A Scalable Platform for Fabricating Biodegradable Microparticles with Pulsatile Drug Release.

Pulsatile drug delivery systems have the potential to improve patient adherence and therapeutic efficacy by providing a sequence of doses in a single injection. Herein, a novel platform, termed Particles Uniformly Liquified and Sealed to Encapsulate Drugs (PULSED) is developed, which enables the high-throughput fabrication of microparticles exhibiting pulsatile release. In PULSED, biodegradable polymeric microstructures with an open cavity are formed using high-resolution 3D printing and soft lithography, filled with drug, and sealed using a contactless heating step in which the polymer flows over the orifice to form a complete shell around a drug-loaded core. Poly(lactic-co-glycolic acid) particles with this structure can rapidly release encapsulated material after delays of 10 ± 1, 15 ± 1, 17 ± 2, or 36 ± 1 days in vivo, depending on polymer molecular weight and end group. The system is even compatible with biologics, releasing over 90% of bevacizumab in its bioactive form after a two-week delay in vitro. The PULSED system is highly versatile, offering compatibility with crystalline and amorphous polymers, easily injectable particle sizes, and compatibility with several newly developed drug loading methods. Together, these results suggest that PULSED is a promising platform for creating long-acting drug formulations that improve patient outcomes due to its simplicity, low cost, and scalability.

BRCA1 identified as a modulator of temozolomide resistance in P53 wild-type GBM using a high-throughput shRNA-based synthetic lethality screening.

Glioblastoma multiforme (GBM), the most common type of primary brain tumor, is universally fatal, with a median survival duration ranging from 12-15 months despite maximum treatment efforts. Temozolomide (TMZ) is the current standard of care for GBM patients; however patients usually develop resistance to TMZ and limits its benefit. The identification of novel synergistic targets in GBM will lead to the development of new targeted drugs, which could be combined with broad-spectrum cytotoxic agents. In this study, we used a high-throughput synthetic lethality screen with a pooled short hairpin DNA repair library, in combination with TMZ, to identify targets that will enhance TMZ-induced antitumor effects. Using an unbiased bioinformatical analysis, we identified BRCA1 as a potential promising candidate gene that induced synthetic lethality with TMZ in glioma sphere-forming cells (GSCs). BRCA1 knockdown resulted in antitumor activity with TMZ in P53 wild-type GSCs but not in P53 mutant GSCs. TMZ treatment induced a DNA damage repair response; the activation of BRCA1 DNA repair pathway targets and knockdown of BRCA1, together with TMZ, led to increased DNA damage and cell death in P53 wild-type GSCs. Our study identified BRCA1 as a potential target that sensitizes TMZ-induced cell death in P53 wild-type GBM, suggesting that the combined inhibition of BRCA1 and TMZ treatment will be a successful targeted therapy for GBM patients.