Targeting Brain Tumors with Nanomedicines: Overcoming Blood Brain Barrier Challenges

Abstract

This review elucidates ongoing research, which show improved delivery of anticancer drugs alone and/ or enclosed in carriers collectively called nanomedicines to cross the BBB/ BTB to kill tumor cells and impact patient survival. We highlighted various advances in understanding the mechanism of BTB function that has an impact on anticancer therapeutics delivery. We discussed latest breakthroughs in developing pharmaceutical strategies, including nanomedicines and delivering them across BTB for brain tumor management and treatment.

Methods

We performed an extensive literature search and highlighted important studies on the regulation of BTB permeability with respect to nanotech-based nanomedicines for targeted treatment of brain tumors. We have reviewed research articles that describe the development of specialized molecules and nanospheres, which carry payload of anticancer agents to brain tumor cells across the BBB/ BTB and avoid drug efflux systems. We highlighted research on the identification and development of targeted anti-cancer drug delivery to brain tumors. In addition, we discussed multimeric molecular therapeutics and nanomedicines that were encapsulated in nanospheres for treatment and monitoring of brain tumors.

Results

In this context, we quoted our research on large conductance calcium-activated potassium channels (BKCa) and ATP-dependent potassium channels (KATP) as portals of enhanced antineoplastic drugs delivery. We showed that several innovative drug delivery agents such as liposomes, polymeric nanoparticles, dendrimers and many such tools can be utilized to improve anticancer drugs and nanomedicines across the BTB to reach brain tumor cells.

Conclusion

This review might interest both academic and drug company scientists involved in drug delivery to brain tumors. We further seek to present evidence that BTB modulators can be clinically developed as combination drug or/ and as stand-alone anticancer drugs. Eventually, it is expected that unrelenting effort from the scientific community in developing novel drug delivery methods should increase the survival rate of brain tumor patients, which is dismally low presently.

INTRODUCTION

The global cases of primary brain tumors were estimated at 256,213 in 2012, and in the USA, it is estimated to be 26,070 in 2017 as per the Central Brain Tumor Registry of the US. It is reasonable to assume that the incidence of secondary (metastatic) brain tumors is 10-fold higher than the primary brain tumors. Available literature indicates that nearly half the number of patients post brain radiation and/or surgical resection develop recurrences in the brain within a year leading to high mortality [1]. Glioma, specifically glioblastoma multiforme (GBM) is a deadly form of brain tumors. The treatment is extremely difficult because cancer cells hide behind BBB. These tumors develop extreme resistance to most treatment modalities. The BBB consisting of cerebral microvessels/ capillaries prevents toxic agents in the circulation and delivery of small and large therapeutic molecules, including nanomedicines and nanospheres. Studies have shown that even a damaged and more permeable BBB can pose serious challenges to drug delivery into the brain for the management of stroke, Alzheimer’s and Parkinson’s diseases [2]. However, even a damaged and more permeable BBB can pose serious challenges to drug delivery into the brain. Hence many methods are employed to get around the BBB and BTB.

Glioma Treatment

Conventional diagnosis and treatment are not effective in reducing glioma patient mortality [3]. In addition, low penetration of anticancer drugs across the BBB/ BTB makes the treatment very difficult. Besides, detecting diffused gliomas using imaging agents on CT and MRI is difficult because the imaging agents do not penetrate the intact BBB at the tumor edges. Hence complete resection of tumor mass is very hard. In order to address this issue, we biochemically modulated BTB to increase permeability to drug and imaging agents, selectively to brain tumors in experimental glioma models.

BBB/ BTB and Drug Delivery

Sufficient quantities of most anti-cancer drugs fail to cross the BTB. The invading glioma cells in the tumor edges are ideal targets for anti-cancer agents due to the presence of unique gene/protein expression pattern [3, 4]. Several promising anticancer drugs are effective against cancers outside the brain but fail against brain tumors in clinical trials, in part due to poor BTB penetration. For instance, Gleevec (Novartis, USA) is less useful against brain cancer due to its poor BTB penetration but has demonstrated efficacy in patients with chronic myelogenous leukemia and gastrointestinal stromal tumor [5]. Similarly, invading edges of brain tumor are not clearly detected by imaging agents as the agents do not penetrate intact BTB easily [5, 6]. Some studies showed that peripheral benzodiazepine receptors (PBRs), which are overexpressed in leading edges of gliomas [7] may be targeted with a PBR ligand linked to contrast enhancing dyes [7, 8] or chemotherapy. Others have used DCE-MRI method to measure the brain vascular permeability [9-10]. In our laboratory, we used KCa and KATP channel openers to increase Magnevist delivery to brain tumor edges as imaged by DCE-MRI [11-13]. In order to develop methods for increasing the delivery of new wave of targeted drug entities referred as nanomedicines to brain tumor, we need to have a precise understanding of the basics of BBB and BTB biology and their permeability regulation.

Popularly known as “neurovascular unit” consisting of endothelial cells (ECs), tight junction proteins (TJp) connecting the ECs, glial, pericytes, and astrocytic foot processes form the BBB. A cartoon (Fig. 1) depicts the key differences in morphology and phenotype, specifically with respect to potassium channel expression on BBB and BTB. Essential nutrients, such as glucose and amino acids get through receptor-mediated endocytosis and cross BBB to maintain vital brain functions. The nutrients and most anticancer drugs (except lipohilic drug entities) that are generally water soluble (hydrophilic) require carrier-mediated transport, receptor-mediated transcytosis and absorptive-mediated transcytosis to enter the brain cells.

Hence drug delivery strategies must involve an understanding of these BBB constituents and their interaction with tumor cells, as well. The BTB around the tumor allows very little while mostly throwing out anticancer drugs by efflux mechanism, including small molecules and therapeutic monoclonal antibodies (MAbs) back to the circulation. Now researchers are working on a variety of carriers such as nanomedicines and nanospheres that might penetrate the BTB. Such nanomedicines armed with targeted drugs are expected to supplement conventional chemotherapy and radiotherapy. The development of nanomedicines for treatment of cancer is defined by their penetration across BTB vasculature that surrounds the tumor. Further nanomedicines’ retention in tumor cells without being expelled by multi-drug resistant P-glycoprotein (Pgp) efflux system (Fig. 2) determines their efficacy. The strategy of targeting tumor blood vessel–specific marker(s) for improving targeted drug delivery has generated great interest in the development of more precise and less toxic anticancer drugs [14, 15]. The real challenge is to improve the bioavailability of cytotoxic agents to neoplasms while minimizing toxicity to normal tissues. More research is required to study how to increase tumor-specific drug delivery and at the same time minimize toxicity to normal tissues. Due to advances in personalized therapy, more targeted drugs like cetuximab (Erbitux®), and therapeutic MAbs like ABX-EGF, EMD 720000, h-R3 and Herceptin, are found to be effective in treating cancers outside the brain. However, they fail to control brain tumors because they fail to cross the BTB in adequate quantity. These targeted anticancer drugs are ineffective to block epidermal growth factor receptors (EGFR), which are often amplified and mutated in human gliomas. Despite evidence of ‘leaky’ tumor centre, the BBB surrounding the proliferating glioma is still impermeable [16, 17]. So low-grade gliomas are insensitive to some chemotherapeutics partly due to incomplete drug delivery across BTB. Therefore, more research is needed to understand the biochemical regulation of the BBB in its normal and abnormal (BTB) states. Then only efforts to deliver therapeutic compounds to brain tumors might yield favourable results.