Established and Emerging Strategies for Drug Delivery Across the Blood-Brain Barrier in Brain Cancer

Abstract

Brain tumors are characterized by very high mortality and, despite the continuous research on new pharmacological interventions, little therapeutic progress has been made. One of the main obstacles to improve current treatments is represented by the impermeability of the blood vessels residing within nervous tissue as well as of the new vascular net generating from the tumor, commonly referred to as blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), respectively. In this review, we focused on established and emerging strategies to overcome the blood-brain barrier to increase drug delivery for brain cancer. To date, there are three broad strategies being investigated to cross the brain vascular wall and they are conceived to breach, bypass, and negotiate the access to the nervous tissue. In this paper, we summarized these approaches highlighting their working mechanism and their potential impact on the quality of life of the patients as well as their current status of development.

Keywords: CED; FUS; blood-brain barrier; brain cancer; drug delivery; nanomedicine.

Figure 1

Anatomy of the neurovascular unit: the blood-brain barrier (BBB) structure is determined by different biological components that organize together in forming the neurovascular unit. Endothelial cells form the lumen of the capillary, interact with the basal lamina and the pericytes embedded in this matrix. The astrocytes, neurons, and microglia cells further support this cellular backbone. Other physical agents determining the barrier function of this specialized endothelium are the tight junctions (TJs) that are expressed between adjacent endothelial cells.

Figure 2

Scheme of brain microdialysis: A catheter is inserted in the brain tissue, while a controlled system (i.e., a syringe pump) injects in the brain a perfusate solution. At the end of the catheter is applied a semi-permeable membrane that allows for the injection of the perfusate, as well as for the collection of the dialysate composed by the perfusate and the brain tissue fluids. The collected dialysate can be eventually analyzed for its molecular content.

Figure 3

Effects of focused ultrasound on BBB permeability: External FUS is applied in combination with microbubbles injection. As a function of the acoustic pressure applied it can be obtained by: inertial cavitation and sonoporation, where relatively high levels of acoustic pressures induce the microparticles to collapse with a consequent controlled breaching of the BBB; and stable cavitation and micro-streaming where relatively low levels of acoustic pressure induce the microbubbles to vibrate increasing the flow shear stress in the proximity of the vascular wall with a consequent increase of the endothelial transport through caveolae.

Figure 4

Gliadel wafers treatment: (a) physical and pharmaceutical features of Gliadel; (b) identification of the brain tumor, (c) maximal safe resection of the tumor tissue, (d) application of the Gliadel wafers in the tumor bed. Up to eight disks can be applied.

Figure 5

BBB negotiation: Current methods to negotiate BBB are obtained by modifying the therapeutic molecules or the carrier surface to increase their affinity for the BBB. They are generally referred to as: (a) adsorptive-mediated transcytosis (AMT) which is based on a positive surface charge of the therapeutics, (b) transporter-mediated transcytosis (TMT) which exploits the affinity of the therapeutics for endothelial transporters (i.e., GLUT1 and choline receptor), and (c) receptor-mediated transcytosis (RMT) which exploits the affinity of the therapeutics for endothelial receptors (i.e., nicotinic acetylcholine receptor, low-density lipoprotein receptor (LDLR), and transferrin receptor (TfR)).

Figure 6

Bradykinin effect on TJs: bradykinin (BK), interacting with its receptors B1R and B2R, induces the intracellular release of Ca²⁺ that can affect occludin polymerization as well as increase the production of nitric oxide that relaxes the junctions. The activation of this pathway is also associated with a decrease in TJ mRNA expression.

Figure 7

Exploiting tumor metabolic changes to overcome the BBB: Brain cancer lesions overexpress GP60 and secreted protein acidic and rich in cysteine (SPARC) that favor albumin nanoparticle trafficking over the BBB as well as cancer cell internalization in the abluminal side, respectively.