The design and development of sophisticated nanoparticles for the targeted delivery of therapeutic drugs to solid tumors holds great promise not only for improving treatment efficacy but also for reducing systemic toxicity. However, the currently low delivery efficiency (about 1-5 % of the injected dose) and the limited tumor penetration of nanoparticles remain two major challenges. Here we report a class of nanoscale superstructures with unusual pH-responsive and size-switching properties for targeting the acidic tumor microenvironment as well as for improved drug tumor penetration. Specifically, the supernanostructurs are constructed by using pegylated polymethacrylate copolymers containing tertiary amine groups (sensitive to pH), and the protonation or deprotonation of these tertiary amines induces a dramatic hydrophobic-hydrophilic transition which drives rapid assembly or disassembly on the nanoscale. These superstructures have a relatively large size of about 80 nm at neutral pH (blood circulation), but once deposited in the acidic tumor microenvironment (pH ~6.5-7.0), they undergo a dramatic and sharp size transition within a very narrow range of acidity (less than 0.1-0.2 pH units), and dissociate rapidly into building blocks (less than 10 nm in diameter). This rapid size-switching feature can not only facilitate nanoparticle extravasation and accumulation via the enhanced permeability and retention (EPR) effect, but also allows faster nanoparticle diffusion and improved tumor penetration. The results demonstrate demonstrate that the high pH sensitivity and particle size switching are indeed viable strategies for improving drug penetration and therapeutic efficacy.

Engineering unusual properties on the nanoscale: Smart nanomicelles for targeting tumor microenvironments

256th National Meeting (2018)

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