Exogenous vitamin C boosts the antitumor efficacy of paclitaxel containing reduction-sensitive shell-sheddable micelles in vivo.
Slow drug release at the tumor tissue and poor tumor penetration are two big challenges for the successful application of nanosystems in tumor therapy. Here, we report that a high concentration of the natural reducing agent vitamin C (VC) triggers rapid extracellular PTX release from PTX-loaded shell-sheddable PEG-SS-PCL micelles (SSM) in tumors in vivo. An in vivo tolerance study showed that VC at a blood concentration of 40mM had little toxicity to nude mice. Notably, SSM rapidly disassembled and released the payloads (Cy5 or PTX) in response to 40mM VC. In vivo near-infrared imaging of tumor-bearing mice showed that with post-injection of VC to establish a blood concentration of 40mM, Cy5 was quickly released from the micelles and diffused deep into the tumor tissue. Biodistribution studies revealed that 6h after the injection of PTX-loaded micelles the highest tumor accumulation was reached, which was set as the injection time for VC. The antitumor efficacy of a combination therapy of PTX-loaded micelles and VC was evaluated in both MCF-7 and U87MG tumor models. In both tumor models, single injections of VC didn't show any antitumor effect, while sequential administration of PTX-loaded SSM and VC exhibited significantly higher tumor inhibition effects and better survival rates as compared to single treatment with PTX-loaded micelles, demonstrating that exogenous administration of VC effectively triggered the release of PTX from SSM in vivo. The combination of reduction-sensitive nanomedicines with exogenous VC appears a promising approach to achieve potent treatment of malignant tumors.
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China; Department of Polymer Chemistry and Biomaterials, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands.
Yaqin
Y
Zhu
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China.
Xiuxiu
X
Wang
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China.
Jian
J
Zhang
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China.
Fenghua
F
Meng
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China.
Chao
C
Deng
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China.
Ru
R
Cheng
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China; Department of Polymer Chemistry and Biomaterials, Faculty of Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands. Electronic address: j.feijen@utwente.nl.
Jan
J
Feijen
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China. Electronic address: zyzhong@suda.edu.cn.
Zhiyuan
Z
Zhong
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002232:Carbocyanines / Q000737:chemistry; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D065546:Drug Liberation; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D009368:Neoplasm Transplantation; D010084:Oxidation-Reduction; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology*; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D013388:Succinimides / Q000737:chemistry*; D013499:Surface Properties
D000970:Antineoplastic Agents; D002232:Carbocyanines; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; D013388:Succinimides; C085321:cyanine dye 5; C016240:polycaprolactone; D011092:Polyethylene Glycols; C050761:polyethylene glycol bis(succinimidyl succinate); D017239:Paclitaxel; D001205:Ascorbic Acid
Biodegradable micelles; Drug release; Paclitaxel; Reduction-sensitive; Tumor penetration; Vitamin C