and DNA damage, ultimately leading to cell death. Beyond their cytotoxic effects, these radionuclide-chelator complexes are valuable for diagnostic purposes in single-photon emission computed tomography (SPECT) and positron emission computed tomography (PET) imaging.

  An essential aspect of radiothermal diagnostics is the requirement that molecular targets serve for both patient diagnosis and treatment. However, using these targets solely for diagnostic purposes may lead to higher radiation exposure and suboptimal image quality due to limited γ-ray abundance. Therefore, employing "Theranostic Pairs" with similar structures and matched radionuclides proves advantageous for diagnostic purposes. The strategy not only reduces the radiation burden but also improves image quality significantly [164].

  Macrocyclic polyamines and their derivatives have been the premium chelating backbone for PET and SPECT contrast agents. Compared to acyclic ligand structures, the multi-dentate structure of macrocyclic polyamine provides enhanced stability for complexation of lanthanides, such as DOTA for many radioactive lanthanides and ⁹⁰Y based on triazide scaffolds tailored for ⁶⁸Ga (NOTA, TRAP, etc). These studies are reviewed in excellent articles [165–167]. DOTA, a macrocyclic polyamine equipped with functional groups, is renowned for its exceptional ability to chelate trivalent lanthanide ions owing to its superior chemical stability. DOTA can be found to have high thermodynamic stability constants (LogK_ML) for both molecular imaging radioactive particles and radioactive therapeutic nuclides. Many researches described the stability constants of DOTA complexes formed by trivalent metal ions [168].

  The radiopharmaceutical design should be consistent for both the diagnostic version (utilizing a radiometal as a photon emitter) and the therapeutic version (utilizing a radiometal as a particle emitter) of PET and SPECT imaging. This consistency helps in coordinating the two radioactive metals effectively. Importantly, two of the most successful "Theranostic Pairs" associated with DOTA in radionuclide therapy have been approved as clinical drugs for cancer treatment. The "Theranostic Pairs" [⁶⁸Ga]Ga-PSMA-617/[¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto) for the treatment of prostate tumors and [⁶⁸Ga]Ga-DOTA-TATE (Netspot)/[¹⁷⁷Lu]Lu-DOTATE (Luathera) for the treatment of neuroendocrine tumors, respectively [169–172].

  PSMA-617 stands out as a highly specific agent tailored to target the prostate-specific membrane antigen (PSMA), a protein often found to be overexpressed in prostate tumor tissue [173,174]. The unique feature renders PSMA-617 an exceptionally promising candidate for radioligand therapy, presenting significant therapeutic opportunities in prostate cancer treatment. In 2014, PSMA-617 gained compelling clinical experience in the diagnosis and radioligand treatment of prostate cancer [175,176]. Subsequently, [¹⁷⁷Lu]Lu-PSMA-617 received FDA approval for prostate cancer treatment in March 2022 (Fig. 15). PSMA-617 secured FDA approval largely on the strength of data derived from the pivotal phase Ⅲ trial VISION. The extensive study, spanning from June 2018 to October 2019 and encompassing 831 patients, yielded compelling evidence affirming the efficacy and safety of PSMA-617 [177]. The adoption of targeted radionuclide therapy employing [¹⁷⁷Lu]Lu-PSMA-617 has led to a remarkable prolongation in imaging progression-free survival and overall survival when contrasted with standard therapy alone. By virtue of its impressive efficacy and minimal adverse effects, PSMA-617 marks a significant stride forward in pioneering a novel treatment approach.

  Figure 15

  

  Figure 15.  Chemical structure of ¹⁷⁷Lu vipivotide tetraxetan, Pluvicto.

  DownLoad: Full-Size Img PowerPoint

  Another approved clinical drug for cancer treatment is [¹⁷⁷Lu]Lu-DOTATATE (Lutathera) (Fig. 16). It received EMA and FDA approval in 2017 and 2018, respectively [170], for the treatment of somatostatin receptors (SSTR includes SSTR1, 2A and B, 3, 4 and 5)-positive neuroendocrine tumors. SSTRs are G-protein-coupled receptors activated by somatostatin that inhibit hormone secretion and cell proliferation [178]. SSTR, highly expressed in the majority of well-differentiated neuroendocrine tumors, stands out as a prime target for therapeutic interventions aimed at managing neuroendocrine tumors. Lutathera conjugates the radionuclide ¹⁷⁷Lu with the growth inhibitor analogue DOTA-TATE, specifically targeting tumor cells expressing somatostatin receptors (SSTR). This targeted approach delivers ionizing radiation to the tumor cells, inducing DNA damage including single- and double-strand breaks, ultimately leading to cell death in both the tumor and its SSTR-positive lesions. In the FDA-approved phase Ⅲ NETTER-1 trial for midgut neuroendocrine tumors (NETs), treatment with [¹⁷⁷Lu]Lu-DOTATATE significantly prolonged progression-free survival (PFS) compared to high-dose octreotide (HR = 0.18, P < 0.0001). Patients also showed improved overall survival (48 months vs. 36.3 months, HR = 0.84, P = 0.3) and higher rates of remission (18% vs. 4% in the octreotide group) [179,180].

  Figure 16

  

  Figure 16.  Chemical structure of [¹⁷⁷Lu]Lu-DOTATATE, Lutathera.

  DownLoad: Full-Size Img PowerPoint

  Radiopharmaceuticals based on the chelation of macrocyclic polyamine analogs are also expected to find application in other promising targets, such as fibroblast activating protein (FAP) [181–184], gastrin-releasing peptide receptor (GRPR) [185,186], human epidermal growth factor receptor type 2 (HER2) [187] and chemokine receptor C-X-CR-4 (CXCR4) [188]. Encouraged by the experience of these achievements, it is believed that radiopharmaceuticals containing macrocyclic polyamines and their analogues as chelating agents will be used for many other cancers and improve theprognosis of patients.

