Injectable hydrogel-based drug delivery systems for enhancing the efficacy of radiation therapy: A review of recent advances

Ningyue Xu Jun Wang Lei Liu Changyang Gong

Citation:  Ningyue Xu, Jun Wang, Lei Liu, Changyang Gong. Injectable hydrogel-based drug delivery systems for enhancing the efficacy of radiation therapy: A review of recent advances[J]. Chinese Chemical Letters, 2024, 35(8): 109225. doi: 10.1016/j.cclet.2023.109225 shu

Injectable hydrogel-based drug delivery systems for enhancing the efficacy of radiation therapy: A review of recent advances

English

  • Cancer, a complex and multigenic disease, presents a significant challenge to global health [1-3], with 19.3 million new cases and around 10 million cancer-related deaths worldwide in 2020 [4]. Conventional treatments such as surgery, chemotherapy, and radiotherapy (RT) are commonly employed, while emerging strategies like immunotherapy and gene therapy show promising potential [5]. Combining these therapies has demonstrated superior efficacy in tumor control [6,7]. As cancer continues to be a major public health concern, advances in treatment modalities are crucial for improving treatment outcomes and patient survival.

    RT is a key component of local cancer treatment that principally utilizes ionizing radiation (such as X-rays, γ-rays, electrons) to irradiate tumors internally or externally, causing DNA damage to cancer cells [8]. RT can be given alone or in combination with surgery, chemotherapy, or immunotherapy for the intent of cure or palliative care (often used to reduce pain or mass effect). RT is estimated to be employed for approximately half of all cancer patients, contributing to 40% of tumor control and saving one million patients per year [9-12]. However, RT-induced tissue injury limits the radiation dose and decreases effectiveness. More importantly, radioresistance is the leading cause of tumor recurrence [13,14]. Thus, enhancing tumor radiosensitivity while minimizing damage to normal tissues is imperative.

    There have been multiple endeavors aimed at addressing these concerns, encompassing the implementation of radiosensitizers and combination therapy [15-19]. However, conventional radiosensitizers encounter limited efficacy in penetrating tumor tissues, thereby constraining their potential as radiosensitizer. Furthermore, the prevailing approaches of administering sensitizers, chemotherapeutics, and immunotherapeutics systemically are associated with potential for eliciting systemic toxicities and various accompanying side effects [20-23].

    RT can benefit from the use of hydrogels as delivery vehicles for therapeutic agents. Hydrogels allow for controlled and sustained release of medication, targeted specifically to the site of treatment. Additionally, they offer a platform for combination therapy by allowing different drugs to be co-delivered. Many studies have demonstrated that the application of hydrogels can alleviate tumor resistance and improve therapeutic efficiency while reducing side effects [24-26].

    In this review, we first provide an overview of hydrogels, their properties, and classification. Next, we will highlight joint application of hydrogels with various RT approaches, including external beam radiation therapy and internal beam radiation therapy, also known as brachytherapy. Finally, we discuss possibilities of incorporating emergent immunotherapy with RT and hydrogels. Through this review, we aim to explore the potential of hydrogels in optimizing RT efficacy and advancing cancer treatment.

    Hydrogels exhibit a three-dimensional cross-linked network structure and utilize water as the dispersing medium. They can be readily synthesized through the copolymerization of water-soluble monomers or the cross-linking of hydrophilic polymer chains. A diverse array of polymers possesses the ability to generate hydrogels, encompassing naturally sourced polymers like hyaluronic acid (HA), chitosan (CS), fibrin and gelatin. Additionally, commonly employed synthetic polymers in hydrogel synthesis comprise polyacrylic acid (PAA), polyvinyl alcohol (PVA), poly(ethylene glycol) (PEG), polyacrylamide (PAAm), and their corresponding derivatives [27-29]. Commonly used polymers with their structures in the preparation of hydrogels are summarized in Fig. 1.

    Figure 1

    Figure 1.  Classic chemical structures of compositions of hydrogels.

    Hydrogels can be synthesized through two main methods: chemical crosslinking and physical crosslinking. Chemical crosslinking involves the use of crosslinking agents or the formation of chemical bonds through crosslinking reactions. These bonds connect polymer chains, resulting in a robust and stable network structure. Common chemical crosslinking techniques include enzymatic approaches, free radical polymerization, and chemical reactions involving complementary functional groups. In contrast, physical crosslinking relies on non-covalent interactions to maintain the structural stability of hydrogels. Notable physical crosslinking methods include ion crosslinking, hydrophobic interactions, and hydrogen bonding [30-32].

    A key attribute of hydrogels is their remarkable swelling capacity, manifesting as their pronounced expansion in aqueous environments while retaining vast amounts of water within their highly structured matrices. In addition, their highly hydrophilic three-dimensional (3D) architecture renders them an attractive platform for incorporating and delivering therapeutic agents [33-35].

    Injectable hydrogels have become popular materials in the biomedical field, marked by their common properties including controllable gelation [36], reliable biocompatibility, biodegradability, and on-demand drug-release capabilities [37], while each type of hydrogel has unique properties. Notably, the chemical and physical properties of hydrogels can be modified to make them more appropriate for the intended application, and their potential is greatly expanding in a broad spectrum of various areas.

    Gelation refers to the process by which a polymer solution transforms into a viscous gel with a reticular cross-linked structure. Physical and chemical stimuli, such as temperature, light, pH, enzymes, electromagnetic radiation, and ultrasound, can trigger hydrogel gelation. This sensitivity of hydrogel gelation to external stimuli makes hydrogels excellent candidates for in situ-forming injectable biomaterials that respond to a variety of triggers. Within an organism, a free-flowing polymer solution can undergo a "sol-gel" transition under mild conditions to form a non-flowing gel after administration via syringes or catheters [38,39]. Injectable hydrogels offer several advantages, including minimally invasive administration, convenient injection, high moldability, and drug encapsulation capability and have been used in RT sensitization. Thermal triggers are commonly used for hydrogels. In this case, the hydrogel solution remains fluid and injectable at room temperature, allowing for large volumes of therapeutic agents to be loaded [40]. Body temperature or thermal therapy can trigger in vivo gelation of the injected hydrogel, subsequently anchoring the therapeutic agents at the injection site to perform their intended functions. For example, a chitosan/β-glycerophosphate hydrogel system can undergo a rapid sol-gel transition within 5 min at 37 ℃ and immobilize Re-188-Tin colloid locally for up to 48 h [41].

