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pH/redox dual-responsive amphiphilic zwitterionic polymers with precisely controlled structure for anti-cancer drug carrier

Abstract

Responding to tumor microenvironment, funictional polymers can serve as preeminent drug carriers for targeted cancer therapy. stimuli-responsive ploymeric drug carriers are reported with inhomogenous anti-tumor effect since the verious polymer structure, resulting carriers with dfifferent charge. Thus, three pH/redox dual-responsive amphiphilic zwitterionic polymers with the same compositions but different loaction of pH/redox responsive units were prepared to understand the relationship betwen polymer structure and anti-tumor effect. Containing poly(ɛ-caprolactone) (PCL), poly(N,N-diethylaminoethyl methacrylate) (PDEA) and poly(2-methacryloyloxyethyl phosphorylcholine )(PMPC), precisely structure controlled polymers PCL-ss-P(DEA-r-MPC) (SDRM), PCL-ss-PDEA-b-PMPC(SDBM) and PCL-PDEA-ss-PMPC (DSM) were constructed and confirmed through NMR, FITR and EA. The formed micelluar drug carriers were characterized for morphology, loading capacity, acid/redox sensitivity, drug release, in vitro cytotoxicity and in vivo antitumor. Micelles with uniform spherical morphologies can effectively encapsulate the anti-tumor drug such as DOX. Among these micelles, DSM@DOX dispaly the excellentest drug encapsulation capacity(13.4%) with neutral surface charge(-1.02 mV) and good stability,which is different from SDRM@DOX with posistive charge(+11.1 mV) and SDBM@DOX of poor stability. All micelles respond to acid and reducing environments and present fast drug release at mildly acidic pH and high concentrations of GSH, exhibiting almost no burst release at the physiological conditions of plasma. Althugh there is no significant difference between these micelles in tumor cell cytotoxicity against MCF-7 and 4T1 cells, stronger internalization of SDRM@DOX and DSM@DOX by the tumor cells was observed than SDBM@DOX. Morover, DSM@DOX has longer blood circulation and more effective tumor site accumulation than the other two micelles. As a result, DSM@DOX shows enhanced antitumor efficacy in 4T1 tumor-bearing mouse with reduced side toxicities. Overall, structure of above polymers significantly influence the in vivo antumor effects of drug carrier through blood circulation and cellular uptake

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Publication details

The article was received on 14 Mar 2019, accepted on 16 May 2019 and first published on 17 May 2019


Article type: Paper
DOI: 10.1039/C9BM00407F
Biomater. Sci., 2019, Accepted Manuscript

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    pH/redox dual-responsive amphiphilic zwitterionic polymers with precisely controlled structure for anti-cancer drug carrier

    Z. Wu, Z. Gan, B. Chen, F. Chen, J. Cao and X. Luo, Biomater. Sci., 2019, Accepted Manuscript , DOI: 10.1039/C9BM00407F

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