Controlling the burst release of amorphous drug–polysaccharide nanoparticle complex via crosslinking of the polysaccharide chains

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High-payload amorphous drug–polysaccharide nanoparticle complex (or nanoplex in short) represents a new class of supersaturating drug delivery systems intended for bioavailability enhancement of poorly-soluble drugs. Not unlike other nanoscale amorphous formulations, the nanoplex exhibits fast dissolution characterized by a burst drug release pattern. While the burst release is ideal for supersaturation generation in the presence of crystallization inhibitor, it is not as ideal for passive targeting drug delivery applications in which the nanoplex must be delivered by itself. Herein we developed nanoplex exhibiting controlled release via crosslinking of the polysaccharide chains onto which the drug molecules were electrostatically bound to. Curcumin and chitosan were used, respectively, as the drug and polysaccharide models with amine-reactive disuccinimidyl tartrate as the crosslinking agent. The crosslinked nanoplex exhibited improved morphology (i.e. smaller size, more spherical, and higher uniformity) that signified its more condensed structure. A twenty-fold reduction in the initial burst release rate with a threefold reduction in the overall dissolution rate was obtained after crosslinking. The slower dissolution was attributed to the more condensed structure of the crosslinked nanoplex that enhanced its dissociation stability in phosphate buffered saline. The reduction in the dissolution rate was proportional to the degree of crosslinking that was governed by the crosslinker to amine ratio. The crosslinking caused slight reductions in the payload and zeta potential of the nanoplex, but with no adverse effect on the cytotoxicity. This proof-of-concept study successfully demonstrated the use of polysaccharide crosslinking to control the drug release from high-payload amorphous drug nanoplex.

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