Modulation of blood-brain tumor barrier for delivery of magnetic hyperthermia to brain cancer

by Selleckchem | Jun 25 2023

Glioblastoma (GBM) is the most invasive brain tumor and remains lack of effective treatment. The existence of blood-brain tumor barrier (BBTB) constitutes the greatest barrier to non-invasive delivery of therapeutic agents to tumors in the brain. Here, we propose a novel approach to specifically modulate BBTB and deliver magnetic hyperthermia in a systemic delivery mode for the treatment of GBM. BBTB modulation is achieved by targeted delivering fingolimod to brain tumor region via dual redox responsive PCL-SeSe-PEG (poly (ε-caprolactone)-diselenium-poly (ethylene glycol)) polymeric nanocarrier. As an antagonist of sphingosine 1-phosphate receptor-1 (S1P1), fingolimod potently inhibits the barrier function of BBB by blocking the binding of sphingosine 1-phosphate (S1P) to S1P1 in endothelial cells. We found that the modulated BBTB showed slight expression level of tight junction proteins, allowing efficient accumulation of zinc- and cobalt- doped iron oxide nanoclusters (ZnCoFe NCs) with enhanced magnetothermal conversion efficiency into tumor tissues through the paracellular pathway. As a result, the co-delivery of heat shock protein 70 inhibitor VER-155008 with ZnCoFe NCs could realize synergistic magnetic hyperthermia effects upon exposure to an alternating current magnetic field (ACMF) in both GL261 and U87 brain tumor models. This modulation approach brings new ideas for the treatment of central nervous system diseases that require delivery of therapeutic agents across the blood-brain barrier (BBB).

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The proposed approach suggests a novel strategy for the treatment of glioblastoma (GBM), a highly invasive brain tumor that lacks effective treatment options. The main challenge in treating brain tumors is the presence of the blood-brain tumor barrier (BBTB), which hinders the delivery of therapeutic agents to the tumor site. However, this approach aims to overcome this barrier and deliver magnetic hyperthermia therapy in a systemic manner.

The method involves the use of a polymeric nanocarrier called PCL-SeSe-PEG (poly (ε-caprolactone)-diselenium-poly (ethylene glycol)) to specifically target the brain tumor region and modulate the BBTB. Fingolimod, an antagonist of sphingosine 1-phosphate receptor-1 (S1P1), is delivered using this nanocarrier to inhibit the barrier function of the blood-brain barrier (BBB). By blocking the binding of sphingosine 1-phosphate (S1P) to S1P1 in endothelial cells, fingolimod disrupts the tight junctions between cells, leading to increased permeability of the BBTB.

The modulated BBTB allows for efficient accumulation of zinc- and cobalt-doped iron oxide nanoclusters (ZnCoFe NCs) in the tumor tissues through the paracellular pathway. These nanoclusters possess enhanced magnetothermal conversion efficiency, which means they can generate heat when exposed to an alternating current magnetic field (ACMF). Additionally, the delivery system co-delivers a heat shock protein 70 inhibitor called VER-155008 along with the ZnCoFe NCs. This combination of magnetic hyperthermia and heat shock protein inhibition results in synergistic therapeutic effects.

Overall, this approach presents a new and promising strategy for treating GBM and other central nervous system diseases that require the delivery of therapeutic agents across the blood-brain barrier. By specifically modulating the BBTB and utilizing magnetic hyperthermia, this method holds potential for improving treatment outcomes for patients with GBM. However, it's important to note that the proposed approach is described within a research context and would require further study and validation before it can be implemented in clinical settings.