The development of minocycline-loaded microparticles and injectable alginate scaffolds composites to prolong release for the treatment of glioblastoma

Glioblastoma multiforme (GBM) is a Grade IV malignant brain cancer characterized by rapid progression and high recurrence. Minocycline (MINO), an antibiotic know to have antiangiogenic properties, has potential for GBM treatment ; however to address the limitations of current therapies, this project integrates two biomaterial-based delivery systems: 1) electrosprayed minocycline-loaded PLGA microparticles, which exhibited a 67-80% burst release within the first hour, and 2) injectable alginate scaffolds, which exhibited a 36-43% burst release within the first day. MINO-loaded MPs alone exhibit a significant burst release that limits sustained therapeutic exposure. The alginate (i.e. a biocompatible polysaccharide) injectable hydrogels are capable of decreasing the burst release compared to MPs and possibly increase the control release of drug. Combining both systems may therefore reduce burst release and extend overall delivery.Thus, the objective of this study was to investigate the drug release kinetics from MINO-loaded MPs, MINO loaded alginate scaffolds and MINO-loaded MPs in alginate scaffolds. MINO-loaded MPs were fabricated via vertical electrospraying using a 0.9 mL/ flow rate, 14kV voltage, and 20 cm distance. Polyethylene glycol (PEG) was incorporated to enhance MINO solubility, and the MPs were collected on copper /glass plates. Sodium alginate scaffolds (2.0 wt/vol%) were prepared by dissolving sodium alginate and calcium carbonate, homogenizing with glucono-delta lactone and with MINO or drug loaded MPs and injecting into 24-well plates to mold them uniformly. Release kinetics for MPs, MINO-loaded scaffolds (scaffold + MINO), and MINO-loaded MP scaffolds (scaffold + MINO-loaded MPs) were assessed in 1x DPBS by measuring MINO absorbance at 350 nm with a microplate reader. The drug release kinetics studied showed high burst release on Day 1 for the Mino-loaded MPs alone (45%), and a substantially reduced initial burst release for the other groups (16% for both scaffold + MINO and and scaffold + MINO-loaded MPs). On Day 2, 3 and 6, MINO-loaded scaffold released significantly more drug compared to MINO-loaded MPs and MINO-loaded MP scaffolds had a trend of having a lower percentage of cumulative release of drug compared to MINO-loaded scaffolds. In conclusion, the combination of MINO and PLGA MINO-loaded MPs with the injectable alginate scaffolds will prolong the release of the therapeutic agents and allow better control of the release kinetics compared to using MPs alone with the MINO-loaded MPs and scaffold combination having a trend of being a more promising for sustained released for localized GBM treatment. Future studies will focus on evaluating U87 cell viability following treatment with the different groups to determine whether the prolonged and controlled release results enhance the cytotoxic effect.