Heterotelechelic polymer prodrug nanoparticles: Adaptability to different drug combinations and influence of the dual functionalization on the cytotoxicity

JOURNAL OF CONTROLLED RELEASE

卷:295

Article

Vinciguerra, Daniele¹  Jacobs, Merel¹  Denis, Stephanie¹  Mougin, Julie¹  Guillaneuf, Yohann²  Lazzari, Gianpiero¹  Zhu, Chen¹  Mura, Simona¹  Couvreur, Patrick¹  Nicolas, Julien¹ 

[1] Univ Paris Sud, Fac Pharm, UMR CNRS 8612, Inst Galien Paris Sud, 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.2018.12.047

来源: Elsevier

【 摘 要 】

Well-defined, heterotelechelic polymer prodrugs for combination therapy were synthesized by using a combination of the drug-initiated nitroxide-mediated polymerization from a gemcitabine-alkoxyamine initiator and the nitroxide exchange reaction using TEMPO-bearing drugs to end-cap the drug-polymer chain-end by a second drug. This methodology was successfully applied to two different clinically relevant combinations, gemcitabine/doxorubicin (Gem/Dox) and gemcitabine/lapatinib (Gem/Lap), showing a certain degree of universality of the synthetic methodology. It also represented the first nanocarrier for the co-delivery of Gem and Lap ever reported. Well-controlled, low molar mass heterotelechelic polymers (M-n = 2100-4090 g.mol(-1), D = 1.18-1.38) with similar to 1:1 drug ratios and high overall drug loadings up to 40 wt% were obtained. They were formulated into nanoparticles by nanoprecipitation and exhibited average diameters in the 34-154 nm range, with narrow particle size distributions (PSD= 0.01-0.22) and excellent colloidal stability over time. Their biological evaluation in terms of drug release and cytotoxicity was performed and compared to that of different monofunctional polymer prodrug formulations. We showed that heterobifunctional polymer prodrugs induced cytotoxicity to MCF-7 cells, with IC50 values in the 120-300 nM range depending on the combination tested. Interestingly, whereas Gem/Dox combination did not lead to noticeable improvement over monofunctional therapies, co-nanoprecipitation of Gem/Lap prodrugs led to synergistic effect.

【 授权许可】

Free