Design, synthesis and characterization of poly-α-glutamic acid (PGA)-based nanocarriers for RNAi delivery

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 encountered pharmacokinetic limitations. To address this, we have designed, synthesized and characterized a library of RNAi nanocarriers based on biodegradable poly-α-glutamic acid (PGA)¹. PGA`s water-solubility, low immunogenicity and low toxicity, make it a great candidate for clinical translation. Amine modifications on the carboxylic groups enabled electrostatic-based complexation with the negatively-charged RNAi, while alkyl moieties facilitated the rearrangement of micellar-like structures^{2, 3}. Furthermore, diameter of ~100 nm enabled to exploit the enhanced permeability and retention (EPR) effect in order to selectively and passively accumulate in tumors⁴. Altogether, our results present a guiding principle for the desired qualities of cationic siRNA delivery platforms⁵. Our active polymers demonstrated efficient in vitro silencing activity alongside biocompatibility and preferential accumulation in tumors². Moreover, Intraperitoneal injected plk1-carrying polyplexes inhibited the growth of ovarian adenocarcinoma tumors⁴, while intravenously administered PGAamine polyplexes carrying a novel combination of plk1 siRNA and miR-34a reduced the growth of pancreatic ductal adenocarcinoma tumors and prolonged the survival of tumor-bearing mice³. These results highlight the great potential of PGAamine as injectable, non-toxic and efficient nanocarrier for RNAi.

References

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3. Gibori, H. Eliyahu, S. Krivitsky, A. et al. Nature Communications 9, 16 (2018).
4. Polyak, D.*; Krivitsky, A.*; et al. J Control Release 257:132-143 (2017).
5. Krivitsky, A.; Krivitsky, V. et al. Polymers 10(5), 548; (2018).