Citation: Yi Cao, Xiaojiao Ge, Yuanyuan Wei, Lulu He, Aiguo Wu, Juan Li. Tumor microenvironment-activatable neuropeptide-drug conjugates enhanced tumor penetration and inhibition via multiple delivery pathways and calcium deposition[J]. Chinese Chemical Letters, ;2024, 35(4): 108672. doi: 10.1016/j.cclet.2023.108672 shu

Tumor microenvironment-activatable neuropeptide-drug conjugates enhanced tumor penetration and inhibition via multiple delivery pathways and calcium deposition

Yi Cao ^{a, b, c} ,
Xiaojiao Ge ^{a, c} ,
Yuanyuan Wei ^{a, c} ,
Lulu He ^{a, c} ,
Aiguo Wu ^{a, c, *,} ,
Juan Li ^{a, c, *,}

a.
Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, Zhejiang International Cooperation Base of Biomedical Materials Technology and Application, Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Materials and Devices, Ningbo Cixi Institute of Biomedical Engineering, Zhejiang Engineering Research Center for Biomedical Materials, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, China
b.
University of Chinese Academy of Sciences, Beijing 100049, China
c.
Advanced Energy Science and Technology Guangdong Laboratory, Huizhou 516000, China

aiguo@nimte.ac.cn

lij@nimte.ac.cn

Received Date: 9 March 2023
Revised Date: 31 May 2023
Accepted Date: 8 June 2023
Available Online: 9 June 2023

Figures(4)

Peptide-drug conjugates have achieved considerable development and application as a novel strategy for targeted delivery of anticancer drugs. Bioactive peptides induced calcium deposition can irreversibly assist inhibition of tumors. However, active regulation of calcium level through signal transduction of bioactive substances has not been reported yet. In this study, novel neuropeptide-doxorubicin conjugates (NP-DOX) with lysosome-specific acid response were described for neuropeptide Y₁ receptor (Y₁R)-overexpressed triple-negative breast cancer. The delivery mechanism of NP-DOX was clarified that diverse pathways were involved, including intracellular and intercellular transport. Importantly, up-regulation of Y₁R-mediated intracellular calcium level via second messenger inositol triphosphate was presented in NP-DOX treated MDA-MB-231 cells. In vivo antitumor efficacy demonstrated that NP-DOX showed less organ toxicity and enhanced tumor inhibition benefited from its controlled release and Y₁R-mediated calcium deposition, compared with free DOX. This bioconjugate is a proof-of-concept confirming that neuropeptide-mediated control of signaling responses in neuropeptide-drug conjugates enables great potential for further applications in tumor chemotherapy.
- Neuropeptide-drug conjugate,
- Tumor penetration,
- Calcium deposition,
- Tumor inhibition,
- Triple-negative breast cancer
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