title: Cancer cell surface induced peptide folding allows intracellular translocation of drug.
abstract: Many lead molecules identified in drug discovery campaigns are eliminated from consideration due to poor solubility and low cell permeability. These orphaned molecules could have clinical value if solubilized and delivered properly. SVS-1 is a de novo designed peptide that preferentially folds at the surface of tumor cells, adopting a β-hairpin conformation that rapidly translocates into the cytoplasm, and ultimately nucleus, of cells. SVS-1 is stable in serum and small molecules attached to the peptide are effectively delivered to cancer cells via mechanisms involving physical translocation and, to a lesser extent, clathrin-dependent endocytosis. For example, ligating the model hydrophobic drug Paclitaxel (PTX) to SVS-1 improved its aqueous solubility by ~1000-fold and successfully delivered and released PTX to cancer cells in vitro and tumors in vivo without toxic adjuvants. These results suggest that SVS-1 can serve as a simple, effective delivery platform for molecules with poor solubility and permeability.
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Medina
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States. Electronic address: Joel.Schneider@nih.gov.
authors.forename: Joel P
authors.initials: JP
authors.lastname: Schneider
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D001692:Biological Transport; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006801:Humans; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D017510:Protein Folding; D044967:Serum / Q000737:chemistry; D012995:Solubility
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D010455:Peptides; C574293:SVS-1 peptide; D017239:Paclitaxel
keywords: Biodistribution; Cell-penetrating peptide; Drug delivery; In vivo efficacy; Paclitaxel; Translocation