Drug Encapsulated Aerosolized Microspheres as a Biodegradable, Intelligent Glioma Therapy
Floyd, Julee Alaina
MetadataShow full item record
The grim prognosis for patients diagnosed with malignant gliomas necessitates the development of new therapeutic strategies for localized and sustained drug delivery to combat tumor drug resistance and regrowth. Here we introduced the novel formulation of drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy (DREAM BIG Therapy) that is applied post-resection. DREAM BIG Therapy consists of three types of microspheres [poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), and poly(å-caprolactone) (PCL)] containing various encapsulated chemotherapeutics, suspended in a degradable, aqueous poly(N-isopropylacrylamide) (PNIPAM) solution. The thermoresponsive PNIPAM solution is capable of suspending drug encapsulated microspheres at room temperature which can be "sprayed on" the post-surgical site. The physiological temperature of the treatment site (37°C) would cause PNIPAM solution to solidify and form an adherent gel layer with entrapped microspheres, providing intimate contact with remaining tumor cells. Over time, PLGA (rapid degradation), PLA (medium speed degradation), and then PCL (slow degradation) microspheres would break down, releasing their drug payloads in a sequential, multi-drug release directly to the tumor site, addressing cancerous regrowth and tumor drug resistance. This dissertation will address the development of DREAM BIG Therapy, from microsphere formulation to pilot in vivo studies. Initial work focused on developing blank and drug encapsulated microspheres using emulsion techniques. Preliminary studies utilized rhodamine B as a model drug for encapsulation in PLGA, PLA, and PCL particles and optimized formulation parameters to achieve a high encapsulation. Then, gefitinib, IgG, and lomustine were encapsulated in PLGA, PLA, and PCL microspheres, respectively, achieving encapsulation efficiencies greater than 80% and drug loadings greater than 0.3%. The in vitro release of gefitinib and IgG were also studied. Gefitinib released from PLGA microspheres over 40 days while the release of IgG from PLA microspheres was slower, over a year long period. The microsphere-PNIPAM system was tested for aerosolized application ex vivo. The aqueous PNIPAM solution suspended the microspheres and was aerosolized before phase transitioning to an adherent gel layer on the tissue, entrapping the microspheres on the tissue surface. Finally, when tested in vivo, the gefitinib encapsulated PLGA microspheres entrapped in PNIPAM slowed the tumor volume growth of a subcutaneous C6 glioma in comparison to blank PLGA microspheres entrapped in PNIPAM. Overall, this research confirms the potential of DREAM BIG therapy for future use with multiple chemotherapeutics and microsphere types to combat gliomas at a localized site.
- Chemical engineering