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

Abstract

Modest tissue penetrance, nonuniform distribution, and suboptimal release of drugs limit the potential of intracranial therapies against glioblastoma. Here, a conformable polymeric implant, μMESH, is realized by intercalating a micronetwork of 3 × 5 μm poly(lactic-co-glycolic acid) (PLGA) edges over arrays of 20 × 20 μm polyvinyl alcohol (PVA) pillars for the sustained delivery of potent chemotherapeutic molecules, docetaxel (DTXL) and paclitaxel (PTXL). Four different μMESH configurations were engineered by encapsulating DTXL or PTXL within the PLGA micronetwork and nanoformulated DTXL (nanoDTXL) or PTXL (nanoPTXL) within the PVA microlayer. All four μMESH configurations provided sustained drug release for at least 150 days. However, while a burst release of up to 80% of nanoPTXL/nanoDTXL was documented within the first 4 days, molecular DTXL and PTXL were released more slowly from μMESH. Upon incubation with U87-MG cell spheroids, DTXL-μMESH was associated with the lowest lethal drug dose, followed by nanoDTXL-μMESH, PTXL-μMESH, and nanoPTXL-μMESH. In orthotopic models of glioblastoma, μMESH was peritumorally deposited at 15 days post-cell inoculation and tumor proliferation was monitored via bioluminescence imaging. The overall animal survival increased from ∼30 days of the untreated controls to 75 days for nanoPTXL-μMESH and 90 days for PTXL-μMESH. For the DTXL groups, the overall survival could not be defined as 80% and 60% of the animals treated with DTXL-μMESH and nanoDTXL-μMESH were still alive at 90 days, respectively. These results suggest that the sustained delivery of potent drugs properly encapsulated in conformable polymeric implants could halt the proliferation of aggressive brain tumors.