  4. Conclusion and future perspective

  This review summarized available studies on the development of macrocyclic polyamines and its derivatives in medicine. Macrocyclic polyamines have the following advantages: (ⅰ) They have a "proton sponge" characteristic that responds to the tumor tissue microenvironment; (ⅱ) Protonation promotes cellular uptake and nuclear accumulation; (ⅲ) Strong metal chelating ability. Therefore, it has been applied in biomedical fields such as anti-tumor and antimicrobial. We classified them based on their mechanisms and analyzed various structural designs and corresponding biological activities. These typical treatment designs, including iron depletion agents, zinc chelators, intracellular ATP depletion, non-viral gene vectors, artificial nucleases, and theragnostic agents, provide valuable theoretical foundations and directions for the future research and application of macrocyclic polyamines. Among them, the most successful applications of DOTA in radionuclide therapy have been approved by the FDA for the treatment of prostate and neuroendocrine tumors, which offered us an exciting prospect that from MRI to actual theranostics agents. In addition, what we want to draw attention to here is the intrinsic activity of macrocyclic polyamine metal complexes, that is, cytotoxicity or not. In many cases as DNA syntheses inhibitors and gene vectors, Zn(Ⅱ) complex or even metal-free ligand can not only achieve DNA damage, but also enhance the transfection effect through good membrane permeability. Therefore, there is still a challenge in using macrocyclic polyamines for biomedical applications, which is how to achieve a balance between "protection" and "damage" when macrocyclic polyamines or their metal complexes interact with targets (such as DNA) in vivo. The utilization of macrocyclic polyamines in medicine holds immense promise and is rapidly expanding. The trend suggests the emergence of safer, more effective, and cost-efficient therapeutic drugs in the near future.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Hao Chang: Writing – review & editing, Writing – original draft, Methodology, Investigation. Renzhong Qiao: Supervision, Conceptualization. Chao Li: Supervision, Conceptualization.

  Acknowledgments

  Authors are thankful to the National Natural Science Foundation of China (Nos. 22177011, 21977012, and 21672021) and the Joint Project of BRCBC (Biomedical Translational Engineering Research Center of BUCT-CJFH) (No. XK2020-06).

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2024.110675.

  
  
• 1. [1]

     L.J. Marton, A.E. Pegg, Annu. Rev. Pharmacol. 35 (1995) 55-91. doi: 10.1146/annurev.pa.35.040195.000415

  2. [2]

     H.M. Wallace, A.V. Fraser, A. Hughes, Biochem. J. 376 (2003) 1-14.

  3. [3]

     E.W. Gerner, F.L. Meyskens, Nat. Rev. Cancer. 4 (2004) 781-792. doi: 10.1038/nrc1454

  4. [4]

     H. Tabor, C.W. Tabor, Anal. Biochem. 274 (1999) 150-150. doi: 10.1006/abio.1999.4227

  5. [5]

     U. Bachrach, Plant Physiol. Bioch. 48 (2010) 490-495.

  6. [6]

     A. Raina, J. Janne, Med. Biol. 53 (1975) 121-147.

  7. [7]

     P. Scherer, H. Kneifel, J. Bacteriol. 154 (1983) 1315-1322. doi: 10.1128/jb.154.3.1315-1322.1983

  8. [8]

     C.W. Tabor, H. Tabor, Annu. Rev. Biochem. 45 (1976) 285-306. doi: 10.1146/annurev.bi.45.070176.001441

  9. [9]

     C. Kahana, J. Biol. Chem. 293 (2018) 18730-18735. doi: 10.1074/jbc.tm118.003339

  10. [10]

      A.E. Pegg, J. Biol. Chem. 291 (2016) 14904-14912. doi: 10.1074/jbc.R116.731661

  11. [11]

      L. Miller-Fleming, V. Olin-Sandoval, K. Campbell, M. Ralser, J. Mol. Biol. 427 (2015) 3389-3406. doi: 10.1016/j.jmb.2015.06.020

  12. [12]

      G. Iacomino, G. Picariello, L. D'Agostino, Biochim. Biophys. Acta 1823 (2012) 1745-1755. doi: 10.1016/j.bbamcr.2012.05.033

  13. [13]

      X.Y. Liang, P.J. Sadler, Chem. Soc. Rev. 33 (2004) 246-266. doi: 10.1039/B313659K

  14. [14]

      J. Wahsner, E.M. Gale, A. Rodríguez-Rodríguez, P. Caravan, Chem. Rev. 119 (2018) 957-1057.

  15. [15]

      S.N.M. Chilla, C. Henoumont, L.V. Elst, R.N. Muller, S. Laurent, Isr. J. Chem. 57 (2017) 800-808. doi: 10.1002/ijch.201700024

  16. [16]

      J.J. Christensen, D.J. Eatough, R.M. Izatt, Chem. Rev. 74 (1974) 351-384. doi: 10.1021/cr60289a003

  17. [17]

      L.F. Lindoy, K.M. Park, S.S. Lee, Chem. Soc. Rev. 42 (2013) 1713-1727. doi: 10.1039/c2cs35218d

  18. [18]

      R.E. Mewis, S.J. Archibald, Coord. Chem. Rev. 254 (2010) 1686-1712. doi: 10.1016/j.ccr.2010.02.025

  19. [19]

      F. Liang, S. Wan, Z. Li, et al., Curr. Med. Chem. 13 (2006) 711-727. doi: 10.2174/092986706776055706

  20. [20]

