Addressing BBB Heterogeneity: A New Paradigm for Drug Delivery to Brain Tumors

Abstract

Effective treatments for brain tumors remain one of the most urgent and unmet needs in modern oncology. This is due not only to the presence of the neurovascular unit/blood–brain barrier (NVU/BBB) but also to the heterogeneity of barrier alteration in the case of brain tumors, which results in what is referred to as the blood–tumor barrier (BTB). Herein, we discuss this heterogeneity, how it contributes to the failure of novel pharmaceutical treatment strategies, and why a “whole brain” approach to the treatment of brain tumors might be beneficial. We discuss various methods by which these obstacles might be overcome and assess how these strategies are progressing in the clinic. We believe that by approaching brain tumor treatment from this perspective, a new paradigm for drug delivery to brain tumors might be established.

Status Quo and Trends of Intra-Arterial Therapy for Brain Tumors: A Bibliometric and Clinical Trials Analysis

“…These technologies are based on local delivery of therapeutics directly to the brain, thereby bypassing the BBB entirely and facilitating smaller initial drug dosage and minimal systemic absorption. They include drug delivery to the cerebrospinal fluid via intrathecal or intraventricular injections and interstitial delivery via biodegradable polymers or catheters [17]. Diffusion-based approaches such as intracavitary wafers placed at the time of tumor resection, intrathecal injection using the Ommaya reservoir, and intraventricular injection via lumbar puncture are limited by the restricted tissue penetrance of most therapeutic agents into structures not immediately adjacent to the brain surface, hindering them from reaching deep and infiltrative tumor cells [21,27,117].…”

“…In this multiomics era of biomedical research, insights into biological aspects of cancer have allowed us to identify potential targets that could improve the clinical course of these devastating diseases [12][13][14][15]. The first-pass effect and the bloodbrain barrier (BBB), however, remain significant obstacles for therapeutic access to the brain and hinder novel therapies from unfolding pharmacologic potential [16][17][18][19][20].…”

“…Intra-arterial injection into intracranial vessels is one such strategy, with the potential to increase drug responses to primary and metastatic brain tumors [21][22][23][24][25][26][27][28][29][30]. Intra-arterial infusion of anti-cancer therapies can be combined with concurrent administration of a variety of agents, including chemical reagents, penetration drug carriers, or microbubbles for focused ultrasound, to selectively open the BBB in areas of interest [17,25,31,32]. By accessing intracranial vessels through peripheral arteries and directly administering BBB-disrupting and therapeutic agents into the arterial supply to the brain, intra-arterial injection facilitates greatly improved local drug delivery, increased intra-tumoral concentration, and lowered systemic exposure [33][34][35][36][37].…”

Think Big, Start Small: How Nanomedicine Could Alleviate the Burden of Rare CNS Diseases

“…However, and in contrast with other organs or tissues, drugs administered intravenously should present either an increased ability to passively diffuse throughout the BBB (such as, for instance, carmustine and temozolomide, two very hydrophobic drugs) or use one of the assisted transcytosis pathways, as schematically described in Figure 2. A recent review by Griffith et al lists the most common transporters and carriers overexpressed at the BBB and which can be potentially used by exogenous molecules to reach the brain parenchyma [43,44].…”

“…In addition to the widely used intravenous administration which requires a specific design of nanoparticles to target and bypass the BBB, another possible yet quite invasive route of administration is direct intracerebral drug infusion. This surgically assisted route of administration can either be achieved via stereotactic injection in the pathological area (i.e., the intraparenchymal route) in order to form local depots or via intraventricular administration [44]. Due to the extremely risky nature of these invasive administration methods, they are mainly restricted for life-threatening conditions and do not allow repetitive injections [45].…”