    Besides, hydrogels in their swollen state exhibit a property of possessing supple, tissue-like mechanical characteristics, which promote biocompatibility with host tissue and reduce the risk of immunogenicity-related complications [42]. In addition to this, hydrogels can degrade via ester hydrolysis, enzymatic hydrolysis, photolytic cleavage, or a combination of these mechanisms and be eliminated from the body [43]. This biocompatibility and biodegradability suggest the potential the safety of hydrogels in RT applications. The complex and heterogeneous nature of the tumor microenvironment (TME) presents challenges for traditional drug delivery methods, including achieving effective drug concentrations, targeting specificity, and sustained release. However, hydrogels offer a solution due to their stable, hydrophilic porous structure. This structure allows hydrogels to encapsulate large amounts of therapeutic agents and hinder their premature release due to the high stiffness in the hydrogel networks [39,44]. The subsequent slow release of the drug occurs by diffusion through the thick gel barrier or due to degradation of the hydrogel [45], enabling controlled drug release and targeted delivery. This approach enhances the efficacy of anti-tumor drugs within the TME [29,46]. Researches have demonstrated that hydrogels can significantly prolong the release of loaded drugs in the body compared to free drugs [24,47,48]. The release rate of the encapsulated drug can be regulated by parameters such as the mesh size, crosslink density, swelling ratio, or degradation rate of hydrogels [49,50]. Furthermore, stimulus-responsive hydrogels can undergo structural changes (volume transitions or gel-solution transitions) in response to physical or chemical stimuli, which can be used to achieve controlled drug release. For example, photothermal agents can transform near-infrared (NIR) laser light into thermal energy, and the increased temperature can soften and melt agarose hydrogels, as well as cause the loaded iron-gallic acid (FeGA) to diffuse into the TME [51].

    Consequently, hydrogels are a promising option for drug delivery as they can prolong drug release and regulate the release rate, making them ideal for drug delivery applications and RT sensitization [52,53].

    Hydrogels can be classified according to different standards, including their origin or source, composition, synthesized methods, cross-linking mechanism, and responsiveness to physical and chemical stimulation (Table S1 in Supporting information) [54-62]. Intelligent hydrogels are becoming increasingly popular in drug delivery applications because they can leverage the unique characteristics of the TME or external stimuli. Unlike non-responsive hydrogels, intelligent hydrogels can change their material properties in response to various triggers such as temperature, pH, light. In the following, we introduce biomedically relevant intelligent hydrogels according to this classification.

    2.3.1   Temperature-responsive hydrogels

    Temperature changes are a simple and safe way to trigger stimuli, making them highly practical. Consequently, temperature-responsive hydrogels have found extensive application in local drug delivery systems. It has been reported that a variety of natural or synthetic materials have been used to develop in-situ thermosensitive hydrogels. These materials include, but are not limited to, CS, and synthetic block copolymers. CS is the major derivative of the partial deacetylation of chitin [63], a positively charged alkaline linear polysaccharide consisting of a random arrangement of D-glucosamine (deacetyl unit) and N-acetyl-D-glucosamine (acetyl unit) through β-1,4 glycosidic linkages [64,65]. CS can interact with β-glycerophosphate disodium salt (β-GP) to form thermoresponsive hydrogels at physiological temperature. These hydrogels remain in a liquid state for an extended period at room temperature or below, but rapidly undergoes gelation upon heating beyond 37 ℃ or above [66,67]. During the sol-gel transition, drugs are encapsulated within the hydrogel matrix and continuously released from the hydrogel surrounding the tumor site. Zhang et al. developed an injectable hydrogel system for localized in-situ treatment of nasopharyngeal carcinoma by combining cisplatin (DDP) with a thermosensitive CS hydrogel. This drug-loaded hydrogel system demonstrated remarkable thermosensitivity near body temperature and facilitated slow drug release, offering valuable insights into the application of hydrogel drug delivery systems to sensitize RT [68].

    Similarly, the synthetic block copolymers such as Pluronic F-127, poly(ε-caprolactone) (PCL)-PEG-PCL, poly(D,L-lactide-co-glycolide) (PLGA)-PEG-PLGA and PEG-PLGA-PEG can be used to produce biodegradable thermosensitive hydrogels, and have been widely studied in the biomedical field for preparing drug delivery systems, tissue repair materials, and biosensors [69,70]. These hydrogels possess the capability to encapsulate radiosensitive drugs and can be directly delivered to the lesion site via injection, thereby enhancing the local control of radiation therapy and minimizing deleterious effects on adjacent healthy tissues [71]. The PEG segment is commonly utilized for enhancing the pharmacokinetic profile, improving pharmaceutical stability, and mitigating the immunogenic and toxic effects of drugs. The hydrophobicity of PLGA or PCL chains allows for stable encapsulation of hydrophobic drugs, which can gradually degrade in vivo via hydrolysis and release the drug payload [72]. The gelation properties of thermosensitive hydrogels can vary depending on the type of triblock copolymers used. For example, compared to PEG-PLGA-PEG, PLGA-PEG-PLGA is recognized to display higher drug loading capacity and superior control release performance for drug delivery, primarily owing to its possession of a larger number of PLGA segments that can provide a greater quantity of drug carriers [73].

    2.3.2   pH-responsive hydrogels

    The low pH of tumor tissue microenvironments presents potential advantages for designing and constructing pH-responsive hydrogels. Such hydrogels can release drugs in response to acidic conditions, while minimizing the release of drugs in alkaline conditions, thereby reducing toxic side effects. This characteristic offers a promising strategy for local drug delivery using pH-responsive hydrogels. For instance, Yin et al. developed a pH-sensitive dextran hydrogel (DEX-HA gel) coated with hyaluronic acid and loaded with therapeutic drugs to enhance RT efficacy in glioblastoma treatment. They observed that the acid-sensitive Schiff base bonds in the DEX-HA macromolecules cleaved under acidic conditions, causing the release of the encapsulated nano-realgar quantum dots (QDs) coupling with 6-AN molecules (NRA QDs) from the degraded gel network structure. In vivo experiments with this hydrogel system demonstrated sustained drug release in the acidic TME of mouse glioblastoma and significantly sensitized RT [74].

