AB001. Development of tumour-targeted therapy for the treatment of adult and paediatric high-grade gliomas.

BACKGROUND: Brain cancer patients, especially those suffering from high-grade gliomas (HGGs) face a bleak future with very dismal long-term disease-free survival outcomes due to the limited treatment options currently available. Therefore, there is an unmet need for new therapeutic intervention that extends patients' progress-free survival and improves their quality of life. A significant hurdle is the inability of current chemotherapy agents to cross the blood-brain barrier (BBB). BBB acts as a protective shield that filters the blood to ensure nothing harmful makes it to the brain. This protection is usually good, but it becomes a problem if you want to deliver therapeutic cancer drugs through it. This barrier blocks 98% of drugs from entering the brain. Even the ones that cross BBB are unevenly distributed in the normal brain and tumour tissue, resulting in mediocre treatment and severe side effects. METHODS: We are developing drug delivery systems that can cross the BBB and facilitate the specific accumulation of drugs in the tumour tissue. This will significantly improve the efficacy of anticancer drugs in treating various brain cancers and reduce systemic toxicity. Our group has explored and developed BBB crossing and tumour targeting near infra-red dyes, which can be covalently attached to Food and Drug Administration (FDA)-approved chemotherapy agents (drug-dye conjugates), thereby delivering it to the tumour tissue. RESULTS: We synthesized such drug-dye conjugates to target various aberrant pathways in HGG and tested these conjugates against patient-derived HGG cell lines. One such conjugate was tested on a mouse model of glioblastoma, an aggressive form of HGG, and shown to cross the BBB and specifically accumulate in tumour tissue, bringing forth tumour burden reduction. CONCLUSIONS: The results obtained from this work serve as proof of principle that enables tumour-specific drug delivery to treat HGG. This work also paves the way for treating other brain cancers and central nervous system (CNS) disorders like Parkinson's and Alzheimer's disease, for which no adequate therapy exists.

Elucidating the cellular uptake mechanisms of heptamethine cyanine dye analogues for their use as an anticancer drug-carrier molecule for the treatment of glioblastoma.

The development of chemotherapies for glioblastoma is hindered by their limited bioavailability and toxicity on normal brain function. To overcome these limitations, we investigated the structure-dependent activity of heptamethine cyanine dyes (HMCD), a group of tumour-specific and BBB permeable near-infrared fluorescent dyes, in both commercial (U87MG) and patient-derived GBM cell lines. HMCD analogues with strongly ionisable sulphonic acid groups were not taken up by patient-derived GBM cells, but were taken up by the U87MG cell line. HMCD uptake relies on a combination of transporter uptake through organic anion-transporting polypeptides (OATPs) and endocytosis into GBM cells. The uptake of HMCDs was not affected by p-glycoprotein efflux in GBM cells. Finally, we demonstrate structure-dependent cytotoxic activity at high concentrations (EC50 : 1-100 µM), likely due to mitochondrial damage-induced apoptosis. An in vivo orthotopic glioblastoma model highlights tumour-specific accumulation of our lead HMCD, MHI-148, for up to 7 days following a single intraperitoneal injection. These studies suggest that strongly ionisable groups like sulphonic acids hamper the cellular uptake of HMCDs in patient-derived GBM cell lines, highlighting cell line-specific differences in HMCD uptake. We envisage these findings will help in the design and structural modifications of HMCDs for drug-delivery applications for glioblastoma.