      P. Lejault, K. Duskova, C. Bernhard, et al., Eur. J. Org. Chem. 2019 (2019) 6146-6157. doi: 10.1002/ejoc.201900870

  21. [21]

      H. Stetter, K.H. Mayer, Chem. Ber. 94 (1961) 1410-1416. doi: 10.1002/cber.19610940602

  22. [22]

      B. Bosnich, M. Tobe, G. Webb, Inorg. Chem. 4 (1965) 1109-1112. doi: 10.1021/ic50030a004

  23. [23]

      N. Curtis, Coord. Chem. Rev. 3 (1968) 3-47. doi: 10.1016/S0010-8545(00)80104-6

  24. [24]

      S. Shinoda, Chem. Soc. Rev. 42 (2013) 1825-1835.

  25. [25]

      L.M. De Leon-Rodriguez, Z. Kovacs, Bioconjug. Chem. 19 (2008) 391-402. doi: 10.1021/bc700328s

  26. [26]

      E.J.T. Kimura, Tetrahedron 48 (1992) 6175-6217.

  27. [27]

      L.J. ZOMPA, Inorg. Chem. 17 (1978) 2531-2536. doi: 10.1021/ic50187a039

  28. [28]

      T.W. Bell, H.J. Choi, W. Harte, J. Am. Chem. Soc. 108 (1986) 7427-7428. doi: 10.1021/ja00283a058

  29. [29]

      E.S. Lee, Z. Gao, Y.H. Bae, J. Control Release 132 (2008) 164-170.

  30. [30]

      D.H. Busch, K. Farmery, V. Goedken, V. Katovic, N. Tokel, Bioinorg. Chem. 100 (1971) 44-78. doi: 10.1021/ba-1971-0100.ch003

  31. [31]

      J.P. Collman, P.W. Schneider, Inorg. Chem. 5 (1965) 1380-1384.

  32. [32]

      I. Rostášová, M. Vilková, Z. Vargová, et al., New J. Chem. 41 (2017) 7253-7259. doi: 10.1039/C7NJ00254H

  33. [33]

      R.J. Motekaitis, B.E. Rogers, D.E. Reichert, A.E. Martell, M.J. Welch, Inorg. Chem. 35 (1996) 3821-3827.

  34. [34]

      E.T. Clarke, A.E. Martell, Inorg. Chim. Acta 190 (1991) 27-36. doi: 10.1016/S0020-1693(00)80228-5

  35. [35]

      E. Mocchegiani, R. Giacconi, M. Malavolta, Trends Mol. Med. 14 (2008) 419-428. doi: 10.1016/j.molmed.2008.08.002

  36. [36]

      T. Mattia, M.L. Massimino, D.M. Agnese, A. Elisa, S. Enzo, Front. Neurosci 11 (2017) 3.

  37. [37]

      L. Fouani, S.V. Menezes, M. Paulson, D.R. Richardson, Z. Kovacevic, Pharmacol. Res. 115 (2017) 275-287.

  38. [38]

      A. Khan, P. Singh, A. Srivastava, Microbiol. Res. 212-213 (2018) 103-111. doi: 10.5958/2277-4912.2018.00019.x

  39. [39]

      T.A. Rouault, W.H. Tong, Trends. Genet. 24 (2008) 398-407. doi: 10.1016/j.tig.2008.05.008

  40. [40]

      K. Richardson, Crit. Rev. Oncol. Hemat. 42 (2002) 65-78.

  41. [41]

      L.M. Bystrom, M.L. Guzman, S. Rivella, Antioxid. Redox. Sign. 20 (2014) 1917-1924. doi: 10.1089/ars.2012.5014

  42. [42]

      G.M. Brittenham, Alcohol 30 (2003) 151-158.

  43. [43]

      V.M. Nurchi, R. Cappai, K. Chand, et al., Dalton Trans. 48 (2019) 16167-16183. doi: 10.1039/c9dt02905b

  44. [44]

      N.T.V. Le, D.R. Richardson, Blood 104 (2004) 2967-2975.

  45. [45]

      J. Blatt, S. Stitely, Cancer Res. 47 (1987) 1749-1750.

  46. [46]

      H.M. Lederman, A. Cohen, J.W. Lee, M.H. Freedman, E.W. Gelfand, Blood 64 (1984) 748-753.

  47. [47]

      K.R. Bridges, A. Cudkowicz, J. Biol. Chem. 259 (1984) 12970-12977.

  48. [48]

      H.S. Chong, X. Ma, H. Lee, et al., J. Med. Chem. 51 (2008) 2208–2215. doi: 10.1021/jm701307j

  49. [49]

      S. Wang, S. Zhang, L. Ke, et al., Bioorg. Med. Chem. Lett. 28 (2018) 117-121. doi: 10.5539/jmr.v10n6p117

  50. [50]

      R.C. Scarrow, K.N. Raymond, Inorg. Chem. 27 (1988) 4140-4149. doi: 10.1021/ic00296a013

  51. [51]

      M. Meyer, J.R. Telford, S.M. Cohen, D.J. White, K.N. Raymond, J. Am. Chem. Soc. 119 (1997) 10093-10103.

  52. [52]

      E.J. Werner, S. Avedano, M. Botta, et al., J. Am. Chem. Soc. 129 (2007) 1870-1871. doi: 10.1021/ja068026z

  53. [53]

      J.M. Harrington, S. Chittamuru, S. Dhungana, et al., Inorg. Chem. 49 (2010) 8208-8221. doi: 10.1021/ic902595c

  54. [54]

      X. Liu, X. Dong, C. He, et al., Bioorg. Chem. 96 (2020) 103574.

  55. [55]

      Z.D. Liu, R.C. Hider, Coord. Chem. Rev. 232 (2002) 151-171.

