Enhanced cellular association of paclitaxel delivered in chitosan-PLGA particles

We have previously demonstrated that the cellular association, cytotoxicity, and in vivo anti-tumor efficacy of paclitaxel are significantly greater when delivered in PLGA microparticles compared to nanoparticles. The purpose of this research is to test the hypothesis that mucoadhesive chitosan promotes adhesion of PLGA particles to mucus on the tumor epithelium, resulting in enhanced cellular association and cytotoxicity of paclitaxel. PLGA particles containing paclitaxel or Bodipy(®) were prepared and chitosan was either adsorbed or chemically conjugated to the particle surface. The cellular association and cytotoxicity of paclitaxel in 4T1 cells was determined. A 4-10 fold increase in cellular association of paclitaxel was observed when chitosan was adsorbed or conjugated to the PLGA particles. Chitosan-conjugated PLGA microparticles were most cytotoxic with an IC(50) value of 0.77 μM. Confocal microscopy demonstrated that chitosan-PLGA microparticles adhered to the surface of 4T1 cells. Pretreatment of either 4T1 cells or chitosan-PLGA particles with mucin resulted in significant increase in cellular association of paclitaxel. A linear correlation was established between theoretical amount of chitosan used and experimentally determined amount of chitosan adsorbed or conjugated to PLGA nanoparticles. In conclusion, cellular association and cytotoxicity of paclitaxel was significantly enhanced when delivered in chitosan-PLGA particles.