4.7 Article

Fabrication of reduction-degradable micelle based on disulfide-linked graft copolymer-camptothecin conjugate for enhancing solubility and stability of camptothecin

Journal

POLYMER
Volume 51, Issue 22, Pages 5107-5114

Publisher

ELSEVIER SCI LTD
DOI: 10.1016/j.polymer.2010.09.004

Keywords

Reduction-degradable; Camptothecin; Micelle

Funding

  1. Chinese Ministry of Science and Technology [2009CB930300]
  2. National Natural Science Foundation of China [50873080]
  3. Shanghai Municipality Commission for Special Project of Nanometer Science and Technology [0952nm05300]
  4. Shanghai Municipality Commission for Non-governmental International [09540709000]
  5. International Corporation [10410710000]
  6. Foundation for New Century Excellent Talents in University of Ministry of Education of China [NCET-10-0435]
  7. Fundamental Research Funds [WUT 2010-II-022, JUSRT30905]

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This research is aimed to develop a reduction-degradable micelle delivery system based on polymer-camptothecin (CPT) conjugate in order to enhance the solubility and stability of CPT in aqueous media. Firstly, disulfide-linked poly(amido amine) (SS-PAA) containing alkyne groups was synthesized by Michael addition polymerization between propargyl amine and N,N'-bis(acryloyl) cystamine (BAC). And then, azide-functionalized CPT derivatives were conjugated with SS-PAA by click cycloaddition. Further grafting of residual alkyne groups in SS-PAA with azide-terminated poly(ethylene glycol) methyl ether (mPEG) gave mPEG-g-SS-PAA-CPT conjugate. At last, micelles with size of ca. 88 nm were fabricated from mPEG-g-SS-PAA-CPT conjugate, suggesting their passive targeting potential to tumor tissue. It was worthy of note that the drug-loaded system of mPEG-g-SS-PAA-CPT micelles improved the solubility and stability of CPT in aqueous media. Owing to the reduction degradability of disulfide linker in main chain of mPEG-g-SS-PAA-CPT, the CPT sustainably release from micelles together with the gradual cleavage of polymer in the presence of dithiothreitol (OTT) at the concentration of simulating the intracellular condition while almost no change occurred at the level of OTT corresponding to extracellular condition. Furthermore, the cell viability results showed the essential decrease of cytotoxicity to L929 cell line. These results present a strategy in designing anti-tumor CPT-polymer conjugates for highly selective delivery to tumor cells. (C) 2010 Elsevier Ltd. All rights reserved.

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