Hyperbranched polymer-derived drug nanocarriers have been synthesized that can change sizes selectively in response to pH. These constructs were composed of tertiary amine-conjugated polycarbonate blocks "grafted from" a hyperbranched polyester polyol core. At neutral pH, unprotonated polycarbonate arms stabilized the copolymer aggregates in the form of nanoparticles with hydrodynamic diameters ranging from 150 to 190 nm. Upon lowering of pH, these larger aggregates disassembled into smaller nanoparticles with diameters of 3-5 nm as directed by protonation of tertiary amine side-chains. The pH-dependent reduction of particle sizes was evident by titrimetric, spectroscopic, dynamic light scattering, transmission electron, and atomic force microscopy-based experiments. We observed that these copolymeric nanoparticles could be loaded with dye and drug molecules either by noncovalent encapsulation or by covalent conjugation. A pH-induced disassembly of the aggregates initiated rapid release of the encapsulated payload, but not of the conjugated ones, thus establishing a controlled rate of therapeutic delivery from the nanostructures over an extended period. We envision that such systems can be used for drug delivery applications where nanoparticle sizes critically govern therapeutic efficiency in a vasculature-poor disease microenvironment such as desmoplasia in pancreatic cancer. Hence, we tested the cellular uptake, cytotoxicity, and chemotherapeutic potential of the size-modifiable nanoaggregates using gemcitabine as a model drug in pancreatic cancer setting. We observed that assembled nanoparticles were biocompatible to noncancerous cells, showed pH-dependent effects on cellular uptake as well as promoted accumulation within cancer cells cultured as 3D spheroids. We also found that when conjugated with gemcitabine, the resulting drug-loaded nanoparticles suppressed proliferation of cancer cells. Collectively, the studies suggested that these synthesized, pH-disassembling nanoscale platform will find applications as biomaterials for constructing a size-transformable drug nanocarriers where reduction of size takes effect near localized disease targets in response to microenvironmental triggers.
Keywords: biomaterials; chemotherapy delivery; hyperbranched polymers; pH-activation; size-modifiable nanoparticles.