Hyaluronic Acid-Polyethyleneimine Nanogels for Controlled DrugDelivery in Cancer Treatment

The emulsion/evaporation method represents a pivotal approach to synthesize nanogels for controlled drug delivery. However, this strategy is constrained to the use of at least one polymer characterized by a phase-selective solubility in organic or aqueous solutions. Consequently, the formulation of nanoscaffolds based solely on hydrophilic polymers is not feasible by this approach, limiting the applicability of the technique. This work shows an innovative emulsion-based strategy, where two polymers insoluble in water-immiscible organic solvents, hyaluronic acid (HA) and polyethyleneimine (PEI), chemically crosslink to produce nanogels. The procedure exploits the interfacial interactions and the coalescence phenomena occurring in a surfactant-free mixed emulsion, composed of HA and PEI aqueous solutions as dispersed phases and a neat organic solvent as the continuous phase. Our method allows us to obtain HA-PEI nanogels characterized by low polydispersity, good colloidal stability, and high batch-to-batch reproducibility. The synthesized nanoscaffolds were validated as nanocarriers for the controlled release of doxorubicin in ovarian cancer, showing a sustained drug release profile (up to 15 days), which enhanced the therapeutic effects compared to the drug administration in the free form. In particular, through an in vitro assay with a CD44 blocking/neutralizing antibody, we showed that the hyaluronan receptor was involved in the nanogel internalization process, suggesting that our nanogel formulation, obtained through a surfactant-free mixed emulsion, is a promising strategy for the design of HA-based nanocarriers for CD44-targeted therapy.