Local delivery with microparticles

Glioblastomas (GB) are poorly understood lethal tumors with a 12-18 month median survival despite aggressive treatment. Rapidly dividing tumor cells, invasion of normal brain tissue, and the growth of new blood vessels from pre-existing ones, or angiogenesis, are three cardinal features of their behavior. There are presently no effective therapeutic agents in the clinic that successfully inhibit these attributes. Tumor growth depends largely on angiogenesis and it has become evident that complex and constantly changing vascular remodeling is taking place during the various phases of tumor development. It is thus very important to conduct research on drug candidates that inhibit tumor angiogenesis and ultimately halt tumor growth.

We have recently demonstrated the growth of subcutaneous glioma tumor growth can be reduced by endogenous inhibitors of angiogenesis delivered locally using a controlled delivery system in the shape of microspheres. The microspheres were composed of PLGA that is approved for use in humans by the Food and Drug Administration. PLGA polymeric microspheres have been used as a sustained delivery system of many proteins, drugs and others factors such as cytokines, hormones, enzymes and vaccines. Due to their size and shape, polymeric microspheres, can easily be implanted by stereotactic injection at the tumor site without the need for a craniotomy and damage to the surrounding brain tissue.

PF-4 is a protein that inhibits angiogenesis. In our studies PF-4/CTF was labeled with rhodamine, which enables the tracking of the release kinetics of peptide from the microspheres, in vitro and in vivo ; and its distribution in vivo without the need for indirect studies with an agent that can differ in both biological and physical properties. We recently demonstrated for the first time the therapeutic efficacy of tailored PLGA microspheres loaded with PF-4/CTF has the ability to significantly inhibit intracranial human glioma growth. MRI was successfully implemented for monitoring the dynamic changes of tumor growth and inhibition in response to the slow release treatment of the polymeric microspheres. This work is conducted in collaboration with Dr. Machluf at the Technion University in Haifa , Israel . She is a world-renowned expert on developing novel drug delivery systems including microparticles.

Related Publications

Benny O, Duvashan-Eshet M, Cargioli T, Bello L, Bikfalvi A, Carroll RS, Machluf M.. Continuous Delivery of Endogenous Inhibitors from PLGA Polymeric Microspheres Inhibits Glioma Tumor Growth. Clinical Cancer Research, 2005; 11:768-776.