    2.3.3   Light-responsive hydrogels

    Light, including NIR, visible light, and ultraviolet radiation, can induce reversible changes in the properties and structure of light-responsive hydrogels. In medicine, these hydrogels, particularly NIR-responsive ones, hold great potential for controlled drug release due to their deeper tissue penetration and ease of manipulation [75].

    The most common method for developing light-responsive injectable hydrogels used in RT sensitization is by incorporating photothermal agents into the hydrogel system. These agents absorb and emit electromagnetic radiation, generating heat that raises the temperature of the system and induces a phase transition of the thermoresponsive hydrogels [76]. Tan et al. developed an injectable hydrogel loaded with Prussian blue (PB) nanoparticles for intratumoral photothermal therapy (PTT) and RT. Upon irradiation with an 808 nm NIR laser, the embedded PB nanoparticles exhibited excellent photothermal effect, resulting in a significant temperature increase. The hydrogel underwent reversible hydrolysis and softening, leading to further release of PB nanoparticles. The photothermal effect of PB nanoparticles, combined with catalase-like activity, improved tumor hypoxia and increased RT sensitivity, leading to substantial tumor suppression without apparent toxicity [77].

    In-situ photopolymerizable hydrogel is another popular light-responsive hydrogel that can trigger in-situ crosslinking and gelation at the administration site under ultraviolet or visible light irradiation, ensuring sustained local delivery. One example of a light-responsive hydrogel is the PEG dimethacrylate (PEG-DMA) hydrogel. It can be locally injected into a tumor and quickly crosslinked in situ through photopolymerization using ultraviolet light, facilitating sustained localized delivery [78]. Danhier et al. developed an injectable PEG-DMA hydrogel that can be photopolymerized for local delivery of temozolomide (TMZ), serving as a postoperative treatment option for glioblastoma [79].

    It is noteworthy that the tissue penetration depth of light remains limited to superficial tumors, thereby posing a challenge to the application of photo-responsive hydrogels for deep-seated tumors.

    2.3.4   Others

    In addition to the intelligent hydrogels mentioned above, other stimulus-responsive in-situ hydrogels have been studied for RT sensitization. Ion-responsive hydrogels are a type of hydrogel that can respond to and interact with external ionic stimuli in the environment. These hydrogels undergo sol-gel phase transitions in the presence of ions such as Ca2+, Mg2+, and their physical and chemical properties can be precisely controlled by modulating factors such as ion type and concentration. Sodium alginate (ALG) is a classical ion-responsive polymer that can be cross-linked in aqueous solutions with multivalent cations, such as Ca2+, Ba2+, and Sr2+, to form stable hydrogels under mild conditions [36,80]. Liu and colleagues developed an in-situ hydrogel system based on ALG to improve the effectiveness of RT. In vivo gelation experiments revealed that the ALG solution quickly formed a gel when exposed to Ca2+ and remained uniformly distributed within the tumor. In vivo experiments have shown long-term relief from tumor hypoxia and complete tumor elimination at low RT doses [81]. ALG's poor cell adhesion can be addressed through modifications. Virgilio et al. used Arg-Gly-Asp (RGD)-modified alginate-based hydrogel as a trap to attract glioblastoma cells and completely eliminated them with a radiation dose of 25 grayunit (Gy) and prevented recurrence while maintaining healthy brain tissue [82]. Gu et al. developed an in-situ hydrogel by grafting mussel-inspired catechol with bioadhesive properties onto ALG (DAA), and "fixed" the radiosensitizer Ta in the tumor site. Their findings indicate that this hydrogel effectively suppressed tumor growth under photothermal-assisted RT without causing any deformities or damage to surrounding normal tissue [83].

    Liu et al. designed an ATP-responsive hydrogel based on ALG by conjugating ALG with ATP-specific aptamers (Aapt) and hybridizing CpG oligodeoxynucleotides (CpG ODN) with Aapt. The ALG-based hydrogel can form in the presence of Ca2+. During local RT, competitive binding between released ATP from dying tumor cells and Aapt triggers an ATP-responsive release of CpG ODN, greatly enhancing the system's anti-tumor immune capacity and subsequently inhibiting tumor growth or metastasis [84].

    External beam radiation is the most common method in the administration of RT, in which radiation emitted by a radioactive source passing through a fixed distance outside the body and irradiates the tumor. Although advanced technology has substantially increased the therapeutic efficacy of RT, it still suffers from some constraints. The constraints include tolerance of normal tissues [85] and tumor resistance to RT [86]. Nearby normal tissues limit the total radiation dose, and tumor resistance directly reduces the efficiency of RT. Many studies have shown that the combination of hydrogels and radiosensitizers could achieve long-term local retention and sustained release, hence improving RT efficacy [26,87,88]. Radiosensitizers increase tumor cell sensitivity to radiation by enhancing radiation-induced primary damage, inhibiting damage repair, and interfering with the cell cycle, resulting in achieving enhanced RT effects [19,89]. According to the linear dimension of the particles, radiosensitizers can be divided into three types: small molecules, biomacromolecules, and nanomaterials [90].

    Oxygen is a key element in the process of RT-induced tumor cell killing, which can fix DNA free radicals (DNA•) generated during RT and prevent cellular repair of DNA damage, leading to DNA breakage and permanent damage [91]. However, widespread hypoxia in solid tumors limits the effect of RT to kill tumor cells [92,93]. Previous studies have demonstrated that oxygen can be used as a radiosensitizer. Therefore, direct supplying of oxygen to the tumor has been proposed as a solution to the problem of tumor hypoxia [94,95]. Although hydrogels have been rarely reported for delivering therapeutic gasses, there are reports showing that hydrogels can be utilized to load oxygen carriers, such as perfluorocarbons (PFC), and efficiently transported oxygen to the tumor [87,96]. As shown in Fig. S1 (Supporting information), Ding et al. constructed an injectable composite hydrogel system based on monomethoxy PEG (mPEG)-PLGA and perfluorooctyl bromide (PFOB) to accomplish local delivery and improve oxygen supply to the tumor [97].

