posted on 2024-01-04, 19:05authored byPerpetue Bataille Backer, Tayo Alex Adekiya, Yushin Kim, Terry-Elinor R. Reid, Michael Thomas, Simeon K. Adesina
Glioblastoma (GBM) is the most aggressive and fatal brain
tumor,
with approximately 10,000 people diagnosed every year in the United
States alone. The typical survival period for individuals with glioblastoma
ranges from 12 to 18 months, with significant recurrence rates. Common
therapeutic modalities for brain tumors are chemotherapy and radiotherapy.
The main challenges with chemotherapy for the treatment of glioblastoma
are high toxicity, poor selectivity, and limited accumulation of therapeutic
anticancer agents in brain tumors as a result of the presence of the
blood–brain barrier. To overcome these challenges, researchers
have explored strategies involving the combination of targeting peptides
possessing a specific affinity for overexpressed cell-surface receptors
with conventional chemotherapy agents via the prodrug approach. This
approach results in the creation of peptide drug conjugates (PDCs),
which facilitate traversal across the blood–brain barrier (BBB),
enable preferential accumulation of chemotherapy within the neoplastic
microenvironment, and selectively target cancerous cells. This approach
increases accumulation in tumors, thereby improving therapeutic efficiency
and minimizing toxicity. Leveraging the affinity of the HAIYPRH (T7)
peptide for the transferrin receptor (TfR) overexpressed on the blood–brain
barrier and glioma cells, a novel T7-SN-38 peptide drug conjugate
was developed. The T7-SN-38 peptide drug conjugate demonstrates about
a 2-fold reduction in glide score (binding affinity) compared to T7
while maintaining a comparable orientation within the TfR target site
using Schrödinger-2022–3 Maestro 13.3 for ligand preparation
and Glide SP-Peptide docking. Additionally, SN-38 extends into a solvent-accessible
region, enhancing its susceptibility to protease hydrolysis at the
cathepsin B (Cat B) cleavable site. The SN-38-ether-peptide drug conjugate
displayed high stability in buffer at physiological pH, and cleavage
of the conjugate to release free cytotoxic SN-38 was observed in the
presence of exogenous cathepsin B. The synthesized peptide drug conjugate
exhibited potent cytotoxic activities in cellular models of glioblastoma
in vitro. In addition, blocking transferrin receptors using the free
T7 peptide resulted in a notable inhibition of cytotoxicity of the
conjugate, which was reversed when exogenous cathepsin B was added
to cells. This work demonstrates the potential for targeted drug delivery
to the brain in the treatment of glioblastoma using the transferrin
receptor-targeted T7-SN-38 conjugate.