Effect of size of PLGA and chitosan-PLGA particles on the cellular association, cytotoxicity, and anti-tumor efficacy of paclitaxel

Based on previous research, it was hypothesized that PLGA microparticles of size range 1 - 2 mum adhered to mucus on the surface of cancer cells that enhanced the cellular association of the drug. The objectives of this research are to: (1) investigate the effect of size of paclitaxel-containing PLGA particles on their anti-tumor efficacy in a mouse model, (2) test the hypothesis that larger microparticles adhere to mucus, and (3) study the effect of modifying the surface of PLGA particles with mucoadhesive chitosan on the cellular association and cytotoxicity of paclitaxel.;When delivered in PLGA microparticles of sizes land 10 mum, paclitaxel arrested tumor growth in balb/c mice for 13 days. The in vitro size-dependent increase in cellular association of paclitaxel was independent of the duration of incubation of the PLGA particles with 4T1 cells, and was significantly enhanced by coating the 4T1 cells or the surface of PLGA particles with mucus. Previous research proved that PLGA particles of size 2 mum adhere to the surface of 4T1 cells. However, confocal microscopy confirmed that the PLGA nanoparticles and microparticles did not adhere to the non mucus-secreting BBMEC.;To test if the addition of mucoadhesive chitosan further increased the cellular association and cytotoxicity of paclitaxel, this polymer was physically adsorbed or chemically conjugated to the surface of PLGA particles of size 400 nm or 2 mum. A 4 to 10 fold increase in cellular association of paclitaxel was observed when chitosan was adsorbed or conjugated to the nanoparticles. Similarly, the cellular association of paclitaxel increased 4 to 6 fold when delivered in chitosan-PLGA microparticles. Chitosan-conjugated PLGA microparticles were most cytotoxic with an IC50 value of 0.77.;In summary, the anti-tumor efficacy of paclitaxel is enhanced when delivered in PLGA microparticles. The cellular association and cytotoxicity of paclitaxel can be further enhanced by delivering the drug in chitosan-PLGA particles.