Universität zu Köln

Cho, Choi-Fong ORCID: 0000-0003-1473-9773, Farquhar, Charlotte E., Fadzen, Colin M., Scott, Benjamin, Zhuang, Pei, von Spreckelsen, Niklas ORCID: 0000-0002-9873-1711, Loas, Andrei, Hartrampf, Nina ORCID: 0000-0003-0875-6390, Pentelute, Bradley L. and Lawler, Sean E. (2022). A Tumor-Homing Peptide Platform Enhances Drug Solubility, Improves Blood-Brain Barrier Permeability and Targets Glioblastoma. Cancers, 14 (9). BASEL: MDPI. ISSN 2072-6694

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Abstract

Simple Summary Glioblastoma (GBM) is a fatal and incurable brain cancer, and current treatment options have demonstrated limited success. Here, we describe the use of a dg-Bcan-Targeting-Peptide (BTP-7) that has BBB-penetrating properties and targets GBM. Conjugation of BTP-7 to an insoluble anti-cancer drug, camptothecin (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 patient-derived GBM xenograft in mice, leading to higher toxicity in GBM cells compared to normal brain tissues and prolonged animal survival. This work demonstrates a proof-of-concept for BTP-7 as a tumor-targeting peptide for therapeutic delivery to GBM. 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Cho, Choi-Fong UNSPECIFIED orcid.org/0000-0003-1473-9773 UNSPECIFIED Farquhar, Charlotte E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fadzen, Colin M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Scott, Benjamin UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhuang, Pei UNSPECIFIED UNSPECIFIED UNSPECIFIED von Spreckelsen, Niklas UNSPECIFIED orcid.org/0000-0002-9873-1711 UNSPECIFIED Loas, Andrei UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartrampf, Nina UNSPECIFIED orcid.org/0000-0003-0875-6390 UNSPECIFIED Pentelute, Bradley L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lawler, Sean E. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-688302
DOI:	10.3390/cancers14092207
Journal or Publication Title:	Cancers
Volume:	14
Number:	9
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTEOLYTIC CLEAVAGE; HYALURONAN-BINDING; IN-VITRO; GLIOMA; BREVICAN; PROTEOGLYCAN; CAMPTOTHECIN; THERAPY; BEHAB; CELLS Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68830