Targeting potassium channels for increasing delivery of imaging agents and therapeutics to brain tumors

Divya Khaitan,Nagendra S Ningaraj

doi:10.3389/fphar.2013.00062

Abstract

Every year in the US, 20,000 new primary and nearly 200,000 metastatic brain tumor cases are reported. The cerebral microvessels/capillaries that form the blood–brain barrier not only protect the brain from toxic agents in the blood but also pose a significant hindrance to the delivery of small and large therapeutic molecules. Different strategies have been employed to circumvent the physiological barrier posed by blood–brain tumor barrier (BTB). Studies in our laboratory have identified significant differences in the expression levels of certain genes and proteins between normal and brain tumor capillary endothelial cells (ECs). In this study, we validated the non-invasive and clinically relevant dynamic contrast enhancing-magnetic resonance imaging (DCE-MRI) method with invasive, clinically irrelevant but highly accurate quantitative autoradiography method using rat glioma model. We also showed that DCE-MRI metric of tissue vessel perfusion-permeability is sensitive to changes in blood vessel permeability following administration of calcium-activated potassium (BKCa) channel activator NS-1619. Our results show that human gliomas and brain tumor ECs that overexpress BKCa channels can be targeted for increased BTB permeability for MRI enhancing agents to brain tumors. We conclude that monitoring the outcome of increased MRI enhancing agents’ delivery to microsatellites and leading tumor edges in glioma patients would lead to beneficial clinical outcome.

Highlights

A significant number of primary tumor cases are reported each year in the US, and the metastatic tumors from systemic cancers are at least 10-fold higher than the primary brain tumors
Different strategies have been employed to circumvent the physiological barrier posed by blood–brain tumor barrier (BTB), often based on a conception of the barrier being controlled by the “neurovascular unit”consisting of endothelial cells (ECs), tight junctional proteins connecting the ECs, glial, pericytes, and astrocytic foot processes, all of which interact with neurons (Quencer and Neuwelt, 2002; Toda, 2003; Zhang et al, 2003; Pardridge, 2004; Rautioa and Chikhale, 2004; Rich and Bigner, 2004; Kinoshita et al, 2006; Lee et al, 2006)
It is incorrect to assume that the disrupted blood–brain barrier (BBB) facilitates drug delivery to gliomas because diffuse tumor cell invasion is a hallmark of even low-grade gliomas

Summary

Introduction

A significant number of primary tumor cases are reported each year in the US, and the metastatic tumors from systemic cancers are at least 10-fold higher than the primary brain tumors. Targeting tumor and tumor blood vessel-specific marker(s) is a good strategy to control tumor growth (Ningaraj et al, 2003a). It is, critical to study whether tumor-specific drug delivery has the potential to minimize toxicity to normal tissues, and improve bioavailability of cytotoxic agents to neoplasms. The BTB is “leaky” in the tumor center, the established microvessels feeding the proliferating glioma edge as well as the brain tissue surrounding the tumor are nearly as impermeable as the BBB (Inamura and Black, 1994; Liu et al, 2001, 2002; Ningaraj et al, 2002, 2003a,b, 2009a,b; Black and Ningaraj, 2004, 2006, 2007; Khaitan et al, 2009). It is incorrect to assume that the disrupted BBB facilitates drug delivery to gliomas because diffuse tumor cell invasion is a hallmark of even low-grade gliomas

Methods

Results

Conclusion