  56. [56]

      T. Zhou, K. Chen, L.M. Kong, et al., Bioorg. Med. Chem. Lett. 28 (2018) 2504-2512.

  57. [57]

      K. Akira, H. Yasushi, H. Manabu, et al., Heterocycles 55 (2001) 2171-2187.

  58. [58]

      T.M. Hoette, R.J. Abergel, J. Xu, R.K. Strong, K.N. Raymond, J. Am. Chem. Soc. 130 (2008) 17584-17592. doi: 10.1021/ja8074665

  59. [59]

      D.G. Workman, M. Hunter, L.G. Dover, D. Tetard, J. Inorg. Biochem. 160 (2016) 49-58.

  60. [60]

      M. Seitz, M.D. Pluth, K.N. Raymond, Inorg. Chem. 46 (2007) 351–353. doi: 10.1021/ic0614869

  61. [61]

      K.F. Kong, L. Schneper, K. Mathee, APMIS 118 (2010) 1-36. doi: 10.1111/j.1600-0463.2009.02563.x

  62. [62]

      K. Bush, P.A. Bradford, Nat. Rev. Microbiol. 17 (2019) 295-306. doi: 10.1038/s41579-019-0159-8

  63. [63]

      B. Karen, Antimicrob. Agents Ch. 62 (2018) 1128.

  64. [64]

      S.S. Jalde, H.K. Choi, J. Microbiol. 58 (2020) 633-647. doi: 10.1007/s12275-020-0285-z

  65. [65]

      K.A. Toussaint, J.C. Gallagher, Ann. Pharmacother. 49 (2018) 86-98.

  66. [66]

      A.M. Somboro, D. Tiwari, L.A. Bester, et al., J. Antimicrob. Chemother. 70 (2015) 1594-1596. doi: 10.1093/jac/dku538

  67. [67]

      E. Boros, C.L. Ferreira, J.F. Cawthray, et al., J. Am. Chem. Soc. 132 (2010) 15726-15733. doi: 10.1021/ja106399h

  68. [68]

      Y. Zhang, H. Hong, J.W. Engle, et al., PLoS One 6 (2011) e28005. doi: 10.1371/journal.pone.0028005

  69. [69]

      A.M. Somboro, D.G. Amoako, J.O. Sekyere, et al., Appl. Environ. Microbiol. 85 (2019) e02077-18.

  70. [70]

      S. McOyi, D.G. Amoako, A.M. Somboro, H.M. Khumalo, R.B. Khan, J. Biochem. Mol. Toxicol. 34 (2020) e22607.

  71. [71]

      N. Tsotetsi, D.G. Amoako, A.M. Somboro, H.M. Khumalo, R.B. Khan, Cytotechnology 72 (2020) 785-796. doi: 10.1007/s10616-020-00422-7

  72. [72]

      R. Azumah, J. Dutta, A.M. Somboro, M. Ramtahal, T. Govender, J. Appl. Microbiol. 120 (2016) 860-867. doi: 10.1111/jam.13085

  73. [73]

      S.B. Falconer, S.A. Reid-Yu, A.M. King, et al., ACS Infect. Dis. 1 (2015) 533-543. doi: 10.1021/acsinfecdis.5b00033

  74. [74]

      F.M. Klingler, T.A. Wichelhaus, D. Frank, et al., J. Med. Chem. 58 (2015) 3626-3630. doi: 10.1021/jm501844d

  75. [75]

      E. Zhang, M.M. Wang, S.C. Huang, et al., Bioorg. Med. Chem. Lett. 28 (2018) 214-221.

  76. [76]

      R.A. Cairns, I.S. Harris, T.W. Mak, Nat. Rev. Cancer 11 (2011) 85-95. doi: 10.1038/nrc2981

  77. [77]

      R. Mo, T. Jiang, R. DiSanto, W. Tai, Z. Gu, Nat. Commun. 5 (2014) 3364.

  78. [78]

      X.R. Song, S.H. Li, H. Guo, et al., Adv. Sci. 5 (2018) 1801201.

  79. [79]

      B. Dietrich, T.M. Fyles, J.M. Lehn, L.G. Pease, D.L. Fyles, J. Chem Soc., Chem. Commun. (1978) 934-936.

  80. [80]

      M.W. Hosseini, J.M. Lehn, L. Maggiora, K.B. Mertes, M.P. Mertes, J. Am. Chem. Soc. 109 (1987) 537-544. doi: 10.1021/ja00236a036

  81. [81]

      M.W. Hosseini, J.M. Lehn, M.P. Mertes, Helv. Chim. Acta 66 (1983) 2454-2466. doi: 10.1002/hlca.19830660811

  82. [82]

      A. Bencini, A. Bianchi, E. Garcia-Espana, et al., Bioorg. Chem. 20 (1992) 8-29.

  83. [83]

      B. Frydman, S. Bhattacharya, A. Sarkar, et al., J. Med. Chem. 47 (2004) 1051-1059.

  84. [84]

      W. Mar, G.T. Tan, G.A. Cordell, et al., J. Nat. Prod. 54 (1991) 1531-1542. doi: 10.1021/np50078a007

  85. [85]

      Y. Yarden, M.X. Sliwkowski, Nat. Rev. Mol. Cell. Biol. 2 (2001) 127-137.

  86. [86]

      N.E. Hynes, H.A. Lane, Nat. Rev. Cancer 5 (2005) 341-354. doi: 10.1038/nrc1609

  87. [87]

      F. Ciardiello, G. Tortora, N. Engl. J. Med. 358 (2008) 1160-1174.

  88. [88]

      R. Roskoski, Pharmacol. Res. 68 (2013) 68-94.

  89. [89]

      J. Mendelsohn, J. Baselga, J. Clin. Oncol. 21 (2003) 2787-2799.

  90. [90]

      M.A. Lemmon, J. Schlessinger, Cell 141 (2010) 1117-1134.

