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

作     者：Yi Cao Xiaojiao Ge Yuanyuan Wei Lulu He Aiguo Wu Juan Li Yi Cao;Xiaojiao Ge;Yuanyuan Wei;Lulu He;Aiguo Wu;Juan Li

作者机构：Ningbo Key Laboratory of Biomedical Imaging Probe Materials and TechnologyZhejiang International Cooperation Base of Biomedical Materials Technology and ApplicationChinese Academy of Sciences(CAS)Key Laboratory of Magnetic Materials and DevicesNingbo Cixi Institute of Biomedical EngineeringZhejiang Engineering Research Center for Biomedical MaterialsNingbo Institute of Materials Technology and EngineeringChinese Academy of SciencesNingbo 315201China University of Chinese Academy of SciencesBeijing 100049China Advanced Energy Science and Technology Guangdong LaboratoryHuizhou 516000China 

出 版 物：《Chinese Chemical Letters》 (中国化学快报（英文版）)

年 卷 期：2024年第35卷第4期

页      面：292-297页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 0703[理学-化学] 10[医学] 

基　　金：financially supported by the Key R&D Program of Zhejiang Province (No.2020C03110) the National Natural Science Foundation of China (Nos.T2222021, 32011530115,32025021) the Science&Technology Bureau of Ningbo City (Nos.2020Z094, 2021Z072) Excellent Member of Youth Innovation Promotion Association Foundation of CAS (No.Y2021079) 

主　　题：Neuropeptide-drug conjugate Tumor penetration Calcium deposition Tumor inhibition Triple-negative breast cancer 

摘      要：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 Y_1 receptor(Y_1R)-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 Y_1 R-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 Y_1R-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.