MESH-Enabled Sustained Delivery of Molecular and Nanoformulated Drugs for Glioblastoma Treatment

Modest tissue penetrance, nonuniform distribution, andsuboptimalrelease of drugs limit the potential of intracranial therapies againstglioblastoma. Here, a conformable polymeric implant, & mu;MESH,is realized by intercalating a micronetwork of 3 x 5 & mu;mpoly(lactic-co-glycolic acid) (PLGA) edges over arraysof 20 x 20 & mu;m polyvinyl alcohol (PVA) pillars for the sustaineddelivery of potent chemotherapeutic molecules, docetaxel (DTXL) andpaclitaxel (PTXL). Four different & mu;MESH configurations wereengineered by encapsulating DTXL or PTXL within the PLGA micronetworkand nanoformulated DTXL (nanoDTXL) or PTXL (nanoPTXL) within the PVAmicrolayer. All four & mu;MESH configurations provided sustaineddrug release for at least 150 days. However, while a burst releaseof up to 80% of nanoPTXL/nanoDTXL was documented within the first4 days, molecular DTXL and PTXL were released more slowly from & mu;MESH.Upon incubation with U87-MG cell spheroids, DTXL-& mu;MESH was associatedwith the lowest lethal drug dose, followed by nanoDTXL-& mu;MESH,PTXL-& mu;MESH, and nanoPTXL-& mu;MESH. In orthotopic models ofglioblastoma, & mu;MESH was peritumorally deposited at 15 days post-cellinoculation and tumor proliferation was monitored via bioluminescenceimaging. The overall animal survival increased from & SIM;30 daysof the untreated controls to 75 days for nanoPTXL-& mu;MESH and90 days for PTXL-& mu;MESH. For the DTXL groups, the overall survivalcould not be defined as 80% and 60% of the animals treated with DTXL-& mu;MESHand nanoDTXL-& mu;MESH were still alive at 90 days, respectively.These results suggest that the sustained delivery of potent drugsproperly encapsulated in conformable polymeric implants could haltthe proliferation of aggressive brain tumors.