Preparation and characterization of multifunctional chitosan microparticles for lung delivery
The aim of this project was to develop a multifunctional approach with an aim of utilizing both chemotherapeutic agent as well as radio frequency (RF) heating for targeted lung cancer therapy. The system designed for achieving this was a chitosan microparticulate system containing iron oxide nanoparticles and gemcitabine as the chemotherapeutic agent. Iron oxide nanoparticles were prepared by chemical co-precipitation. The iron oxide nanoparticles were made water dispersible by adding an oleic acid-poloxamer coat to the surface of the iron oxide particles. These nanoparticles were incorporated into chitosan microparticles along with gemcitabine by spray drying using a Buchi Mini Spray dryer B-290. The particle size of iron oxide nanoparticles determined by laser light scattering was 123.15 ± 12.98nm (n=3). However, the TEM results revealed a particle size of 17.47 nm± 2.15nm. The larger particle size by laser light scattering which measures the hydrodynamic diameter, could be due to oleic acid and poloxamer associated with nanoparticles and its hydration when dispersed in water. The chitosan microparticles prepared had a d0.5 of 1.59 ± 0.35µm (n=3) and a surface charge of 25.16 ± 0.18mV. The entrapment efficiency of gemcitabine in the chitosan microparticles was found to be 92.30 ± 5.7%. The loading of iron oxide nanoparticles into chitosan matrix was found to be 11.83 ± 3.4%, respectively. DSC studies suggest that the drug is present in non- crystalline state in the chitosan matrix. The TGA studies revealed that the percent weight loss from the spray dried particles at 120ᴼC was around 10%. Aerosol testing of the prepared microparticles on the NGI suggested that the microparticles have a polydisperse population with a fine particle fraction of 47.5%. The application of RF exposure for 500 seconds shows a linear increase in temperature with increase in exposure time. The in vitro release studies showed a significant release (up to 70%) of Gemcitabine over a period of 72 hours and also indicated that release of Iron oxide from the system was negligible. The magnetometer readings indicated that the magnetic properties of nanoparticles are well retained in the chitosan microparticles. The cellular uptake studies display similar cellular uptake behavior for drug solutions treatments and gemcitabine iron oxide microparticle treatments. However the cellular cytotoxicity observed was higher in the gemcitabine iron oxide microparticle treatments compared to drug solutions treatments. The radiofrequency heating experiments conducted on cell suspensions shows a significant heating due to magnetic hyperthermia causing cellular death. Thus it can be concluded that a combination of radiofrequency and chemotherapy with a single system can be achieved and result in particles that are functional in both aspects
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