  91. [91]

      D. Lichosyt, P. Dydio, J. Jurczak, Chem. Eur. J. 22 (2016) 17673-17680. doi: 10.1002/chem.201603555

  92. [92]

      X. Wang, J. Liu, W. Zhang, et al., ACS Med. Chem. Lett. 7 (2016) 1044-1049. doi: 10.1021/acsmedchemlett.6b00221

  93. [93]

      A.L. McIver, W. Zhang, Q. Liu, et al., ChemMedChem 12 (2017) 207-213. doi: 10.1002/cmdc.201600589

  94. [94]

      Y. Ju, J. Wu, X. Yuan, et al., J. Med. Chem. 61 (2018) 11372-11383. doi: 10.1021/acs.jmedchem.8b01612

  95. [95]

      Q. Ryan, A. Ibrahim, M.H. Cohen, et al., Oncologist 13 (2008) 1114-1119. doi: 10.1634/theoncologist.2008-0816

  96. [96]

      A.K. Tiwari, K. Sodani, C.L. Dai, C. R Ashby, Z.S. Chen, Curr. Pharm. Biotechno. 12 (2011) 570-594.

  97. [97]

      M.M. Gottesman, I.H. Pastan, J. Natl. Cancer Inst. 107 (2015) djv222. doi: 10.1093/jnci/djv222

  98. [98]

      D.S. Martin, D. Spriggs, J.A. Koutcher, Apoptosis 6 (2001) 125-131.

  99. [99]

      E. Batrakova, S. Li, W. Elmquist, et al., Br. J. Cancer 85 (2001) 1987-1997.

  100. [100]

       Q. Guo, Y. Liu, Z. Wang, et al., Acta Biomater. 122 (2021) 343-353.

  101. [101]

       Q. Guo, Y. Liu, G. Mu, et al., Biomater. Sci. 8 (2020) 5638-5646. doi: 10.1039/d0bm01001d

  102. [102]

       J. Gao, Z. Wang, Q. Guo, et al., Theranostics 12 (2022) 1286-1302. doi: 10.7150/thno.67543

  103. [103]

       Z.R. Yang, H.F. Wang, J. Zhao, et al., Cancer Gene Ther. 14 (2007) 599-615. doi: 10.1038/sj.cgt.7701054

  104. [104]

       R. Niven, R. Pearlman, T. Wedeking, et al., J. Pharm. Sci. 87 (1998) 1292-1299.

  105. [105]

       R. Mohammadinejad, A. Dehshahri, V. Sagar Madamsetty, et al., J. Control Release 325 (2020) 249-275.

  106. [106]

       L.M.P. Vermeulen, J.C. Fraire, L. Raes, et al., Int. J. Mol. Sci. 19 (2018) 2400. doi: 10.3390/ijms19082400

  107. [107]

       D.C. Chang, Y.M. Zhang, J. Zhang, Y.H. Liu, X.Q. Yu, RSC Adv. 7 (2017) 18681-18689.

  108. [108]

       Y.M. Zhang, D.C. Chang, J. Zhang, Y.H. Liu, X.Q. Yu, Bioorg. Med. Chem. 23 (2015) 5756-5763.

  109. [109]

       H.J. Wang, X. He, Y. Zhang, et al., RSC Adv. 5 (2015) 59417-59427.

  110. [110]

       H.J. Wang, Y.H. Liu, J. Zhang, et al., Biomater. Sci. 2 (2014) 1460-1470.

  111. [111]

       B. Wang, W.J. Yi, J. Zhang, et al., Bioorg. Med. Chem. Lett. 24 (2014) 1771-1775.

  112. [112]

       Z. Huang, Y.H. Liu, Y.M. Zhang, et al., Org. Biomol. Chem. 13 (2015) 620-630.

  113. [113]

       W.J. Yi, X.C. Yu, B. Wang, et al., Chem. Commun. 50 (2014) 6454-6457.

  114. [114]

       Z. Huang, Y.M. Zhang, Q. Cheng, et al., J. Mater. Chem. B 4 (2016) 5575-5584.

  115. [115]

       Q.F. Zhang, B. Wang, D.X. Yin, et al., RSC Adv. 4 (2014) 59164-59174.

  116. [116]

       Q. Liu, W.J. Yi, Y.M. Zhang, et al., Chem. Biolo. Drug Des. 82 (2013) 376-383. doi: 10.1111/cbdd.12159

  117. [117]

       C.H. Jones, C.K. Chen, A. Ravikrishnan, S. Rane, B.A. Pfeifer, Mol. Pharm. 10 (2013) 4082-4098. doi: 10.1021/mp400467x

  118. [118]

       Y.M. Zhang, Z. Huang, J. Zhang, et al., Biomater. Sci. 5 (2017) 718-729.

