title: Fibrin matrices enhance the transplant and efficacy of cytotoxic stem cell therapy for post-surgical cancer.
abstract: Tumor-homing cytotoxic stem cell (SC) therapy is a promising new approach for treating the incurable brain cancer glioblastoma (GBM). However, problems of retaining cytotoxic SCs within the post-surgical GBM resection cavity are likely to significantly limit the clinical utility of this strategy. Here, we describe a new fibrin-based transplant approach capable of increasing cytotoxic SC retention and persistence within the resection cavity, yet remaining permissive to tumoritropic migration. This fibrin-based transplant can effectively treat both solid and post-surgical human GBM in mice. Using our murine model of image-guided model of GBM resection, we discovered that suspending human mesenchymal stem cells (hMSCS) in a fibrin matrix increased initial retention in the surgical resection cavity 2-fold and prolonged persistence in the cavity 3-fold compared to conventional delivery strategies. Time-lapse motion analysis revealed that cytotoxic hMSCs in the fibrin matrix remain tumoritropic, rapidly migrating from the fibrin matrix to co-localize with cultured human GBM cells. We encapsulated hMSCs releasing the cytotoxic agent TRAIL (hMSC-sTR) in fibrin, and found hMSC-sTR/fibrin therapy reduced the viability of multiple 3-D human GBM spheroids and regressed established human GBM xenografts 3-fold in 11 days. Mimicking clinical therapy of surgically resected GBM, intra-cavity seeding of therapeutic hMSC-sTR encapsulated in fibrin reduced post-surgical GBM volumes 6-fold, increased time to recurrence 4-fold, and prolonged median survival from 15 to 36 days compared to control-treated animals. Fibrin-based SC therapy could represent a clinically compatible, viable treatment to suppress recurrence of post-surgical GBM and other lethal cancer types.
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: 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; D001932:Brain Neoplasms / Q000601:surgery / Q000628:therapy*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D005337:Fibrin / Q000494:pharmacology*; D005909:Glioblastoma / Q000601:surgery / Q000628:therapy*; D006801:Humans; D008819:Mice, Nude; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D033581:Stem Cell Transplantation; D054457:Tissue Scaffolds / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D005337:Fibrin
keywords: Cancer; Cytotoxic stem cell; Fibrin scaffold; Molecular imaging; Surgical resection