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Identification of Novel Medulloblastoma Cell-Targeting Peptides for Use in Selective Chemotherapy Drug Delivery.

Authors :
Tjandra KC
McCarthy N
Yang L
Laos AJ
Sharbeen G
Phillips PA
Forgham H
Sagnella SM
Whan RM
Kavallaris M
Thordarson P
McCarroll JA
Source :
Journal of medicinal chemistry [J Med Chem] 2020 Mar 12; Vol. 63 (5), pp. 2181-2193. Date of Electronic Publication: 2019 Aug 01.
Publication Year :
2020

Abstract

Medulloblastoma is a malignant brain tumor diagnosed in children. Chemotherapy has improved survival rates to approximately 70%; however, children are often left with long-term treatment side effects. New therapies that maintain a high cure rate while reducing off-target toxicity are required. We describe for the first time the use of a bacteriophage-peptide display library to identify heptapeptides that bind to medulloblastoma cells. Two heptapeptides that demonstrated high [E1-3 ( 1 )] or low [E1-7 ( 2 )] medulloblastoma cell binding affinity were synthesized. The potential of the peptides to deliver a therapeutic drug to medulloblastoma cells with specificity was investigated by conjugating E1-3 ( 1 ) or E1-7 ( 2 ) to doxorubicin ( 5 ). Both peptide-drug conjugates were cytotoxic to medulloblastoma cells. E1-3 doxorubicin ( 3 ) could permeabilize an in vitro blood-brain barrier and showed a marked reduction in cytotoxicity compared to free doxorubicin ( 5 ) in nontumor cells. This study provides proof-of-concept for developing peptide-drug conjugates to inhibit medulloblastoma cell growth while minimizing off-target toxicity.

Details

Language :
English
ISSN :
1520-4804
Volume :
63
Issue :
5
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
31347843
Full Text :
https://doi.org/10.1021/acs.jmedchem.9b00851