Local endostatin treatment of gliomas administered by microencapsulated producer cells

Abstract

We describe a technique for the treatment of malignant brain tumors based on local delivery of the anti-angiogenic protein endostatin from genetically engineered cells encapsulated in ultrapure sodium alginate. Alginate consists of L-guluronic and D-mannuronic acid, which in the presence of divalent cations forms an extended gel network, in which cells reside and remain immunoisolated, when implanted into the rat brain. Here, we show that endostatin-transfected cells encapsulated in alginate maintain endostatin secretion for at least four months after intracerebral implantation in rats. During the implantation period 70% of the encapsulated cells remained viable, as opposed to 85% in in vitro-cultured capsules. Rats that received transplants of BT4C glioma cells, together with endostatin-producing capsules (0.2 microg/ml per capsule), survived 84% longer than the controls. The endostatin released from the capsules led to an induction of apoptosis, hypoxia, and large necrotic avascular areas within 77% of the treated tumors, whereas all the controls were negative. The encapsulation technique may be used for many different cell lines engineered to potentially interfere with the complex microenvironment in which tumor and normal cells reside. The present work may thus provide the basis for new therapeutic approaches toward brain tumors.

Inhibition of medulloblastoma cell invasion by Slit

“…Microencapsulation bioreactor technology has been used to assess the efficacy of antiangiogenic compounds on glioma growth (Joki et al, 2001;Read et al, 2001). Sodium alginate bioreactors provide an isolated environment for continuous protein delivery.…”

“…Sodium alginate bead cell encapsulation for treatment of brain tumors has been described (Read et al, 2001). Briefly, a stock solution of 0.137 M NaCl, 5.5 mM D-glucose, 5.45 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid (HEPES) was prepared at a pH of 7.3.…”

The role of nitric oxide in cancer

“…In order to make the NO-generating cells suitable for therapeutic delivery they have been encapsulated within a semipermeable alginate-poly-L-lysine membrane. Encapsulated cells are protected from environmental stresses encountered in the host (such as the host immune response) and can be delivered to tumour site(s) in a nude mouse model [58], [59]. Following delivery, high concentrations of NO and reactive nitrogen species can be generated by administration of the appropriate inducer.…”

Structure and Function of Collagen‐Derived Endostatin Inhibitors of Angiogenesis

“…Clinical studies appear feasible in the near future, given the high human endostatin production (300 mg/l) in yeast (19) and quite a few anti-angiogenic components are currently under study in clinical trials (3). There are already a few studies in animal models on potential delivery strategies for endostatin, using in situ gene transfection (49) or the inoculation with endostatin-producing transfected cells after their encapsulation into alginate beads (50,51). The latter strategy may allow the local, multifocal therapy of tumors as shown for an aggressive intracerebral glioma (51).…”