A Tumor-Homing Peptide Platform Enhances Drug Solubility, Improves Blood–Brain Barrier Permeability and Targets Glioblastoma
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cancers-14-02207-v3.pdf
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16.29 MB
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Checksum (MD5)
03148c37b6ab76e43a3a52c55b3d32ae
Author(s)
Cho, Choi-Fong
Farquhar, Charlotte E.
Fadzen, Colin M.
Scott, Benjamin
Zhuang, Pei
von Spreckelsen, Niklas
Loas, Andrei
Hartrampf, Nina
Pentelute, Bradley L.
Lawler, Sean E.
Date Issued
April 28, 2022
Publisher
Multidisciplinary Digital Publishing Institute
Citation
Cancers 14 (9): 2207 (2022)
Version
Final published version
Abstract
Background: Glioblastoma (GBM) is the most common and deadliest malignant primary brain tumor, contributing significant morbidity and mortality among patients. As current standard-of-care demonstrates limited success, the development of new efficacious GBM therapeutics is urgently needed. Major challenges in advancing GBM chemotherapy include poor bioavailability, lack of tumor selectivity leading to undesired side effects, poor permeability across the blood–brain barrier (BBB), and extensive intratumoral heterogeneity. Methods: We have previously identified a small, soluble peptide (BTP-7) that is able to cross the BBB and target the human GBM extracellular matrix (ECM). Here, we covalently attached BTP-7 to an insoluble anti-cancer drug, camptothecin (CPT). Results: We demonstrate that conjugation of BTP-7 to CPT improves drug solubility in aqueous solution, retains drug efficacy against patient-derived GBM stem cells (GSC), enhances BBB permeability, and enables therapeutic targeting to intracranial GBM, leading to higher toxicity in GBM cells compared to normal brain tissues, and ultimately prolongs survival in mice bearing intracranial patient-derived GBM xenograft. Conclusion: BTP-7 is a new modality that opens the door to possibilities for GBM-targeted therapeutic approaches.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Center for Environmental Health Sciences
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DOI of Published Version
https://doi.org/10.3390/cancers14092207