    PFOB is a typical member of PFC for oxygen delivery. This system showed a strong oxygen loading capacity and slowly released entrapped oxygen from the hydrogel over 3 h at body temperature. Oxygen-enriched composite hydrogel combined with RT effectively relieved the hypoxic TME and significantly suppressed tumor growth in 4T1 tumor-bearing mice. Additionally, the system has the potential to achieve synergistic enhancement of chemo-RT by encapsulating chemotherapeutic drugs in future work. Nishioka et al. investigated sodium hyaluronate containing hydrogen peroxide as a radiation sensitizer, utilizing its ability to elevate intratumoral oxygen levels and reduce peroxidase activity. They developed a novel gelatin-based hydrogel system with hydrogen peroxide that demonstrated prolonged radio-modulating effects up to 72 h after administration, showing promising therapeutic outcomes in tumor treatment [98-100]. Additionally, hydrogels can deliver hypoxic cytotoxins to the TME. Hypoxic cytotoxins selectively target cells under hypoxia and reduce their proportion in tumors, so as to improve the efficacy of RT [101]. This property effectively distinguishes tumor tissues from normal tissues. Tirapazamine (TPZ) is a typical hypoxia-specific cytotoxin that can be specifically reduced in hypoxic cells, forming radicals and causing DNA double-strand breaks through a topoisomerase II-dependent process [102,103]. Wang et al. constructed a Bi-ALG-based multi-functional hydrogel (Bi2S3/ALG@TPZ) as a radiosensitizer (Fig. S2 in Supporting information) [26]. This Bi2S3/ALG@TPZ hydrogel demonstrated a highly effective anti-tumor impact of RT via the complementary anti-tumor effects of hypoxia-specific TPZ cytotoxicity and RT-induced tumor death.

    Hydrogels have been investigated as a regional and intratumoral delivery system for other small molecule drugs to be applied in combined chemo-radiotherapies. Encapsulating chemotherapeutic drugs in a hydrogel can limit drug distribution to normal tissues, enhance tumoral drug retention, and improve tumor responses to irradiation while reducing chemotherapeutic drug-induced toxicity in normal tissues [104]. Paclitaxel (PTX) is a chemotherapeutic drug that has the potential to be a powerful radiosensitizing agent due to its ability to arrest cells in the radiosensitive G2 and M phases and stimulate reoxygenation of hypoxic tumor cells [105-107]. Banerjee et al. developed a liposome-in-gel-PTX (LG-PTX) system by incorporating PTX-loaded liposomes into a gellan hydrogel to allow localized PTX administration [88]. They found that the percentage of apoptotic cells in B16F10 melanoma cell line was significantly increased when LG-PTX and fractionated radiation were used together. The combination of LG-PTX with RT increased radiosensitization while not increasing damage to normal tissue in B16F10 tumor-bearing mice. In addition, other chemotherapeutic agents, such as cytarabine (Ara-C) [108] and DDP [109,110], have been studied in combination with localized tumor therapy. Zhang et al. synthesized an injectable CS/DDP hydrogel system formed by a thermosensitive CS hydrogel and DDP that could be used in combination with RT to treat nasopharyngeal carcinoma in situ [68]. It was found that sustained slow release of DDP from CS hydrogels increased the percentage of cells in the G2/M phase, thereby improving the sensitivity of tumor cells to RT, reducing tumor metabolism, angiogenesis and proliferation, and ultimately increasing the apoptotic induction. The combination of CS/DDP hydrogel and RT showed tumor growth inhibition, lower side effects, and longer survival time in 5–8F xenografted BALB/c nude mice. Lin et al. encapsulated Ara-C in an injectable hydrogel delivery system (Ara-HA-Tyr) consisting of hyaluronic acid-tyramine conjugates (HA-Tyr) and investigated its sensitization in cancer cells [111]. They found that Ara-HA-Tyr could block the cell cycle in the G2/M phase, resulting in enhanced RT, increased apoptosis of lung tumor cells, and inhibited tumor growth.

    Hydrogels can potentially load various medicines concurrently to improve RT effect. A dual drug delivery system (PDMP) was prepared through the combination of a DDP-containing thermosensitive hydrogel (PEG-PCL-PEG/DDP, PECE/DDP) and PTX-loaded polymeric micelles for the simultaneous delivery of DDP and PTX [112]. PDMP combined with RT treatment was beneficial in inducing apoptosis, inhibiting tumor growth, and prolonging survival.

    The use of hydrogels in the combination of targeted therapy and RT has also attracted the interest of researchers. Anlotinib (AL) hydrochloride is a small-molecule tyrosine (Tyr) kinase inhibitor that can block angiogenic and proliferative signaling [113,114]. Local application of AL during RT may reduce tumor hypoxia and improve RT-induced resistance. Lin et al. encapsulated AL within HA-Tyr hydrogel (AL-HA-Tyr) to enable sustained release, alleviate tumor hypoxia, and increase the RT efficacy [115]. Compared to RT alone, AL-HA-Tyr combined with RT significantly improved hypoxia, inhibited tumor growth, and prolonged the survival of mice harboring Lewis lung carcinoma tumors, while reducing systemic side effects. Similarly, the Tyr kinase inhibitor sunitinib can also enhance radiosensitivity when combined with RT by inducing cell cycle arrest, DNA damage, and reducing angiogenesis. Fu et al. synthesized a matrix metalloproteinase (MMP)-responsive hydrogel containing sunitinib nanoparticles, which effectively increased radiation sensitivity and prevented local breast cancer recurrence [116].

    Along with small molecules, biomacromolecules such as proteins, peptides, and nucleotides are also capable of acting as radiosensitizers.

