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.
A droplet-based microfluidic process relying on an actuated flow-focusing device was used for the in-flow synthesis of hyaluronic acid-polyethyleneimine nanogels with improved drug delivery properties.
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