  119. [119]

       R.M. Zhao, Y. Guo, H.Z. Yang, J. Zhang, X.Q. Yu, New J. Chem. 45 (2021) 13549-13557. doi: 10.1039/d1nj02115j

  120. [120]

       Y.M. Zhang, J. Zhang, Y.H. Liu, et al., RSC Adv. 10 (2020) 39842-39853. doi: 10.1039/d0ra08027f

  121. [121]

       Q.Y. Yu, Y. Guo, J. Zhang, Z. Huang, X.Q. Yu, J. Mater. Chem. B 7 (2019) 451-459. doi: 10.1039/c8tb02414f

  122. [122]

       Y. Guo, Q.Y. Yu, J. Zhang, et al., New J. Chem. 43 (2019) 16138-16147. doi: 10.1039/c9nj03242h

  123. [123]

       Z. Huang, Y.P. Xiao, Y. Guo, et al., Eur. Polym. J. 170 (2022) 111153.

  124. [124]

       Z. Chen, S. Liu, W. Liu, et al., ACS Biomater. Sci. Eng. 7 (2021) 5678-5689. doi: 10.1021/acsbiomaterials.1c01115

  125. [125]

       X.Y. Sun, Y.X. Liang, Y.N. Gao, et al., J. Mater. Chem. B 11 (2023) 8943-8955. doi: 10.1039/d3tb01282d

  126. [126]

       Q. Wang, X.Y. Liu, F. Tang, Z.L. Lu, Chin. Sci. Bull. 67 (2022) 2298-2317. doi: 10.1360/tb-2022-0216

  127. [127]

       H.Z. Yang, J. Zhang, Y. Guo, L. Pu, X.Q. Yu, ACS Appl. Bio. Mater. 4 (2021) 5717-5726. doi: 10.1021/acsabm.1c00484

  128. [128]

       L.L. Ma, M.X. Liu, X.Y. Liu, et al., J. Mater. Chem. B 8 (2020) 3869-3879. doi: 10.1039/d0tb00321b

  129. [129]

       X.Y. Liu, J.B. Yang, C.Y. Wu, et al., J. Mater. Chem. B 10 (2022) 945-957. doi: 10.1039/d1tb02352g

  130. [130]

       C. Li, H. Tian, N. Rong, et al., Biomacromolecules 12 (2011) 298-305. doi: 10.1021/bm100819z

  131. [131]

       D. Fischer, Y. Li, B. Ahlemeyer, J. Krieglstein, T. Kissel, Biomaterials 24 (2003) 1121-1131.

  132. [132]

       S. Choksakulnimitr, S. Masuda, H. Tokuda, Y. Takakura, M. Hashida, J. Control. Release 34 (1995) 233-241.

  133. [133]

       M. Metzke, N. O'Connor, S. Maiti, E. Nelson, Z. Guan, Angew. Chem. Int. Ed. 117 (2005) 6687-6691. doi: 10.1002/ange.200501944

  134. [134]

       L. Li, F. Zhao, B. Zhao, et al., Macromol. Biosci. 15 (2015) 912-926. doi: 10.1002/mabi.201400518

  135. [135]

       A.L. Lewis, Z.L. Cumming, H.H. Goreish, et al., Biomaterials 22 (2001) 99-111.

  136. [136]

       C. Ma, J. Zhang, L. Guo, et al., Mol. Pharm. 13 (2016) 47-54. doi: 10.1021/acs.molpharmaceut.5b00396

  137. [137]

       C. Ma, X. Zhang, C. Du, et al., Bioconjug. Chem. 27 (2016) 1005-1012. doi: 10.1021/acs.bioconjchem.6b00048

  138. [138]

       J. Luten, J. Van Steenis, R. Van Someren, et al., J. Control. Release 89 (2003) 483-497.

  139. [139]

       Y.J. Jun, J.H. Kim, S.J. Choi, et al., Bioorg. Med. Chem. Lett. 17 (2007) 2975-2978.

  140. [140]

       H.K. de Wolf, J. Luten, C.J. Snel, et al., J. Control. Release 109 (2005) 275-287.

  141. [141]

       C. Li, C. Ma, P. Xu, et al., J. Phys. Chem. B 117 (2013) 7857-7867. doi: 10.1021/jp312766u

  142. [142]

       C. Li, H. Tian, S. Duan, et al., J. Phys. Chem. B 115 (2011) 13350-13354. doi: 10.1021/jp206199b

  143. [143]

       D. Desbouis, I.P. Troitsky, M.J. Belousoff, L. Spiccia, B. Graham, Coordin. Chem. Rev. 256 (2012) 897-937.

  144. [144]

       M. Shokeen, C.J. Anderson, Acc. Chem. Res. 42 (2009) 832-841. doi: 10.1021/ar800255q

  145. [145]

       T. Joshi, B. Graham, L. Spiccia, Acc. Chem. Res. 48 (2015) 2366-2379. doi: 10.1021/acs.accounts.5b00142

  146. [146]

       J. Hormann, J. Malina, O. Lemke, et al., Inorg. Chem. 57 (2018) 5004-5012. doi: 10.1021/acs.inorgchem.8b00027

  147. [147]

       M. Liu, X.Q. Song, Y.D. Wu, J. Qian, J.Y. Xu, Dalton Trans. 49 (2020) 114-123.

  148. [148]

       A. Adhikari, N. Kumari, M. Adhikari, et al., Bioorg. Med. Chem. 25 (2017) 3483-3490.

  149. [149]

       Z.F. Wang, X.F. Zhou, Q.C. Wei, et al., Eur. J. Med. Chem. 238 (2022) 114418.

  150. [150]

       Q.P. Qin, Z.Z. Wei, Z.F. Wang, et al., Chem. Commun. 56 (2020) 3999-4002. doi: 10.1039/d0cc00524j

  151. [151]

       D.Y. Zeng, G.T. Kuang, S.K. Wang, et al., J. Med. Chem. 60 (2017) 5407-5423. doi: 10.1021/acs.jmedchem.7b00016

  152. [152]

       M.C. Heffern, N. Yamamoto, R.J. Holbrook, A.L. Eckermann, T.J. Meade, Curr. Opin. Chem. Biol. 17 (2013) 189-196.