    Endostatin (ES), a 20 kDa proteolytic fragment of the C-terminal non-collagen (NC1) domain of collagen type XVIII, is an endogenous inhibitor of angiogenesis that can specifically inhibit endothelial cell proliferation and angiogenesis [117,118], alleviate tumor hypoxia, and enhance sensitivity to RT [119,120]. As shown in Fig. S3 (Supporting information), Lin et al. synthesized an ES-loaded hydrogel drug (ES/HA-Tyr) using HA-Tyr-as a carrier to concentrate ES in tumor tissues while delivering a modest amount to normal tissues [121]. ES was continuously released from the injectable hydrogel and showed enhanced inhibition of proliferation of human umbilical cord vascular endothelial cells (HUVECs) ability to reduce hypoxia in tumor tissue, provide powerful synergistic therapeutic effects in RT, and had significantly fewer side effects compared to free ES. ES sustained released from the injectable hydrogel and showed a stronger ability to inhibit the proliferation of human umbilical vascular HUVECs, reduce hypoxia in tumor tissues, and provided powerful synergistic therapeutic effects in RT. In Lewis lung cancer xenograft models, the combination of ES/HA-Tyr and RT effectively enhanced anti-tumor effects and significantly reduced side effects compared to free ES.

    Cyclooxygenase 2 (COX-2) inhibitors were found to enhance tumors' response to radiation in several studies [122-124]. Liu et al. designed a supramolecular hydrogel (N-P hydrogel) by a coassembly of DDP and nonsteroidal anti-inflammatory drug (NSAID)-capped short peptides, in which naproxen (Npx) was used to inhibit the activity of COX-2, and D-Phe-D-Phe and D-Tyr were used to form hydrogels [125]. It has been demonstrated that N-P hydrogel could block the cell cycle in the G2/M phase, sensitize cancer cells to ionizing radiation (IR), and inhibit COX-2 activity and expression to promote apoptosis.

    PTEN is a tumor suppressor gene that can inhibit the activity of phosphatidylinositol-3-kinase (PI3K) through lipid phosphatase function and plays a crucial role in cancer occurrence [126,127]. Meanwhile, loss of PTEN leads to the up-regulation of phosphorylated-Akt and Bcl-2, resulting in RT-resistant cancers [128]. There is considerable evidence that PTEN gene therapy can effectively treat chemoresistant or radioresistant patients when combined with chemotherapy or RT [129,130]. Hirao et al. reported a microsphere of cationized gelatin hydrogels incorporating PTEN plasmid DNA (GelaTen) that can induce the expression of PTEN over time [131]. Combination therapy with GelaTen and RT suppressed tumor growth significantly, and in the subcutaneous PC3-Bcl-2 prostate cancer tumor-bearing mice models, 30% of tumors (3 out of 10 mice) completely vanished when treated with GelaTen and RT. The combination of GelaTen and RT enhanced the efficacy of radiation, increased apoptosis induction, and promoted the effects of tumor growth suppression.

    The development of nanoparticles has provided novel attempts and has expanded the horizon for radiosensitizers. Previous studies have demonstrated that high-atomic-based nanomaterials have become a well-known radiosensitizer. They can strongly absorb radiant energy and release it via the emission of secondary electrons such as photons, Auger electrons and Compton electrons [132,133], leading the IR energy to be deposited at the local site [134,135]. In addition to using high photoelectric absorption to achieve physical dose enhancement, they can catalyze radical reactions to enhance the effects of radiation, disrupt the cell cycle and inhibit DNA repair during the biological phase. In addition to nanoparticles containing high-Z elements, other types of nanoparticles such as selenium and iron nanoparticles have also shown the ability to enhance RT by different mechanisms. Although nanoparticles can be used as drug delivery carriers themselves, hydrogels surpass them in terms of drug loading capacity and drug release duration. Additionally, hydrogels can be utilized to encapsulate nanoparticles, creating hybrid biomaterial systems that enable controlled drug delivery. These systems not only preserve the structural integrity and functionality of the embedded nanoparticles but also afford enhanced flexibility to augment overall therapeutic outcomes [136].

    3.3.1   High-atomic-based nanomaterials

    Gold (Z = 79) nanoparticles (AuNPs) have been investigated as typical nanomaterials radiosensitizers for their high X-ray absorption and radiation concentration [137,138]. Hainfeld et al. demonstrated the radio enhancement effect of 1.9 nm diameter AuNPs in mice carrying subcutaneous EMT-6 breast cancer for the first time [139]. Pan et al. proposed that gold nanoparticles may generate reactive oxygen species (ROS) and potentially lead to oxidative stress amplified by mitochondrial damage [140]. Several studies have shown that the radiosensitizing effect of AuNPs is related to nanoparticle size, surface functionalization modification and distribution [141-143]. Although the radiosensitizing effect of AuNPs has been confirmed, there remain several obstacles for future application, including the opsonization and uptake of the NPs by macrophages in the spleen and liver, intratumoral heterogeneity, and a relatively low rate of clearance from circulation and tissues [144,145].

    Hydrogels have been widely explored as vehicles for AuNPs presenting a potential solution to the aforementioned challenges. Moreover, concurrent delivery of AuNPs and other drugs enables the combination of RT and chemotherapy. Zhang et al. developed an F127 thermosensitive hydrogel loaded with DOX PEG modified AuNPs. This hydrogel was able to continuously release the nanoparticles for more than 12 h after being injected into a tumor [146]. Those AuNPs-loaded hydrogels could greatly improve RT efficacy of tumors under X-ray irradiation, and the effect was amplified when DOX was added. Similarly, Shakeri-Zadeh et al. constructed a nanocomplex (ACA) by co-incorporating DDP and AuNPs into an alginate hydrogel [147]. The ACA nanocomplex achieved a synergistic effect of AuNPs, DDP and radiation, which greatly inhibited tumor growth. In addition, AuNPs can be used as a light-responsive nanomaterial to generate heat under laser irradiation for PTT [148]. Moustakis et al. proposed an alginate-based hydrogel co-loaded with DDP and AuNPs (ACA) to combine PTT, chemotherapy, and RT [149,150]. AuNPs in hydrogels can not only transform photon energy into heat for effective thermal ablation of cancer under laser irradiation, but they can also significantly enhance the efficacy of RT via high Z-radiation sensitization. The intracellular ROS level was elevated by 4.4-fold, and the gene expression of Bax was up-regulated by 4.5-fold under 532 nm laser irradiation and 6 MV X-ray. This hydrogel provided a thermo-chemo-radio treatment that inhibited tumor growth in the mouse CT26 colon cancer.

