Amphiphilic Poly(α)glutamate Polymeric Micelles for Systemic Administration of siRNA to Tumors

Adva Krivitsky advashy@gmail.com Dina Polyak Anna Scomparin Shay Eliyahu Ronit Satchi-Fainaro
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

RNAi therapeutics carried a great promise to the area of personalized medicine: the ability to target “undruggable” oncogenic pathways. Nevertheless, their efficient tumor targeting via systemic administration had not been resolved yet. Recurring attempts to use naked unmodified RNAi for therapeutic purposes raised many difficulties, tackled by the development of various RNAi delivery approaches. Despite high expectations, these delivery approaches have encountered pharmacokinetic limitations, such as aggregation tendency, short in vivo circulation time, accumulation in reticuloendothelial system (RES) organs, and toxicity. These limitations raised the need for proper characterization and the substantial investigation of the relationship between structure, physico-chemical properties and activity as a fundamental tool in the quest for the ideal RNAi delivery vehicle. To address this, we have designed, synthesized and characterized a library of RNAi delivery vehicles based on biodegradable poly-α-glutamic acid (PGA)1. PGA`s water-solubility, low immunogenicity and low toxicity at doses required for activity, makes it a great candidate for clinical translation. Amine modifications on the pending carboxylic groups enabled electrostatic-based complexation with the negatively-charged RNAi, while alkyl moieties facilitated the rearrangement of micellar-like structures2. Physico-chemical characterization of our PGAamine-based polymers and siRNA library of polyplexes revealed diameter range of 50-250 nm, enabling to exploit the enhanced permeability and retention (EPR) effect in order to selectively and passively accumulate in tumors3. Altogether, our results present a guiding principle for the desired qualities of cationic siRNA delivery platforms. Our active polymers demonstrated efficient in vitro silencing activity alongside biocompatibility and preferential accumulation in tumors paving the way for further development for increased biostability and in vivo gene silencing.

  1. Krivitsky, A.*; Polyak, D.* et al. Biomacromolecules 12;17(9):2787-800 (2016).
  2. Krivitsky, A.* Polyak, D.* Scomparin, A et al. Nanomedicine: Nanotechnology, Biology, and Medicine, in press (2017).
  3. Polyak, D.*; Krivitsky, A.*; Scomparin, A.* et al. J Control Release 257:132-143 (2017).









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