Feature Article: Polymeric Nanoparticulate Drug Delivery Through The Blood Brain Barrier

Abstract

Alzheimer's disease (AD) is the most common cause of dementia among the elderly, affecting 5% of Americans over age 65, and 20% over age 80. An excess of senile plaques (β-amyloid protein) and neurofibrillary tangles (tau protein), ventricular enlargement, and cortical atrophy characterizes it. Unfortunately, targeted drug delivery to the Central Nervous System (CNS), for the therapeutic advancement of neurodegenerative disorders such as Alzheimer's, is complicated by restrictive mechanisms imposed at the blood brain barrier (BBB). Opsonization by plasma proteins in the systemic circulation is an additional impediment to cerebral drug delivery. Here, we attempt to show that biodegradable polymeric nanoparticles (NPs) with appropriate surface modifications can deliver drugs of interest beyond the BBB for diagnostic and therapeutic applications, thus allowing the study of neurological disorders. Particularly, the radiolabelled Cu²⁺ or Fe³⁺ metal chelator Clioquinol (CQ), which has a high affinity for amyloid plaques with a radioisotope ¹²⁵I, and encapsulated ¹²⁵I-CQ within small, spherical, lipophilic drug carriers are capable of crossing the BBB. In this feature article, the biodistribution patterns of such nanoparticle drug carriers in wild type Swiss Webster mice are compared with free ¹²⁵I-CQ. The physicochemical properties of the NPs at different surfactant concentrations, stabilizers, and amyloid-affinity agents could influence the transport mechanism.

Keywords:

• amyloid-beta protein
• blood brain barrier
• Alzheimer's disease
• clioquinol
• AD metallobiology

Acknowledgments

This work was supported by NIH F31 GM06638-03. The authors thank Drs. Charles White and Dwight German for supply of brain tissue, and the UT Southwestern Medical Center Alzheimer's Disease Center (ADC) for support of this work. The investigations were conducted in conjunction with Cancer Imaging Program Pre-ICMC P20 CA086354. This report represents the research efforts under the triangular MOU between the University of Texas Southwestern Medical Center at Dallas, the University of Texas at Dallas and Karnatak University, Dharwad, India.

Notes

21. Roney C., Arora V., Kulkarni, P., Bennett M., Antich P., Bonte F., unpublished data.