While drug-loaded liposomes have garnered several notable successes as cancer treatments (e.g., DoxilTM, ONIVYDE®, Marqibo®, and Myocet®), the relatively large sizes (hydrodynamic diameter (DH) = ~100 nm) of these early systems are still of concern as they can result in non-optimal biodistributions and severe side effects. Thus, size-reduction of these particles to 15-50 nm has been proposed as a strategy for overcoming these problems and enhancing their therapeutic efficacies in a broad range of diseases. Unfortunately, while liposomes of this size regime, commonly known as ultrasmall unilamellar vesicles (uSUVs), can be synthesized, they have very poor colloidal and membrane stabilities due to their highly strained, acute membrane curvature, which leads to payload leakage, inter-particle fusion, and lipid membrane aggregation. This presentation will show how these problems can be overcome through the integration of a stimuli-responsive poly(acrylic) acid (Chol-PAA) polymer shell into uSUVs template. The resulting polymer-grafted liposomes (PGLs) are stable for months in biologically relevant media and exhibited over 10-fold enhanced cargo retention. In addition, the polymer shell of the PGL can undergo hydrogen-bonding-induced aggregation upon acidification to release a significant amount of payload from the liposomal core, a mechanism that has been verified in silico by coarse-grained molecular dynamics simulations. The colloidal stability of PGLs can be further increased by crosslinking the polymer shell while maintaining the stimuli-responsive release ability at acidic target sites such as tumor microenvironment and cellular endosome and lysosome. Together with the possibility for targeting, our modular design of a polymer shell that provide uSUVs with excellent cargo retention capability and acid-triggered drug release ability can greatly facilitate this platform for the selective delivery of anti-cancer drugs to a broad range of disease sites while reducing their side effects.

Highly stable, ultrasmall liposomes with stimuli-responsive drug-release capability for cancer therapy

256th National Meeting (2018)

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