Diversely substituted poly(N-vinyl amide) derivatives towards non-toxic, stealth and pH-responsive lipid nanocapsules.

ABSTRACT

Surface modification of lipid nanocapsules (LNC) is necessary to impart stealth properties to these drug carriers and enhance their accumulation into the tumor microenvironment. While pegylation is commonly used to prolong the circulation time of LNC, the increased presence of anti-PEG antibodies in the human population and the internalization issues associated to the PEG shell are strong incentives to search alternatives. This work describes the development of amphiphilic poly(N-vinyl amide)-based (co)polymers, including pH-responsive ones, and their use as LNC modifiers towards improved drug delivery systems. RAFT polymerization gave access to a series of LNC modifiers composed of poly(N-methyl-N-vinyl acetamide), poly(N-vinyl pyrrolidone) or pH-responsive vinylimidazole-based sequence bearing a variety of lipophilic end-groups, namely octadecyl, dioctadecyl or phospholipid groups, for anchoring to the LNC. Decoration of the LNC with these families of poly(N-vinyl amide) derivatives was achieved via both post-insertion and per-formulation methods. This offered valuable and non-toxic LNC protection from opsonization by complement activation, emphasized the benefit of dioctadecyl in the per-formulation approach and highlighted the great potential of poly(N-methyl-N-vinyl acetamide) as PEG alternative. Moreover, incorporation of imidazole moieties in the shell of the carrier imparted pH-responsiveness to the LNC likely to increase the cellular uptake in the acidic tumor microenvironment, opening up new possibilities in the field of active targeting.