A pH-responsive prodrug delivery system of 10-HCPT for controlled release and tumor targeting

Abstract

Yang Liu,1–3 Dan Li,2 Xinhong Guo,2 Haiwei Xu,2 Zhi Li,2 Yanling Zhang,2 Chuanjun Song,4 Ruhan Fan,2 Xing Tang,1,* Zhenzhong Zhang2,* 1Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 2Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 3Department of Pharmaceutics, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan, Zhengzhou, 4Department of Organic Chemistry, College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, People’s Republic of China *These authors contributed equally to this work Abstract: We synthesized a pH-responsive conjugate of 10-hydroxycamptothecin-thiosemicarbazide-linear polyethylene glycol 2000 (PEG2000). The conjugate was confirmed by matrix-assisted laser desorption time of flight mass spectrometry, 1H NMR, and 13C NMR. The water solubility of the prodrug was increased by over 3,000 times; much longer body circulation time, higher tumor-targeting ability, and reduced toxicity were observed, compared with commercial 10-HCPT injection. The linker contains a pH-sensitive hydrazone bond, which breaks under low pH conditions in the tumor microenvironment. The conjugates showed good stability in phosphate-buffered saline (pH 7.4) and rat plasma. This amphiphilic conjugate could self-assemble into nanosized micelles of 80–100 nm. Cytotoxicity assay results indicate significantly higher efficacy of the conjugate (IC50 [half maximal inhibitory concentration] =0.117 µM on SW180 cells) than 10-HCPT solution (IC50 =0.241 µM on SW480 cells). Cellular uptake analysis suggested its rapid internalization and nuclear transport. Pharmacokinetic analysis of the conjugates demonstrated that the conjugate circulated for a longer time in the blood circulation system (T2/1 =10.516±1.158 h) than did 10-HCPT solution (T2/1 =1.859±1.385 h), and that it also enhanced the targeting and mean residence time (MRT0–inf =39.873±4.549 h) in the tumor site, compared with 10-HCPT (MRT0–inf =9.247±1.026 h). Finally, the conjugate demonstrated an increased tumor growth inhibition effect (TIR =82.66%±7.175%) in vivo and lower side effects than 10-HCPT (TIR =63.85%±5.233%). This prodrug holds great promise in improving therapeutic efficacy and overcoming multidrug resistance. Keywords: 10-hydroxycamptothecin, conjugate, controlled release, prodrug, pH-responsive, hydrazone

Keywords

• 10-hydroxycamptothecin
• conjugate
• controlled release;
• prodrug