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Enzyme/pH-Sensitive polyHPMA-DOX Conjugate as Biocompatible and Efficient Anticancer Agent


In this study, to enhance the therapeutic function and reduce the side-effect of doxorubicin (DOX), a biodegradable N-(2-hydroxypropyl) methacrylamide (HPMA) polymer-DOX conjugate has been prepared through reversible addition fragmentation chain transfer (RAFT) polymerization and conjugating chemistry, and the anticancer agent DOX was covalently linked to the polymeric vehicle through a pH-responsive hydrazone bond. The cellular mechanisms of the conjugate were explored, and the therapeutic indexes were studied as well. The high molecular weight (MW) polymeric conjugate (94 kDa) is degraded into products with low MW (45 kDa) in the presence of lysosomal cathepsin B, and also show a pH-responsive drug release behavior. In vitro cellular mechanisms studies reveal that the polymeric conjugate is uptaken by the 4T1 cells, leading to cell apoptosis and cytotoxicity to cancer cell, while the polymeric conjugate demonstrates excellent in vivo biosafety even at a high dose. Compared to to free DOX, the conjugate has a much longer half-decay time in pharmacokinetics and accumulates in tumors with a much higher amount. The conjugate therefore has a much greater in vivo anticancer efficacy against 4T1 xenograft tumors as well as shows subtle side-effects, which are confirmed via tumor size and weight, immunohistochemistry and histological studies. Overall, this polymeric conjugate may be used as an enzyme/pH-sensitive anticancer agent.

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Publication details

The article was received on 25 Jan 2018, accepted on 07 Mar 2018 and first published on 07 Mar 2018

Article type: Paper
DOI: 10.1039/C8BM00095F
Citation: Biomater. Sci., 2018, Accepted Manuscript
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    Enzyme/pH-Sensitive polyHPMA-DOX Conjugate as Biocompatible and Efficient Anticancer Agent

    Y. Ou, K. Chen, H. Cai, H. Zhang, Q. Gong, J. Wang, W. Chen and K. Luo, Biomater. Sci., 2018, Accepted Manuscript , DOI: 10.1039/C8BM00095F

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