  153. [153]

       P.B. Cressey, A. Eskandari, P.M. Bruno, et al., ChemBioChem 17 (2016) 1713-1718. doi: 10.1002/cbic.201600368

  154. [154]

       R. Barth, A. Soloway, Cancer Res. 50 (1990) 1061-1070.

  155. [155]

       T.R. Murray-Stewart, P.M. Woster, R.A. Casero, Biochem. J. 473 (2016) 2937-2953.

  156. [156]

       H. Ueda, M. Suzuki, R. Kuroda, T. Tanaka, S. Aoki, J. Med. Chem. 64 (2021) 8523-8544. doi: 10.1021/acs.jmedchem.1c00445

  157. [157]

       H. Ueda, M. Suzuki, Y. Sakurai, T. Tanaka, S. Aoki, Eur. J. Inorg. Chem. (2022) e202100949.

  158. [158]

       S. Tan, D. Sun, J. Lyu, et al., Bioorg. Med. Chem. 23 (2015) 5672-5680.

  159. [159]

       C. Li, F. Zhao, Y. Huang, et al., Bioconjug. Chem. 23 (2012) 1832-1837. doi: 10.1021/bc300162g

  160. [160]

       C. Ma, J. Zhang, L. Guo, et al., Mol. Pharm. 13 (2016) 47-54. doi: 10.1021/acs.molpharmaceut.5b00396

  161. [161]

       M. Wojnilowicz, A. Glab, A. Bertucci, F. Caruso, F. Cavalieri, ACS Nano 13 (2018) 187-202.

  162. [162]

       S. Okamoto, T. Shiga, N. Tamaki, Molecules 26 (2021) 2232. doi: 10.3390/molecules26082232

  163. [163]

       K. Herrmann, M. Schwaiger, J.S. Lewis, et al., Lancet Oncol. 21 (2020) e146-e156.

  164. [164]

       H.A. Holik, F.M. Ibrahim, A.A. Elaine, et al., Molecules 27 (2022) 3062. doi: 10.3390/molecules27103062

  165. [165]

       T.J. Wadas, E.H. Wong, G.R. Weisman, C.J. Anderson, Chem. Rev. 110 (2010) 2858-2902. doi: 10.1021/cr900325h

  166. [166]

       E.W. Price, C. Orvig, Chem. Soc. Rev. 43 (2014) 260-290.

  167. [167]

       F. Roesch, P. J Riss, Curr. Top. Med. Chem. 10 (2010) 1633-1668. doi: 10.2174/156802610793176738

  168. [168]

       Z. Baranyai, G. Tircsó, F. Rösch, Eur. J. Inorg. Chem. 2020 (2020) 36-56. doi: 10.1002/ejic.201900706

  169. [169]

       U. Hennrich, M. Eder, Pharmaceuticals 15 (2022) 1292. doi: 10.3390/ph15101292

  170. [170]

       U. Hennrich, K. Kopka, Pharmaceuticals 12 (2019) 114. doi: 10.3390/ph12030114

  171. [171]

       U. Hennrich, M. Benešová, Pharmaceuticals 13 (2020) 38. doi: 10.3390/ph13030038

  172. [172]

       C. Liu, T. Liu, N. Zhang, et al., Eur. J. Nucl. Med. Mol. Imaging 45 (2018) 1852-1861. doi: 10.1007/s00259-018-4037-9

  173. [173]

       I. Heidegger, C. Kesch, A. Kretschmer, et al., Ther. Adv. Med. Oncol. 14 (2022) 1-10. doi: 10.2307/j.ctv2ngx62z.7

  174. [174]

       D.G. Bostwick, A. Pacelli, M. Blute, P. Roche, G.P. Murphy, Cancer 82 (1998) 2256-2261.

  175. [175]

       A. Afshar-Oromieh, H. Hetzheim, C. Kratochwil, et al., J. Nucl. Med. 56 (2015) 1697-1705. doi: 10.2967/jnumed.115.161299

  176. [176]

       C. Kratochwil, F.L. Giesel, M. Stefanova, et al., J. Nucl. Med. 57 (2016) 1170-1176. doi: 10.2967/jnumed.115.171397

  177. [177]

       O. Sartor, J. de Bono, K.N. Chi, et al., N. Engl. J. Med. 385 (2021) 1091-1103. doi: 10.1056/nejmoa2107322

  178. [178]

       M.J. Klomp, S.U. Dalm, M. de Jong, et al., Rev. Endocr. Metab. Disord. 22 (2021) 495-510. doi: 10.1007/s11154-020-09607-z

  179. [179]

       J. Strosberg, G. El-Haddad, E. Wolin, et al., N. Engl. J. Med. 376 (2017) 125-135. doi: 10.1056/NEJMoa1607427

  180. [180]

       J. Strosberg, E. Wolin, B. Chasen, et al., J. Clin. Oncol. 36 (2018) 2578-2584. doi: 10.1200/jco.2018.78.5865

  181. [181]

       L. Zhao, B. Niu, J. Fang, et al., J. Nucl. Med. 63 (2022) 862-868. doi: 10.2967/jnumed.121.263016

  182. [182]

       J. Zang, X. Wen, R. Lin, et al., Theranostics 12 (2022) 7180-7190. doi: 10.7150/thno.79144

  183. [183]

       M. Xu, P. Zhang, J. Ding, et al., J. Nucl. Med. 63 (2022) 952-958. doi: 10.2967/jnumed.121.262533

  184. [184]

       L. Zhao, J. Chen, Y. Pang, et al., Mol. Pharm. 19 (2022) 3640-3651. doi: 10.1021/acs.molpharmaceut.2c00424

  185. [185]

       T.T. Huynh, E.M. van Dam, S. Sreekumar, et al., Pharmaceuticals 15 (2022) 728. doi: 10.3390/ph15060728

  186. [186]

       E. Gourni, L. Del Pozzo, E. Kheirallah, et al., Mol. Pharm. 12 (2015) 2781-2790. doi: 10.1021/mp500671j

  187. [187]

       A.V.F. Massicano, B.V. Marquez-Nostra. S.E. Lapi, Mol. Imaging 17 (2018) 1-11.

