In order to overcome the limiting features generally encountered with drug-loaded nanoparticles (NPs) (e.g., burst release, poor drug loading), we aimed at designing a new class of efficient anticancer nanoparticles based on well-defined polymer prodrugs obtained by controlled/living radical polymerization (CLRP). We recently proposed a new approach to prepare well-defined amphiphilic macromolecular prodrugs by nitroxide-mediated polymerization (NMP)1 of isoprene from an anticancer drug-bearing alkoxyamine initiator (Fig. 1). They self-assembled into narrowly-dispersed nanoparticles and showed remarkable in vitro and in vivo anticancer activities.2 To further investigate the diversity and universality of this approach, it was adapted to another anticancer drug, cladribine (Cla). We selected Cla as an anticancer drug due to its demonstrated efficacy in the treatment of hairy cell leukaemia. Our strategy was illustrated by the synthesis of Cla-diglycolic-polyisoprene (Cla-digly-PI) of different molecular weights. NPs of 100–150 nm in diameter with drug content ranging from 6 to19 wt.% were obtained by nanoprecipitation in water of the desired polymer prodrugs. The use of NMP enabled the preparation of polymer conjugates with variable chain lengths in a facile way. Significant anticancer activities were observed in vitro on L1210 cells (mouse lymphocytic leukemia) with tunable IC50 ranging from micromolar to nanomolar values. In summary, a series of cladribine-polyisoprene prodrugs were synthesized by drug-initiated NMP, leading to efficient anticancer NPs. Furthermore, this strategy allowed for fine-tuning the polymer chain length, which is crucial to determine structure-activity relationships and to design optimized drug delivery systems. References 1. Nicolas, J.; Guillaneuf, Y.; Lefay, C.; Bertin, D.; Gigmes, D.; Charleux, B. Prog. Polym. Sci. 2013, 38, 63 2. Harrisson, S.; Nicolas, J.; Maksimenko, A.; Bui, D. T.; Mougin, J.; Couvreur, P. Angew. Chem., Int. Ed. 2013, 52, 6.

Efficient anticancer polymer prodrug nanoparticles from drug-initiated controlled/living radical polymerization

251st National Meeting (2016)

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