title: 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 (bENS(sTR)) reduced the volume of established GBM xenografts 3-fold. Mimicking clinical GBM patient therapy, lining the post-operative GBM surgical cavity with bENS(sTR) 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.
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Juli R
authors.initials: JR
authors.lastname: Bagó
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Guillaume J
authors.initials: GJ
authors.lastname: Pegna
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Onyi
authors.initials: O
authors.lastname: Okolie
authors.affiliation: Joint Department of Biomedical Engineering at University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, 27695, USA.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Mohiti-Asli
authors.affiliation: Joint Department of Biomedical Engineering at University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, 27695, USA; College of Engineering, University of Missouri, Columbia, MO, 65211, USA.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Loboa
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Biomedical Research Imaging Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. Electronic address: hingtgen@email.unc.edu.
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Hingtgen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001921:Brain / Q000473:pathology / Q000601:surgery; D001932:Brain Neoplasms / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D002460:Cell Line; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D005909:Glioblastoma / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D006801:Humans; D008819:Mice, Nude; D057139:Nanofibers / Q000737:chemistry* / Q000648:ultrastructure; D011091:Polyesters / Q000737:chemistry; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000166:cytology; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D011091:Polyesters; C033616:poly(lactide)
keywords: Cancer; Cytotoxic stem cell; Electrospun nanofibrous scaffolds; Molecular imaging; Surgical resection