Biotin-decorated all-HPMA polymeric micelles for paclitaxel delivery

JOURNAL OF CONTROLLED RELEASE

卷:328

Article

Wang, Yan¹  van Steenbergen, Mies J.¹  Beztsinna, Nataliia¹  Shi, Yang²  Lammers, Twan²  van Nostrum, Cornelus F.¹  Hennink, Wim E.¹ 

[1] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Dept Pharmaceut, Universiteitsweg 99, NL-3508 TB Utrecht, Netherlands

[2] RWTH Aachen Univ Clink, Inst Expt Mol Imaging, Dept Nanomed & Theranost, Forckenbecktrasse 55, D-52074 Aachen, Germany

关键词: Polymeric micelles;    N-2-Hydroxypropyl methacrylamide;    Biotin;    Drug targeting;    Nanomedicines;   

DOI  :  10.1016/j.jconrel.2020.09.013

来源: Elsevier

【 摘 要 】

To avoid poly(ethylene glycol)-related issues of nanomedicines such as accelerated blood clearance, fully N-2-hydroxypropyl methacrylamide (HPMAm)-based polymeric micelles decorated with biotin for drug delivery were designed. To this end, a biotin-functionalized chain transfer agent (CTA), 4-cyano-4-[(dodecylsulfanylthiocarbonyl)-sulfanyl]pentanoic acid (biotin-CDTPA), was synthesized for reversible addition-fragmentation chain-transfer (RAFT) polymerization. Amphiphilic poly(N-2-hydroxypropyl methacrylamide)-block-poly(N-2-benzoyloxypropyl methacrylamide) (p(HPMAm)-b-p(HPMAm-Bz)) with molecular weights ranging from 8 to 24 kDa were synthesized using CDTPA or biotin-CDTPA as CTA and 2,2 '-azobis(2-methylpropionitrile) as initiator. The copolymers self-assembled in aqueous media into micelles with sizes of 40-90 nm which positively correlated to the chain length of the hydrophobic block in the polymers, whereas the critical micelle concentrations decreased with increasing hydrophobic block length. The polymer with a molecular weight of 22.1 kDa was used to prepare paclitaxel-loaded micelles which had sizes between 61 and 70 nm, and a maximum loading capacity of around 10 wt%. A549 lung cancer cells overexpressing the biotin receptor, internalized the biotin-decorated micelles more efficiently than non-targeted micelles, while very low internalization of both types of micelles by HEK293 human embryonic kidney cells lacking the biotin receptor was observed. As a consequence, the paclitaxel-loaded micelles with biotin decoration exhibited stronger cytotoxicity in A549 cells than non-targeted micelles. Overall, a synthetic pathway to obtain actively targeted poly(ethylene glycol)-free micelles fully based on a poly(HPMAm) backbone was established. These polymeric micelles are promising systems for the delivery of hydrophobic anticancer drugs.

【 授权许可】

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