Use of FLOSEAL® as a scaffold and its impact on induced neural stem cell phenotype, persistence, and efficacy

Abstract

Induced neural stem cells (iNSCs) have emerged as a promising therapeutic platform for glioblastoma (GBM). iNSCs have the innate ability to home to tumor foci, making them ideal carriers for antitumor payloads. However, the in vivo persistence of iNSCs limits their therapeutic potential. We hypothesized that by encapsulating iNSCs in the FDA‐approved, hemostatic matrix FLOSEAL®, we could increase their persistence and, as a result, therapeutic durability. Encapsulated iNSCs persisted for 95 days, whereas iNSCs injected into the brain parenchyma persisted only 2 weeks in mice. Two orthotopic GBM tumor models were used to test the efficacy of encapsulated iNSCs. In the GBM8 tumor model, mice that received therapeutic iNSCs encapsulated in FLOSEAL® survived 30 to 60 days longer than mice that received nonencapsulated cells. However, the U87 tumor model showed no significant differences in survival between these two groups, likely due to the more solid and dense nature of the tumor. Interestingly, the interaction of iNSCs with FLOSEAL® appears to downregulate some markers of proliferation, anti‐apoptosis, migration, and therapy which could also play a role in treatment efficacy and durability. Our results demonstrate that while FLOSEAL® significantly improves iNSC persistence, this alone is insufficient to enhance therapeutic durability.

Injectable pH Thermo-Responsive Hydrogel Scaffold for Tumoricidal Neural Stem Cell Therapy for Glioblastoma Multiforme

“…The most significant challenge with neural stem cell therapy for treatment of post-surgical GBM is the fast clearance observed from the site of implantation. Several commercially available and synthetic-based polymer systems have been investigated as a delivery approach to overcome this clinical limitation [ 13 , 14 , 15 , 16 , 17 , 18 ]. However, there are several factors to consider when designing a polymer-based scaffold material to encapsulate and deliver neural stem cells.…”

“…Unlike other studies that have explored the use of biomaterials for the delivery of NSCs, the present work has focused on elucidating the impact of (1) NSCs on biomaterial properties and (2) biomaterials on NSC functionality [ 13 , 14 , 15 , 16 , 17 , 18 ]. Although previous studies showed that other scaffold materials possess the ability to enhance in vivo NSC persistence, in the present report we highlight key features and/or properties that can influence overall efficacy of NSC-laden CS and CS-CNC hydrogels.…”

“…Furthermore, modifications to the scaffold properties such as morphology, diameter, porosity, and size did not have a significant clinical impact on efficacy [ 15 ]. Given the limitations of these approaches, there have been other strategies aimed at exploring biomaterials that can (1) encapsulate neural stem cells and (2) maintain a physiological environment applicable for neural stem cell viability and retention following implantation [ 16 , 17 , 18 ]. Preclinical studies utilizing commercially available synthetic extracellular-matrix based materials have shown to increase NSC persistence from 2 weeks to 95 days [ 18 ] and extend overall survival in mice following implantation [ 16 ].…”

Current approaches in enhancing TRAIL therapies in glioblastoma

“…FLOSEAL-encapsulated, TRAIL-secreting hiNSCs persisted in the brain for 95 days in a murine recurrent GBM model, and the mice survived 30–60 days longer than the control mice that were treated with nonencapsulated TRAIL-secreting hiNSCs. 58 Hence, patient-derived tumor-homing stem cells that deliver TRAIL to tumor sites hold potential as drug delivery vehicles.…”

“… 91 For example, patients could receive maximal surgical resection and TRAIL-secreting personalized stem cells encapsulated with biodegradable hemostatic agents such as FLOSEAL to prevent tumor recurrence. 58 , 92 In addition, TRAIL sensitizers could minimize the effects of TRAIL resistance. For patients who are ineligible for surgery, chemotherapy, and radiation could be accompanied by administration of either TRAIL proteins encapsulated NPs or TRAIL genes encapsulating NPs to target both intrinsic and extrinsic apoptotic pathways.…”