Glioblastoma Multiforme (GBM) is a highly malignant, topographically diffuse, grade IV astrocyma that is surgically difficult to remove and impossible to completely resect. It is classified as the most common malignant glioma with 15,000 new cases of GBM in the United States each year. In the past few decades, the respective five-year and ten-year survival rates are a dismal 4.5% and 2.7%, with a median survival of around 14.6 months, despite medical advances in GBM combination therapies. Drug delivery to GBM is especially complicated due to the presence of the blood brain barrier (BBB). Thus, innovative drug delivery systems that can permeabilize the BBB and target tumor sites effectively are extremely relevant.
The “Trojan Bull Drug Delivery System (DDS)” is a dual ligand system that safely allows passage of liposome-encapsulated drugs through the highly-selective blood brain barrier (BBB) to the gliomas. The first ligand is conjugated to Apolipoprotein E (APOE) which facilitates BBB receptor-mediated transcytosis via Low Density Lipoprotein) (LDL) receptors, This ligand has a pH-sensitive hydrazone bond that cleaves off in endosomal compartments (pH gradient 5.5-6.0) and at the tumor site due to the acidic nature of the microenvironment, allowing for more specific uptake of the second ligand. The second ligand is conjugated to Epidermal Growth Factor (EGF) which targets overexpressed EGF receptors on the gliomas, thus delivering the drug to tumor-specific sites. Our liposomal DDS can be adapted to carry a wide range of therapeutics and target other inaccessible brain diseases as well by taking advantage of the APOE ligand and modifying the tumor-specific ligand. Overall, the design of our double-targeted “Trojan Bull” system over non-targeted ones allow drugs to cross the BBB, and deliver drugs to specific sites on the tumor which can reduce unwanted side effects, eliminate the need for invasive surgical resections and provide an innovative drug delivery strategy for complicated tumors like glioblastoma.