Ph.D Thesis


Ph.D StudentOfra Benny
SubjectDevelopment of Polymeric Microspheres Releasing Angiogenesis
Inhibitors and Anti-cancer Drugs for the Treatment
of Glioma Tumor
DepartmentDepartment of Biotechnology and Food Engineering
Supervisor Full Professors Machluf Marcelle
Full Thesis textFull thesis text - English Version


Abstract

My thesis focuses on the development of polymeric microspheres releasing angiogenesis inhibitors and anti-cancer drug.

The common systemic drug administration requires repeated large doses of drug administrations, due to short half-lives of drugs in blood, and low availability at target organs. Large drug doses may cause side-effects and high costs. To overcome these problems, microspheres for drug delivery are being used to release drugs continuously, resulting in significant therapeutic outcome over longer periods of time, using decreased drug quantities. However, when using unstable drugs or factors, it is vital to choose parameters which retain the biological activity of these factors after release from the microspheres.

In our study we focused on a challenging therapeutic problem: brain tumor. The main goal was to introduce an efficient polymeric-microspheres delivery system for unstable factors - endogenous angiogenesis inhibitors and synthetic chemotherapeutic drugs - for the treatment of glioma.

Glioblastoma (GBM), the highest grade of glioma, is an aggressive brain tumor. The current treatments - surgery, radiotherapy and chemotherapy - are ineffective and GBM remains incurable. One of the major characteristics of GBM is angiogenesis - the formation of new blood vessels from pre-existing ones. The growth of solid tumors is critically dependent upon angiogenesis, making angiogenesis inhibition a powerful anticancer therapeutic approach. However, angiogenesis inhibitors often unstable and require high systematic levels.

Microspheres composed of Poly(lactic-co-glycolic)acid (PLGA) were developed for release of two endogenous inhibitors of angiogenesis: PEX and PF4/CTF, as well as a synthetic anti-cancer drug. In the first step, we characterize the microspheres in terms of morphology, degradation and release kinetics.  The next step was to incorporate the ant-cancer drug, PEX and PF4/CTF in PLGA microspheres. The biological activity of these factors was confirmed in-vitro in various cell culture assays. We clearly demonstrated that all the factors retained their biological activity, even several days after release from the microspheres. In-vivo studies in mice models (subcutaneous and intracranial tumors) revealed that a single local injection of PLGA microspheres, significantly reduced tumor volume many days post treatment. Immonohistochemical studies were performed in order to determine proliferation, apoptosis and angiogenesis. Our findings indicate that PLGA microspheres loaded with anti-cancer drugs and unstable factors as endogenous inhibitors of angiogenesis, is efficient system to treat brain tumors. We believe that this system may offer an alternative treatment for glioma patients in the future, and that this delivery method has significant advantages over the current systemic treatments.