Electrospun nanofibrous scaffolds increase the efficacy of stem cell-mediated therapy of surgically resected glioblastoma

Abstract

Engineered stem cell (SC)-based therapy holds enormous promise for treating the incurable brain cancer glioblastoma (GBM). Retaining the cytotoxic SCs in the surgical cavity after GBM resection is one of the greatest challenges to this approach. Here, we describe a biocompatible electrospun nanofibrous scaffold (bENS) implant capable of delivering and retaining tumor-homing cytotoxic stem cells that suppress recurrence of post-surgical GBM. As a new approach to GBM therapy, we created poly(l-lactic acid) (PLA) bENS bearing drug-releasing human mesenchymal stem cells (hMSCs). We discovered that bENS-based implant increased hMSC retention in the surgical cavity 5-fold and prolonged persistence 3-fold compared to standard direct injection using our mouse model of GBM surgical resection/recurrence. Time-lapse imaging showed cytotoxic hMSC/bENS treatment killed co-cultured human GBM cells, and allowed hMSCs to rapidly migrate off the scaffolds as they homed to GBMs. In vivo, bENS loaded with hMSCs releasing the anti-tumor protein TRAIL (bENSsTR) reduced the volume of established GBM xenografts 3-fold. Mimicking clinical GBM patient therapy, lining the post-operative GBM surgical cavity with bENSsTR implants inhibited the re-growth of residual GBM foci 2.3-fold and prolonged post-surgical median survival from 13.5 to 31 days in mice. These results suggest that nanofibrous-based SC therapies could be an innovative new approach to improve the outcomes of patients suffering from terminal brain cancer.

Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells

“…Such an aggregation causes the nanoparticles to behave like larger particles [58] and may affect systemic delivery for therapeutic application in the brain. However, evaluation of potential therapeutics through direct intratumoral injection including nanoparticle delivery to in vivo models of GBM [59, 60] or at the point of patient tumor resection or biopsy [61–65] in several studies indicates that such systemic transport challenges can be circumvented to facilitate therapeutic delivery in a clinical setting.…”

Tissue engineering scaffolds in the treatment of brain disorders in geriatric patients

“…Of interest to this work is the use of tissue engineering scaffolds for brain cavity reconstruction after surgery (Figure ). A group of researchers have extensively studied the prospect of cell‐mediated therapy using cytotoxic tumor cells . The group fabricated a fibrin scaffold and seeded it with hMSCs which was later transplanted in a mice brain tumor cavity.…”

Emerging Roles of Electrospun Nanofibers in Cancer Research

“…The results divulged an effective inhibition of regrowth of residual glioblastoma and a significantly longer median survival time in mice after implantation to the surgical cavity, in comparison to cells without releasing TRAIL cultured on nanofiber implants. [16] …”

“…[15] Another application is that drug-loaded fibrous matrices are implanted into the post-operative tumor cavity immediately following resection of tumors, with the aim of killing residual tumor cells and inhibiting recurrence of tumors. [16] The third application is that drug-loaded fragmented nanofibers are intra-tumorally injected, which can be fabricated by cutting aligned electrospun fibers under cryogenic conditions. [17] In the future work, regenerative medicine should be combined with cancer therapies allowing simultaneous cancer suppression and tissue regeneration after resection of tumors.…”