A facile route to heterotelechelic polymer prodrug nanoparticles for imaging, drug delivery and combination therapy

JOURNAL OF CONTROLLED RELEASE

卷:286

Article; Proceedings Paper

Vinciguerra, Daniele¹  Denis, Stephanie¹  Mougin, Julie¹  Jacobs, Merel¹  Guillaneuf, Yohann²  Mura, Simona¹  Couvreur, Patrick¹  Nicolas, Julien¹ 

[1] Univ Paris Sud, CNRS, Inst Galien Paris Sud, Fac Pharm,UMR 8612, 5 Rue Jean Baptiste Clement, F-92296 Chatenay Malabry, France

[2] Aix Marseille Univ, CNRS, Inst Chim Radicalaire, UMR 7273, Campus St Jerome,Ave Escadrille Normandie Niemen, F-13397 Marseille 20, France

关键词: Polymer;    Nanoparticles;    Prodrug;    Cancer;    Combination therapy;    Drug delivery;   

DOI  :  10.1016/j.jconrel.2018.08.013

来源: Elsevier

【 摘 要 】

A facile and general synthetic methodology has been developed to prepare high drug loading heterotelechelic polymer prodrug nanoparticles; that are nanoparticles obtained by formulation of linear polymers bearing two different molecules at both extremities (at least one of them being a drug). The method relied on the combination of the drug-initiated method to obtain a-functional polymer prodrugs by nitroxide-mediated polymerization, followed by the nitroxide exchange reaction from a functional nitroxide to install another molecule of interest at the. chain-end. To validate the proof of concept, two different combinations have been synthesized using polyisoprene (PI) as the polymer building block: one based on gemcitabine and rhodamine (Gem-PI-Rho) for drug delivery and imaging purposes, and one with aminoglutethimide and doxorubicin (Agm-PI-Dox) for combination therapy purposes. Fluorescent polymer prodrug nanoparticles (D-z = 161 nm) were easily obtained by co-nanoprecipitation of Gem-PI and 5 wt% of Gem-PI-Rho. They were observed by confocal microscopy and they also induced significant cytotoxicity on the human breast cancer cell line MCF-7. As for combination therapy purposes, Agm-PI-Dox nanoparticles (D-z = 63-122 nm) led to enhanced cytotoxicity against MCF-7 cells compared to both monofunctional polymer prodrug nanoparticles (ca. 50% decrease in IC50 vs. Agm-PI and 65% decrease in IC50 vs. PI-Dox) or their equimolar co-nanoprecipitation. This simple and general methodology may pave the way to the design of a broad range of different heterotelechelic polymer prodrug nanoparticles.

【 授权许可】

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