In order to overcome the limiting features generally encountered with drug-loaded nanoparticles for drug delivery (e.g., burst release, poor drug loading, etc), the design and the evaluation of novel nanoparticulate systems based on macromolecular prodrug amphiphiles are reported.The strategy relies on the controlled growth of a hydrophobic and biocompatible polymer from an anticancer drug-bearing initiator, in order to position one chemotherapeutic at the extremity of each polymer chain (Fig. 1). Polyisoprene (PI) has been chosen as hydrophobic polymer due to its biocompatibility whereas we selected gemcitabine (Gem) as a drug, because of its demonstrated activity against a wide range of solid tumors.Due to the amphiphilic nature of the resulting Gem-PI conjugates, they spontaneously self-assembled in aqueous solution to form stable, narrowly-dispersed nanoparticles of 130-160 nm in diameter. These nanoconstructs exhibited efficient anticancer activities both in vitro on various cancer cell lines as well as in vivo on human pancreatic carcinoma-bearing mice, while suppressing the inherent toxicity of the Gem. The accurate control of the polymer chain length also led to preliminary structure-activity relationships.This new methodology tends to be universal and versatile as it is virtually applicable to multiple hydrophobic polymers (this was illustrated with the use of a polymer based on squalene, a natural lipid) and multiple drugs, and consequently to different pathologies.

Novel nanoparticles with in vivo anticancer activity from well-defined polymer prodrug amphiphiles

248th National Meeting (2014)

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