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Identification of Novel Medulloblastoma Cell-Targeting Peptides for Use in Selective Chemotherapy Drug Delivery.
- 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.
- Subjects :
- Antineoplastic Agents pharmacokinetics
Antineoplastic Agents pharmacology
Blood-Brain Barrier drug effects
Blood-Brain Barrier metabolism
Brain Neoplasms metabolism
Cell Line
Cell Line, Tumor
Child
Doxorubicin pharmacokinetics
Doxorubicin pharmacology
Drug Carriers chemistry
Drug Delivery Systems
Humans
Medulloblastoma metabolism
Oligopeptides chemistry
Peptide Library
Antineoplastic Agents administration & dosage
Brain Neoplasms drug therapy
Doxorubicin administration & dosage
Drug Carriers metabolism
Medulloblastoma drug therapy
Oligopeptides metabolism
Subjects
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