Abstract
The presence of barriers, such as the blood–brain barrier (BBB) and brain–tumor barrier (BTB), limits the penetration of antineoplastic drugs into the brain, resulting in poor response to treatments. Many techniques have been developed to overcome the presence of these barriers, including direct injections of substances by intranasal or intrathecal routes, chemical modification of drugs or constituents of BBB, inhibition of efflux pumps, physical disruption of BBB by radiofrequency electromagnetic radiation (EMP), laser-induced thermal therapy (LITT), focused ultrasounds (FUS) combined with microbubbles and convection enhanced delivery (CED). However, most of these strategies have been tested only in preclinical models or in phase 1–2 trials, and none of them have been approved for treatment of brain tumors yet. Concerning the treatment of brain metastases, many molecules have been developed in the last years with a better penetration across BBB (new generation tyrosine kinase inhibitors like osimertinib for non-small-cell lung carcinoma and neratinib/tucatinib for breast cancer), resulting in better progression-free survival and overall survival compared to older molecules. Promising studies concerning neural stem cells, CAR-T (chimeric antigen receptors) strategies and immunotherapy with checkpoint inhibitors are ongoing.
Highlights
An exception is represented by the recent randomized open-label phase III study DEPOSEIN, in which patients with neoplastic meningitis from breast cancer were randomly assigned to systemic chemotherapy versus systemic chemotherapy plus intrathecal liposomal cytarabine: an improvement of PFS in the arm treated with intrathecal injections was observed [44]
Another strategy proposed by Bobo et al [94] to bypass blood-brain barrier (BBB) in patients with glioblastoma is local drug delivery by convection-enhanced delivery (CED), which consists in the maintenance of a continuous pressure gradient and the creation of a fluid convection by the implantation into the tumor of a reservoir-catheter system, leading to the distribution of the drugs
In the last few decades, a better understanding of BBB/brain–tumor barrier (BTB) physiology has led to the development of a multitude of strategies to target brain tumor cells; most of them have been tested only in pre-clinical models or in small phase 1–2 trials, and none has been approved for treatment of both primary brain tumors or brain metastases
Summary
The brain is extremely sensitive to a wide range of circulating toxic substances, and neuronal function needs an optimal microenvironment, maintained by three main different barrier systems: the blood-brain barrier (BBB), the blood cerebro-spinal fluid barrier (BCSFB) and the meningeal barrier [1,2]. Endothelial cells, localized in the inner blood vessel layer, are connected by tight junctions (TJs) formed by proteins like claudin -3, -5, occludins and zonula occludens proteins -1, -2, -3 They limit the paracellular diffusion of substances, such as solutes, ions and water, and create high electrical resistance (>1800 Ω × cm2 ) to the diffusion of polar molecules [7]. AMT allows the transcytosis through the BBB of large molecules not requiring interaction with a receptor This nonspecific process is mediated by the negative charge of the surface layer of glycans and glycoproteins called the glycocalyx, which enables the binding of cationic molecules that are internalized. Neuronal supply for oxygen and nutrients is traduced in chemical messages by the release of neurotransmitters like glutamate and GABA (gamma-aminobutyric acid): astrocytes are able to detect glutamate and GABAergic neuronal levels and convert those signals into vasomotor commands, in order to increase blood and nutrient supply for neurons [25]
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