    In addition to gold, bismuth (Z = 83) and tantalum (Z = 73) have also can be added to the hydrogel as a radiosensitizer. Wang et al. introduced Bi3+ into alginate and formed Bi2S3 NPs by in situ reaction with Na2S to form a Bi2S3/alginate (ALG) hydrogel [26]. Bi2S3 NPs could not only convert NIR light energy into heat for effective thermal ablation of cancer but also increase the local radiation dose through high-Z radiosensitization, thus significantly enhancing radiation damage. Similarly, Gu et al. loaded biocompatible polyvinylpyrrolidone-modified tantalum nanoparticles (Ta@PVP NPs) onto dopamine-modified ALG to form an in situ hydrogel (Fig. S4 in Supporting information) [67]. This hydrogel has been shown to significantly enhance the efficacy of RT in oral squamous cell carcinoma, demonstrating its potential as a promising radiosensitizing agent.

    3.3.2   Iron nanoparticles

    Iron nanoparticles can also serve as radiosensitizers, which can be used as Fenton reaction catalysts to induce cell death [151,152] and boost the therapeutic efficacy of RT. Hong et al. developed an agarose-based injectable hydrogel containing FeGA for radiation sensitization and photothermal delivery [51]. The hydrogel acted as a FeGA storage. FeGA-mediated PTT generated mild heat locally under an 808 nm laser irradiation, causing agarose hydrogel dissolution; then, FeGA nanomaterials diffused into the local TME. Importantly, the Fenton reaction catalyzed by Fe2+ can produce a large amount of OH which can cause substantial mitochondrial damage, reduce RT resistance, and increase tumor cell radiation sensitivity [51]. The combination of PTT and RT through the light-controlled hydrogel system has shown significant therapeutic effects. Besides, the presence of Sn2+/Sn4+ and Fe2+/Fe3+ redox pairs in bimetallic oxides such as tin-iron oxygen (SnFe2O4, denoted as SFO) allows SFO to show excellent OH production via Fenton-like reactions, while also reducing glutathione (GSH) and catalyzing endogenous H2O2 to produce O2 to modulate the TME for enhanced RT cancer treatment [153]. Huang et al. developed an injectable agarose hydrogel containing SFO nanoparticles (SIS) for combined RT and photothermal treatment [154]. The agarose hydrogel underwent reversible hydrolysis and softening under a NIR laser at 808 nm, and SIS diffusion into local TME increased radiosensitivity by depleting intracellular GSH, as well as catalyzing the conversion of H2O2 to O2. This hydrogel effectively combined low-dose RT and PTT and greatly increased the efficacy of cancer RT in a mouse tumor model without significant toxic effects.

    3.3.3   Other types of nanomaterials

    Selenium (Se) has been shown to enhance the anticancer efficacy of X-rays by activating diverse ROS-mediated signaling pathways [155], and thus Se-containing hydrogels have been investigated in RT sensitization. Chen et al. synthesized a thermosensitive hydrogel based on PLGA-PEG-PLGA loading sorafenib (SOR) and SeNPs (Fig. S5 in Supporting information) [40]. The composite exhibited a sol-to-gel transition and steadily released SOR and SeNPs after being injected into HepG2 tumor-bearing nude mice. The result showed this hydrogel enhanced tumor sensitivity to X-ray irradiation and improved tumor suppression.

    Prussian blue nanoparticles (PBNPs) act as photothermal therapeutic agents while also possessing peroxidase-like activity, which can decompose endogenous H2O2 and produce large amounts of O2 to alleviate tumor hypoxia and achieve enhanced radiosensitivity [77]. Therefore, Tan et al. developed an injectable hybrid light-controlled hydrogel system by encapsulating PBNPs in agarose hydrogel. The hydrogel could effectively conduct combination thermo-RT to eliminate primary tumors, and greatly improved the therapeutic effect of RT.

    Brachytherapy, also known as internal beam radiation therapy, is an important form of radiation therapy that involves placing a sealed radioactive source in or near the area that needs to be treated. Compared with external beam radiation therapy, brachytherapy can be delivered closer to tumor tissues for continuous irradiation, allowing for higher local doses within tumor tissues while reducing the exposure to adjacent normal structures and resulting in fewer complications [156]. Cobalt-60, iridium-192, cesium-137, and iodine-125 are commonly used radioactive sources over these years, because their radiation has strong ionizing effects and biological effects while having a weak penetrating ability. Brachytherapy is usually used for prostate cancer [157], breast cancer [158], cervix cancer [159], intraocular tumors [160], and so on. However, brachytherapy also has certain limitations, such as complex placement and removal procedures, toxic effects of radioisotopes led by systemic administration, uneven dose distribution within the tumor, and leakage from the tumor site. An increasing number of studies have shown that the use of radioisotope-loaded biodegradable hydrogels can overcome these deficiencies and improve the safety and efficacy of brachytherapy [41,161]. Hydrogels can be used to load larger doses of radioisotopes and enhance the accumulation and retention of radioisotopes in the tumor region by intratumoral or peritumoral injection. In addition, hydrogels can serve as a platform for synergistic therapy of brachytherapy and other treatment modalities to further enhance efficacy.

    Hydrogels as a biocompatible and biodegradable material have been used as delivery carriers for different types of radioisotopes. For example, Shih et al. reported brachytherapy by direct infusion of 188Re-EL/hydrogel (188Re-ELH) consisting of PEG-PLGA-PEG with ECD-labeled 188Re [162]. 188Re-ELH resulted in radioactivity retention for more than 48 h and enhanced the therapeutic efficacy of 188Re-EL at the tumor site. In addition, hydrogels have been used to load 131I to kill tumor cells by consistently producing low-penetrating β particles. Azab et al. prepared a 131I–NC loaded Ct hydrogel (131I–NC–Ct) for primary therapy or surgical adjuvant therapy of breast cancer [163,164]. After being injected into tumor mice models, those 131I–NC–Ct biodegradable hydrogel implants induced significant growth delay in tumors and prevented recurrence and metastasis. Other studies have found that 90Y-loaded hydrogels also showed great potential for tumor brachytherapy [165,166].

