Safe and efficient vectors for gene delivery are eagerly sought to enable the realization of the full potential of gene therapies.  Several recent reports in the literature have shown that phosphonium-based polymers could represent an efficient and less toxic alternative to the ubiquitous polyammoniums for siRNA and DNA delivery applications.  We have developed a new diblock copolymer based on the degradable polyphosphoester-block-poly-(L-lactide) (PPE-b-PLLA) skeleton, functionalized with trialkylphosphonium side groups via a thiol-yne click reaction.  The synthesis of clickable 2-mercaptoethyltrialkylphosphonium salts is described, and it is shown that bulky phosphonium salts bearing long alkyl chains (butyl and ethyl) performed poorly in thiol-yne reactions, whereas the trimethylphosphonium derivative added more efficiently.Preliminary investigations on the diblock have confirmed its low toxicity towards 293T cells.  An Alexa Fluor� 488 dye (A488)/polymer conjugate has been synthesized by Cu-assisted azide-alkyne click chemistry to allow for the tracking of the polymer in cell transfection experiments.  The supramolecular assembly of the copolymer strands into spherical micellar aggregates has been confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM).  Thiol-ene/yne click reactions were performed to crosslink the shells of non-dye-labeled micelles using a PEG-based dithiol to yield novel phosphonium-based cSCKs that were evaluated for their toxicity, binding efficiency towards DNA and siRNA, and transfection efficiency.

Development of phosphonium-based shell-crosslinked knedel-like  nanoparticles for gene delivery

248th National Meeting (2014)

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