Clickable polyethyleneimine incorporated into triblock copolymeric micelles as an efficient platform in the delivery of siRNA to NSCLC cells.

The efficacy of transfection vectors to cross the endosomal membrane into the cytosol is a central aspect in the development of nucleic acid-based therapeutics. The challenge remains the same: Delivery, Delivery, Delivery. Despite a rational and appropriate construct of triblock polymeric micelles, which could serve as an ideal platform for the co-delivery of siRNAs and hydrophobic anticancer drugs, we show here its inability to properly convey oligonucleotides to their final destination. In order to overcome biological barriers, a linear PEI comprising two orthogonal groups was synthesized, holding an appropriate balance between safety and efficacy. Micellar carriers were then formulated with this polymer to enhance endosomal siRNA release. This chemical technology also addresses the two major challenges to consider when developing novel micellar products for siRNA delivery, namely cytotoxicity of polycations and endosomal escape. Herein, we demonstrate successful release of siRNA using a polymer tailoring strategy combined with a relevant in vitro approach, considering STAT3 as a promising target in the treatment of non-small cell lung cancer (NSCLC).

Characterization of the Interaction of Polymeric Micelles with siRNA: A Combined Experimental and Molecular Dynamics Study.

The simulation of large molecular systems remains a daunting challenge, which justifies the exploration of novel methodologies to keep computers as an ideal companion tool for everyday laboratory work. Whole micelles, bigger than 20 nm in size, formed by the self-assembly of hundreds of copolymers containing more than 50 repeating units, have until now rarely been simulated, due to a lack of computational power. Therefore, a flexible amphiphilic triblock copolymer (mPEG45-α-PLL10-PLA25) containing a total of 80 repeating units, has been emulated and synthesized to embody compactified nanoconstructs of over 900 assembled copolymers, sized between 80 and 100 nm, for siRNA complexing purposes. In this study, the tailored triblock copolymers containing a controlled number of amino groups, were used as a support model to address the binding behavior of STAT3-siRNA, in the formation of micelleplexes. Since increasingly complex drug delivery systems require an ever more optimized physicochemical characterization, a converging description has been implemented by a combination of experimentation and computational simulations. The computational data were advantageous in allowing for the assumption of an optimal N/P ratio favoring both conformational rigidifications of STAT3-siRNA with low competitive phenomena at the binding sites of the micellar carriers. These calculations were consistent with the experimental data showing that an N/P ratio of 1.5 resulted in a sufficient amount of complexed STAT3-siRNA with an electrical potential at the slipping plane of the nanopharmaceuticals, close to the charge neutralization.