    It is worth noting that local targeted delivery of radionuclides through hydrogels can prolong the tumor retention of radionuclides and thus kill more tumor cells. Kim et al. synthesized a temperature-sensitive hydrogel (GEL) to distribute indium-111 (In-111) as micron-size radioactive RT sources [167]. The release speed of In-111 was faster in the first 10 h and slower at later time points, leading 49% In-111 retention after 24 h and 44% retention after 48 h. The Yang group found that hydrogel microparticles based on 131I-labeled HA derivatives can prolong local retention beyond 3 weeks [168].

    The application of hydrogels in brachytherapy combination therapy has also been investigated in recent years. Hydrogels can co-load with radioisotopes (such as 131I, 188Re-Tin) and chemotherapeutic agents (such as CPT and DOX) to improve efficacy [69]. Liu et al. reported a hybrid BSA/CMC nano gel formed by the self-assembly of carboxymethylcellulose (CMC) and bovine serum albumin (BSA) for the co-delivery of the radionuclide 131I and CPT [169]. The combination therapy achieved a significant synergistic effect and effectively inhibited primary tumor growth in a C57BL/6 LLC tumor model. Shieh et al. reported a thermosensitive hydrogel containing 188Re-Tin colloid and pegylated liposomal DOX (Lipo-Dox) [70]. This co-delivery method had a good therapeutic impact against murine BNL liver tumor in mice with hepatocellular carcinoma (HCC) and did not cause more toxic effects. As shown in Fig. S6 (Supporting information), Dong et al. constructed a novel thermosensitive micellar-hydrogel formed through thermo-induced self-aggregation of DOX-loaded micelles solution with 131I labeled HA [69]. When the 131I and DOX co-loaded hydrogel was injected into the tumor site, it could exhibit a sol-to-gel transition, fixing 131I at the injection site and continuously releasing DOX to enhance the radiation response. Besides, Azab et al. reported that TMZ and 131I could be co-loaded in an injectable CS hydrogel and completely fill in the surgical cavity in brain tumors [170]. The hydrogel acting as a carrier allowed TMZ consistently to release over 48 h, while 131I emitted a homogeneous radiation dose to promote the local effect in the tumor site over 42 days, which significantly inhibited tumor growth and improved survival in mice with established tumors.

    Hydrogels have been utilized to load photothermal agents for the combination of phototherapy and RT. Phototherapy is a viable modality for tumor ablation using light, photosensitizers, and oxygen to stimulate photosensitizers and has been shown to have a powerful RT-sensitizing effect [171,172]. Phototherapy includes PTT and photodynamic therapy (PDT). PTT causes localized thermal damage, while PDT generates ROS to damage local tissue [173,174]. Photothermal heating can overcome hypoxia-related radioresistance and increase the radiosensitivity of tumors by promoting tumor blood flow. Liu et al. investigated the combination of PTT with brachytherapy [76]. They designed an in situ PEG double acrylates (PEGDA)-based hybrid hydrogel system containing 131I-labeled copper sulfide (CuS/131I) nanoparticles (CuS/131I NPs). The CuS/131I NPs could be heated up under a 915 nm near-infrared laser, and the CuS/131I-PEGDA/AIPH solution rapidly transformed into a gel, thus CuS/131I NPs could be immobilized at the injection site. The combination therapy significantly inhibited tumor growth and prolonged the survival of 4T1 tumor-bearing mice for more than 60 days. The combination of PDT and radionuclide brachytherapy via hydrogel has also demonstrated powerful anti-tumor effects [76]. Liu et al. developed a cysteine-containing ELP (cELP) based hydrogel as a photoradiation-controlled intratumoral depot (PRCITD) to deliver photosensitizer chlorin-e6 (Ce6) and radionuclide [175]. Ce6 generated ROS under 660 nm light which induced cELP cross-linking into stable hydrogels and improved radionuclide retention within the tumor. In addition, ROS can induce tumor cell death and improve overall tumor response to RT. This treatment strategy considerably inhibited cancer growth in a Ce6 dose-dependent manner and minimized side effects.

    In addition to chemotherapy and phototherapy, many other strategies can be combined with brachytherapy through hydrogels to promote the antitumor effects of ionizing radiation. For instance, the SmacN7 peptide conjugated with cell membrane-permeable oligosarginine (denoted as SmacN7-R9) was a radiosensitizer that could promote caspase activation pathways by blocking the binding between caspase-9 and XIAP and can be loaded in radioiodinated thermosensitive supramolecular hydrogel to enhance the radiosensitivity of cancer cells [176]. Improving tumor oxygenation by catabolizing endogenous H2O2 and alleviating tumor hypoxia is also a strategy to enhance radiation damage. Liu et al. labeled catalase (Cat) with the therapeutic radioisotope 131I (131I-Cat), and mixed it into the alginate-based hydrogel (131I-Cat/ALG) [81]. 131I-Cat was distributed homogeneously throughout the tumor and rapidly induced the breakdown of endogenous tumor H2O2 to O2 to increase tumor oxygenation after being injected into the tumor site. This 131I-Cat/ALG could effectively overcome tumor hypoxia and greatly improve the efficacy of 131I in animal models. They further used 131I-Cat/ALG in conjunction with the immune-adjuvant CpG or a cytotoxic T lymphocyte associate protein-4 (CTLA-4) checkpoint inhibitor, which both triggered remarkable systemic anti-tumor therapeutic responses and significantly prevented cancer metastasis.

