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

  • J Med Chem. 2020 Mar 12;63(5):2181-2193. doi: 10.1021/acs.jmedchem.9b00851.
Kristel C Tjandra  1  2 ,  Nigel McCarthy  3 ,  Lu Yang  3 ,  Alistair J Laos  1  2 ,  George Sharbeen  4 ,  Phoebe A Phillips  1  4 ,  Helen Forgham  3  1  5 ,  Sharon M Sagnella  3 ,  Renee M Whan  1  6 ,  Maria Kavallaris  3  1  5 ,  Pall Thordarson  1  2 ,  Joshua A McCarroll  3  1  5
Affiliations
  • 1. Australian Centre for Nanomedicine, ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, UNSW Sydney, Sydney, NSW 2052, Australia.
  • 2. School of Chemistry, UNSW Sydney, Sydney, NSW 2052, Australia.
  • 3. Tumour Biology & Targeting Program, Children's Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre, Sydney, NSW 2031, Australia.
  • 4. Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, and School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia.
  • 5. School of Women's and Children's Health, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2052, Australia.
  • 6. Biomedical Imaging Facility Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW 2052, Australia.
PMID: 31347843 DOI: 10.1021/acs.jmedchem.9b00851
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.