Chitosan (CS) and dextran sulfate (DS) are charged polysaccharides (glycans), which form polyelectrolyte complex-based nanoparticles when mixed under appropriate conditions. The glycan nanoparticles are useful carriers for protein factors, which facilitate the in vivo delivery of the proteins and sustain their retention in the targeted tissue. The glycan polyelectrolyte complexes are also ideal for protein delivery, as the incorporation is carried out in aqueous solution, which reduces the likelihood of inactivation of the proteins. Proteins with a heparin-binding site adhere to dextran sulfate readily, and are, in turn, stabilized by the binding. These particles are also less inflammatory and toxic when delivered in vivo. In the protocol described below, SDF-1α (Stromal cell-derived factor-1α), a stem cell homing factor, is first mixed and incubated with dextran sulfate. Chitosan is added to the mixture to form polyelectrolyte complexes, followed by zinc sulfate to stabilize the complexes with zinc bridges. The resultant SDF-1α-DS-CS particles are measured for size (diameter) and surface charge (zeta potential). The amount of the incorporated SDF-1α is determined, followed by measurements of its in vitro release rate and its chemotactic activity in a particle-bound form.
Dextran sulfate (DS) and chitosan (CS) nanoparticles (NPs) have a glycan matrix that may be useful for in vivo delivery of proteins. Current procedures for the formation of DS‐CS NPs with incorporated proteins is to first combine DS or CS with the protein of interest and then proceed to particle formation. In general, this process requires a significant amount of protein for particle formation, and after the reaction the unincorporated protein cannot be easily recovered for future incorporation. Considering the high cost and limited availability of various recombinant therapeutic proteins, in this study we investigated whether proteins can be incorporated efficiently in pre‐formed DS‐CS NPs. To do so, DS‐CS NPs were formulated, prepared on a large scale, and lyophilized. The reconstituted DS‐CS NPs were sized 333±16 nm, with a polydispersity of 0.119±0.026 and zeta potential of ‐32.4±1.4 mV. Stromal cell‐derived factor‐1α (SDF‐1α) was loaded onto the DS‐CS NPs at various concentrations. At the ratio of SDF‐1α to DS of 0.02:1, 85±8 % of the loaded SDF‐1α was incorporated in the NPs. The resulted particles (SDFNPs) had a diameter of 393±17 nm, a polydispersity of 0.147±0.032, and a zeta potential of ‐28.6±1.9 mV. The incorporated SDF‐1α had the same chemotactic activity as that of free SDF‐1α. Administration of aerosolized SDFNP to the lungs of rats showed that ~ 30% SDF‐1α remained in the tissue at 72 hr after the delivery, while free SDF‐1α was mostly cleared from the lung (~97%) after 16 hr. This study shows that pre‐formed DS‐CS NPs incorporated SDF‐1α with high efficiency, and can be a useful vehicle for delivery of recombinant therapeutic proteins to the lung parenchyma.
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