    Immunotherapy has been considered as one of the most promising cancer therapies, and hydrogels may also facilitate the combination of RT and immunotherapies to enhance radiation-induced immune responses and improve treatment efficacy. Immunotherapy focuses on modulating the immune system to eradicate cancer cells and prevent recurrence and metastasis. With the advent of immunotherapy in oncology therapy [177], RT has been abundantly demonstrated to act not only as a local cytotoxic agent but also to have multiple immune-modulatory effects on the TME and to improve systemic antitumor immunity [178,179]. There is evidence that local RT can trigger antigens release, activate anti-tumor T cells, and enhance the infiltration of activated T cells to reject tumors [180]. Hydrogels are pivotal in the integration of RT and immunotherapy, acting as versatile drug delivery platforms that regulate the TME, enhance drug delivery, and synergistically augment the impact of both treatments. This comprehensive approach leads to a more effective treatment strategy for tumors [181-183]. The use of cytokines and immune adjuvants is highly effective in enhancing anti-tumor immune responses and promoting radiation-induced immunogenic cell death (ICD). Liu et al. encapsulated interferon-α2b (IFN-α2b) into macroporous hydrogels as an enhancement factor to stimulate T cells and used low-dose irradiation to increase the accumulation of T cells in tumor regions [184]. Implanting hydrogels locally offers a safe and controlled method for sustained release of IFN-α2b, increasing the susceptibility of gastric cancer cells to T-cell-mediated cytotoxicity. Additionally, low-dose irradiation facilitates the accumulation and infiltration of T-cells in subcutaneous tumors. The integration of IFN-α2b-loaded hydrogels with RT presents an innovative approach that enhances the anti-cancer efficacy of T-cells against gastric cancer. Chen et al. designed a hydrogel that can continuously release stimulator of interferon genes (STING) agonist ADU-S100 (ADU) and adenovirus-PD1 (AAV-PD1) locally (Fig. S7 in Supporting information). ADU activates the STING pathway to improve tumor immunogenicity, while AAV-PD1 restores subsequent therapeutic immune responses. When combined with RT, this hydrogel demonstrates a remarkable ability to enhance the sustained infiltration of T-cells while restoring their effector functions. Consequently, it elicits robust anti-tumor immune responses and effectively suppresses tumor growth. Furthermore, the treatment induces durable immune memory to prevent the recurrence of GBM [185]. Liu et al. reported a smart hydrogel that released CpG oligonucleotides in response to in situ ATP [84]. The smart hydrogel could release immune adjuvants CpG upon sensing ATP leaked from dead tumor cells after RT. The released CpG has been shown to enhance anti-tumor immune therapy for RT. Furthermore, Researchers have attempted to improve RT and inhibit tumor recurrence by remodeling macrophages to reconstruct immunosuppressive TME. Liu et al. developed a novel Toll-like receptor (TLR) 7/8 agonist-conjugated radiosensitive peptide hydrogel that suppressed M2 macrophages, repolarized TAMs to the M1 phenotype, activated anti-tumor immunity, and downregulated regulatory T cells (Treg) to enhance RT and improve tumor treatment outcomes [186]. These researchers ingeniously designed the combination of radiation therapy and immunotherapy by using an implantable hydrogel, which appeared to be a new route in better cancer treatment.

    Research on cancer vaccines has been a focused and trending issue in recent years. Cancer vaccines control or eliminate tumors by enhancing or reactivating the patient's immune system [187,188]. Tumor antigens utilized in vaccines come in a variety of forms, including tumor cells [189], tumor-associated proteins or peptides [190], and tumor antigen-expressing genes [191]. Hydrogels can serve as a vaccination platform and be engineered to produce a powerful and long-lasting response in modulating immune cell interactions [192]. In addition, RT targeted to the tumor has the potential to turn the irradiated tissue into a vaccine in situ [193]. For example, Bruyns et al. developed a strategy of hydrogel-based combined vaccination that used in vivo tumor irradiation as a source of tumor antigens for DC vaccines and an exogenous source of GM-CSF [194].

    RT is currently an important treatment in oncology, but its clinical efficacy is limited by RT resistance and tolerance of normal tissue. Over the last few decades, hydrogels have been intensively explored as a promising material in the biomedical field for their low toxicity, excellent biocompatibility, and biodegradability. The incorporation of hydrogels for the delivery of radiosensitizers and other therapeutic agents with varying sizes and modes of action has significantly enhanced tumor suppression while reducing systemic toxicity. Hydrogels in brachytherapy not only offer the radionuclide sources to overcome brachytherapy's limitations, but also serve as a platform for combinatorial treatment with local chemotherapy, immunotherapy, and phototherapy. In addition, immunotherapy and RT have shown the potential for synergistic treatment by using hydrogels. These advancements have highlighted the potential of hydrogels in improving the efficacy of RT.

    Despite recent advancements in hydrogel-based RT combination therapy, current efforts remain primarily focused on basic research. Although the therapeutic potential of hydrogels has been explored in cancer patients (NCT02891460, NCT02307487), the current emphasis on hydrogel-based systems combined with RT remains primarily on fundamental research. While progress has been achieved, additional investigations are necessary to facilitate the translation of these findings into clinical applications. From a clinical perspective, there are still challenges and issues need to be addressed. Hydrogels should maintain their structural integrity and functionality over an extended period to allow for sustained drug release or prolonged therapeutic effects. However, challenges arise from potential degradation or mechanical instability caused by enzymatic degradation, hydrolysis, or environmental changes. Achieving precise and controlled release of therapeutic agents from hydrogels is vital for optimizing treatment outcomes. Nevertheless, accurately controlling the biodegradation rate of hydrogels to achieve sustained, predictable, and adjustable drug release profiles poses a challenge. Furthermore, incorporating external stimulus-responsive systems adds complexity that must be addressed to enable triggered release. Tumor complexity and heterogeneity also make hydrogel design highly complex, necessitating further optimization of their synthesis and preparation processes for improved drug delivery efficiency and stability. More research is also required to explore the application of hydrogel-based drug delivery systems for RT sensitization, including optimal combination strategies and radiation dose selection. Future studies should prioritize resolving these challenges and promoting the clinical application of hydrogel-based drug delivery systems.

    In conclusion, leveraging the potential of hydrogels presents a transformative opportunity to revolutionize cancer treatment strategies, leading to improved patient prognosis and reduced treatment-related challenges.

    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.

    This work was supported by Funds of Sichuan Province for Distinguished Young Scholar (No. 2021JDJQ0037), Key Research and Development Program of Sichuan Province (No. 2023YFS0153), and 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (No. ZYYC08002).

    Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2023.109225.


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  • Figure 1  Classic chemical structures of compositions of hydrogels.

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  • 发布日期:  2024-08-15
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