79 Role of HA-Based Gels in Developing Novel Therapies for Malignant Brain Tumors Glioblastoma selleck chemical (GBM) is the most common primary brain tumor in adults with a very poor prognosis.80-82 Currently, treatment for GBM is maximal surgical tumor resection (debulking)83 followed by radiation therapy, with concomitant and adjuvant chemotherapy.84,85 However, recurrence rates of GBM and the associated patient mortality are nearly 100%. Despite the numerous pre-clinical studies, most in vivo GBM models do not mimic the clinical scenario of surgical debulking and focus on treating solid intact intracranial tumors. Therefore, in light of the central role tumor resection plays in clinical GBM therapy, development and implementation of mouse models of GBM resection are a necessity.

86 In a recent study, we have developed a mouse resection model of GBM in cranial windows using malignant GBM cells engineered with fluorescent and bioluminescent proteins, which allow real time visualization of both growth and resection of tumors in vivo thereby simulating the clinical scenario of GBM resection. While resection of the primary tumor mass has shown clinical benefit, adjuvant chemotherapy has provided limited additional benefit (Fig. 2A).80,84 One of the major impediments to the efficient delivery of many therapeutic molecules is the blood brain barrier (BBB)87 and vascular dysfunction in the tumor,88 which prevents many drugs from reaching brain tumor cells. One of the approaches to overcome the drug delivery problems to intracranial tumors is to develop onsite means to deliver novel tumor specific agents.

There are a number of limitations to effectively test stem cell-based therapeutic interventions in a mouse model of GBM resection, including developing methods to introduce stem cells into the resection cavity to prevent rapid ��wash-out�� of a significant number of cells by cerebrospinal fluid (CSF). Additionally, it is critical to allow efficient secretion of anti-GBM therapies and retain the ability of stem cells to migrate from the resection cavity into the parenchyma toward invasive tumor deposits. Due to their ability to provide a physiologic environment that promotes stem cell survival while permitting easy in vivo transplantation and cell retention, we utilized sECMs that are based on a thiol-modified hyaluronic acid (HA) and a thiol reactive cross-linker (polyethylene glycol diacrylate), which provides biocompatibility, physiological relevance, and customizability (Fig.

1).26 Figure 2. Stem Cells engineered to express S-TRAIL have therapeutic efficacy in mouse tumor model of GBM resection. (A) Photomicrographs of mice bearing established U87-mCherry-Fluc GBM tumors in the cranial window that … In our recent study, we first assessed the influence of sECMs on stem cell survival in vivo and Entinostat showed that there was a significant increase in cell viability in mice bearing sECM encapsulated NSC as compared with the non-encapsulated NSC (Fig.