  188. [188]

       N. Liu, Q. Wan, Z. Cheng, Y. Chen, Curr. Top. Med. Chem. 19 (2019) 17-32.

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  Figure 1  Structures of representative (A) parent and (B) armed macrocyclic polyamines, and (C) some variants.

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  Figure 2  (A) Structures and antiproliferative activities against cancer cells of classic hydrophilic iron chelators DFO, DTPA. (B) Anti-tumor cell activity of NETA, NE3TA and NE3TA-Bn and their respective derivatives (C-NETA, C-NE3TA and N-NE3TA) (C) Fluorescence images of HT29 cells with C-NE3TA-NBD incubation. (D) Anti-tumor cell activity of p-NO₂-PhPr-NE3TA and p-NH₂-PhPr-NE3TA.

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  Figure 3  Representative structures of macrocyclic polyamines and 3,2-HOPO chelators linked by alkyl chain.

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  Figure 4  Structures of TACN and 1,2-HOPO chelators applied in microbial growth inhibition. Copied with permission [59]. Copyright 2016, Elsevier.

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  Figure 5  Structures of (A) NODAGA and its short peptide derivatives (B) NOTE dithiocarbamate.

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  Figure 6  Inhibitory effects of [13]-, [16]-, [17]-, [18]- and [20]-membered macrocyclic polyamines on DuPro and PC-3 cell line.

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  Figure 7  (A) Structures, antiproliferative activities and in vitro kinase inhibitory activity of 4-anilinoquinazoline incorporated with macrocyclic polyamines, Lapa-Gefi-TACN and Lapa-Gefi-Cyclen. (B) ATP levels in A549 cells after 72 h of co-incubation with compounds. (C) Representative photographs of tumors after treatment by Lapa-Gefi-Cyclen, and H&E staining images. Copied with permission [94]. Copyright 2018, American Chemical Society.

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  Figure 8  Inhibitory effects of (A) HCPT-FFFK-Cyclen. Copied with permission [100]. Copyright 2020, Elsevier. (B) CRB-FFFK-Cyclen. Copied with permission [101]. Copyright 2021, Royal Society of Chemistry. (C) LND-GFFYK-Cyclen in different tumor cell lines. Copied with permission [102]. Copyright 2022, Ivyspring International.

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  Figure 9  (A) Hydrophobic derivatives of cyclen as cationic liposomes. (B) Schematic diagram of cationic lipid assembly of single tailed and double tailed aliphatic chains. Copied with permission [117]. Copyright 2013, American Chemical Society. (C) Amphiphilic polymers based on cyclen liposomes as non-viral gene vectors.

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  Figure 10  (A) Zn(Ⅱ)-cyclen multifunctional complex Zn-PCD and Zn-PCA. (B) Gluciferase transfection efficiency (a and c) and cytotoxicity (b and d) of Zn-PCA and Zn-PCD in 3T3 and PC3 cells, respectively. (C) EGFP transfection efficiency of Zn-PCD in suspension cells 293F. Copied with permission [124]. Copyright 2021, American Chemical Society.

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  Figure 11  (A) Chemical structures of CNN2 and TPP. (B) Release of pDNA from CNN2-DT/pDNA NPs in PBS with H₂O₂ or NTR, H₂O₂, and NTR. (C) Viability of HeLa cells after incubation with different treatments. (D) Tumors weight of the mice after tail vein injection of different treatments on day 15 from each group and tumor growth inhibition (TGI) rate after tail vein injection of different treatments. Copied with permission [125]. Copyright 2023, Royal Society of Chemistry.

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  Figure 12  (A) Structural design of AQ-based Cu(Ⅱ) complexes, anti-proliferation activities to A549 and cytotoxicity to NHDF cell lines. (B) AFM plot of plasmid pSP73 DNA linearised in the presence of 1.56 µmol/L (left) and 3.13 µmol/L (right) of Cu(Ⅱ)L₄. (C) Schematic diagram of Cu(Ⅱ)L₄ binding to DNA. Copied with permission [146]. Copyright 2018, American Chemical Society.

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  Figure 13  Structures and inhibitory effects of (A) btan metal complexes, (B) Zn(Ⅱ)-cyclen-(Trp)₂, (C) Zn(BQTC) and (D) Co(Ⅲ)-cyclam on the growth of different cancer cell lines. (E) Bright-field images of HMLER-shEcad mammospheres. Copied with permission [153]. Copyright 2016, Wiley-VCH Verlag.

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  Figure 14  (A) Structures and antiproliferation activities of Naphthalimides-cyclam. (B) Binding mode for naphthalimides-cyclam (R₂ = n - C₈H₁₇) with topo Ⅰ/DNA (PDB ID: 1K4T) and (C) topo Ⅱ/DNA (PDB ID: 4G0V) complexes. Copied with permission [158]. Copyright 2015, Elsevier.

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  Figure 15  Chemical structure of ¹⁷⁷Lu vipivotide tetraxetan, Pluvicto.

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  Figure 16  Chemical structure of [¹⁷⁷Lu]Lu-DOTATATE, Lutathera.

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