(186ae) Engineering Ionically-Gelled Chitosan Nanoparticles Containing the Nucleoside Analog, Gemcitabine

Fergusson, A., Virginia Tech
Davis, R. M., Virginia Tech
Engineering ionically-gelled chitosan nanoparticles containing the nucleoside analog, gemcitabine

Austin Fergusson1, Richey M. Davis2, 3

1Translational Biology, Medicine, and Health Graduate Program

2Macromolecules Innovation Institute

3Department of Chemical Engineering

Virginia Tech, Blacksburg, VA 24061

Gemcitabine (Gemzar) is a potent, FDA-approved cancer therapeutic for the treatment of late-stage pancreatic cancer. Once inside of a cell, gemcitabine inhibits DNA synthesis by terminating DNA strand elongation which leads to rapid cell death. Despite gemcitabine’s successful use in treating various cancers, its efficacy is limited by rapid enzymatic degradation and transporter-mediated trafficking into cells. A nanoparticle drug delivery system could protect gemcitabine from degradation and bypass the need for a transporter. Flash Nanoprecipitation (FNP) can produce nanoparticle populations with well-defined sizes and high drug loading capacities for lipophilic therapeutics (Log P = 3.5); for charged, hydrophilic therapeutics, additional charge interactions or some entrapment mechanism is needed. Prior work using a slow nanoprecipitation method resulted in significant loadings of gemcitabine in chitosan nanoparticles when the Pluronics F-68 PEO-PPO-PEO triblock copolymer was present. We hypothesized chitosan coacervation could provide an avenue to encapsulate hydrophilic therapeutics using FNP and produce nanoparticles with high loading capacities of gemcitabine. The pKa value of chitosan, 6.5, also provides a useful pH-sensitive release mechanism for entrapped drugs.

Chitosan nanoparticles containing gemcitabine loaded at > 12 wt% were fabricated using FNP with ionic gelation. We employed a factorial experimental design to examine the FNP formulation parameters that promoted gemcitabine encapsulation. Nanoparticle sizes ranging from ~ 150 – 650 nm were observed. This presentation will focus on the factorial design and optimization of the FNP formulation, synthesis, and characterization of these chitosan nanoparticles including particle size, zeta potential, and gemcitabine loading and release kinetics. The use of FNP reduces the time necessary to achieve a well-defined chitosan nanoparticle population using ionic gelation and simplifies the process of scaling-up nanoparticle production.