Identification of Novel Medulloblastoma Cell-Targeting Peptides for Use in Selective Chemotherapy Drug Delivery.
Kristel C TjandraNigel McCarthyLu YangAlistair J LaosGeorge SharbeenPhoebe A PhillipsHelen ForghamSharon M SagnellaRenee M WhanMaria KavallarisPall ThordarsonJoshua A McCarrollPublished in: Journal of medicinal chemistry (2019)
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.
Keyphrases
- induced apoptosis
- drug delivery
- blood brain barrier
- cell cycle arrest
- cancer therapy
- oxidative stress
- endoplasmic reticulum stress
- single cell
- young adults
- squamous cell carcinoma
- stem cells
- mass spectrometry
- high resolution
- climate change
- mesenchymal stem cells
- brain injury
- risk assessment
- adverse drug
- subarachnoid hemorrhage
- anti inflammatory