(110a) Single Phase Reaction-Precipitation Systems for the Synthesis of Poly (?-Amino Esters) Nanogels

Poly (β-Amino Esters) (PBAE) are a a class of versatile, pH sensitive, hydrolytically biodegradable polymers with tunable degradation and release properties. These polymers have shown a great potential as a matrix for gene and small molecule drug delivery via classic drug encapsulation/formulation approaches. Moreover, PBAE can be polymeric prodrugs, wherein active agents (e.g., curcumin, quercetin) can be acrylated and subsequently conjugated into the polymeric backbone of the resulting hydrogel, greatly enhancing the release rate and providing a mechanism for stabilizing highly labile drugs.

However, owing to the high reactivity of the monomers and stability concerns of the ensuing particles, standard oil-water nano-emulsion methods are not amendable to their formation. Further, nanoprecipitation, when done in two immiscible organic solvent suspension systems, can lead to aggregation and instability during the purification processes. In this work, a novel approach to formulate anti-oxidant conjugated nanogels in a single organic phase system is explored where two multifunctional monomers, when added in appropriate concentrations in an organic solvent, react with each other and form stable nanogel/nanoparticle suspension.  These nanogels are then subsequently coated with PEG to prevent post purification (via centrifugation) instability. In the present research, quercetin was used as the molecule of interest as it possesses strong anti-oxidative, anti-inflammatory and anti-cancerous properties. To formulate nanoparticles (NPs), quercetin multiacrylate (QMA) was reacted with a secondary diamine (DA), (N,N’ dimethyl-1-3 propanediamine) in acetonitrile via a Michael addition reaction to form a crosslinked polymeric nanoparticle suspension. Different monomer concentrations were used to obtain variable particle sizes. The obtained NP suspension was then reacted with polyethylene glycol methyl ether methacrylate (PEGMEMA Mn=5000) for one hour to cap unreacted amines with PEG and increase the particle stability. Purification of NPs was done via centrifugation followed by re-suspension in fresh acetonitrile.

The yield of the reaction was between 83-97% as determined from UV-Vis spectroscopy. The size of synthesized NPs ranged from 200-400nm as observed using SEM and DLS. Upon hydrolysis in PBS with pH 7.4 at 37^oC, NPs showed prolonged and uniform release of active quercetin for at least 36 hours, which was studied using UV-Vis spectroscopy.