The Dengue virus is known to switch its surface morphology from topologically smooth to ‘bumpy’ on changing host and this morphological transition appears to be important for the efficient infection of humans. Moreover, such viruses possess pH-sensitive surface domains that enable efficient exit from the endosomes during infection. Herein we design fully synthetic Dengue virus-mimicking nanoparticles in order to target cancer cells. More specifically, sterile pH-responsive methacrylic triblock copolymer vesicles were prepared from diblock copolymer precursor vesicles via RAFT seeded emulsion polymerization of 2-(diisopropylamino)ethyl methacrylate (DPA). Microphase separation between the two immiscible hydrophobic membrane-forming blocks produces a distinctive framboidal morphology, with surface globule dimensions of the order of 20 nm. In addition, the steric stabilizer layer comprises a binary mixture of two highly biocompatible water-soluble polymers, poly(glycerol monomethacrylate) (PGMA) and poly(2-(methacryloyloxy)ethyl phosphorylcholine) (PMPC). The PMPC chains are present at a relatively low level (3 mol %), but its phosphorylcholine groups are important because they promote efficient intracellular uptake via SRB-1 receptors. These framboidal vesicles are colloidally stable at neutral pH, but undergo irreversible dissociation on lowering the pH as the tertiary amine groups on the PDPA block become protonated and hence hydrophilic. Such vesicles are preferentially taken up by triple negative human breast cancer cells with highly expressed SR-B1 receptors and weakly expressed CD-36 receptors, whereas negligible uptake is observed for both human dermal fibroblasts and normal breast cancer cells that do not express the SRB-1 receptor. Moreover, functional biomolecules (e.g. plasmid DNA) can be delivered to cell nuclei while maintaining high cellular viability.

Dengue virus-mimicking pH-responsive framboidal block copolymer vesicles

254th National Meeting (2017)

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