Ultrasound-mediated disruption of the blood tumor barrier for improved therapeutic delivery

Abstract

The blood-brain barrier (BBB) is a major anatomical and physiological barrier limiting the passage of drugs into brain. Central nervous system tumors can impair the BBB by changing the tumor microenvironment leading to the formation of a leaky barrier, known as the blood-tumor barrier (BTB). Despite the change in integrity, the BTB remains effective in preventing delivery of chemotherapy into brain tumors. Focused ultrasound is a unique noninvasive technique that can transiently disrupt the BBB and increase accumulation of drugs within targeted areas of the brain. Herein, we summarize the current understanding of different types of targeted ultrasound mediated BBB/BTB disruption techniques. We also discuss influence of the tumor microenvironment on BBB opening, as well as the role of immunological response following disruption. Lastly, we highlight the gaps between evaluation of the parameters governing opening of the BBB/BTB. A deeper understanding of physical opening of the BBB/BTB and the biological effects following disruption can potentially enhance treatment strategies for patients with brain tumors.

Low-Intensity Focused Ultrasound Technique in Glioblastoma Multiforme Treatment

“…Moreover, there are the presence of receptors and channels such as ATP-binding cassette transporters (ABC efflux transporters) on both the luminal and the abluminal sides of the capillaries, which actively efflux substances out of the CNS ( 16 , 23 ). These most commonly include ABCG2/BCRP, ABCB1/MDR1, ABCC1, ABCC4, ABCC5, ABCA2, and ABCA8 which can egress a large variety of lipid-soluble molecules ( 15 , 21 ). This could explain why cerebral ECs contain significantly higher amounts of mitochondria compared to other tissues ( 22 ).…”

“…On the other hand, the barrier between the newly synthesized microvasculature in a tumor microenvironment and its adjacent expanding tumor, which is formed due to the increased nutritional/oxygen demands, is termed the blood-tumor barrier (BTB) ( 1 ). While the tumor is rapidly proliferating, it compresses the existing vasculature, stimulating the secretion of VEGF (in the hypoxic zone) and triggering angiogenesis-related genes such as hypoxia-inducible factor 1α (HIF1α) ( 15 , 16 ). This results in angiogenesis (to ensure adequate nutritional/oxygen supply) where abnormal new vessels are synthesized, which are relatively more tortuous as well as heterogeneous and leaky ( 15 , 16 ).…”

“…While the tumor is rapidly proliferating, it compresses the existing vasculature, stimulating the secretion of VEGF (in the hypoxic zone) and triggering angiogenesis-related genes such as hypoxia-inducible factor 1α (HIF1α) ( 15 , 16 ). This results in angiogenesis (to ensure adequate nutritional/oxygen supply) where abnormal new vessels are synthesized, which are relatively more tortuous as well as heterogeneous and leaky ( 15 , 16 ). These neo-barriers are modified versions of the original BBB, which have several altered properties compared to the latter ( Box 1 ), such as a decrease or loss of TJs (including their respective proteins such as ZO-1, claudin-3, claudin-5, and occludins), irregular mural cells (pericyte, astrocytes, and microglia) distribution and disruption of astrocytic end-feet which further compromises the barrier integrity ( 1 , 15 , 16 ).…”

“…The BBB, which was described over 100 years ago (in 1913 by Goldmann), is known to impede the delivery of macromolecular (>500 Da) up to 100% and micro-molecular drugs up to 98% from the peripheral circulation to the brain, including chemotherapeutics, thereby leaving the most novel and promising therapeutics unexploited ( 12 – 15 ). Despite the presence of the BBB, several techniques exist to deliver therapeutics in the CNS, either by bypassing or penetrating them (summarized in Table 1 ).…”

Modulation of the blood-tumor barrier to enhance drug delivery and efficacy for brain metastases

“…The LIFU medicated increase in BBB permeability occurs by a combination of physical effects on the NVU and secondary inflammatory responses. 81 Under the exposure of focused ultrasound, microbubbles undergo oscillations within the vasculature impacting the endothelial cell membrane. The exerted pressure of the microbubble against spaces between endothelia transiently increases the aqueous diffusion of drugs into the brain.…”