title: Therapeutic Efficacy of a Family of pHLIP-MMAF Conjugates in Cancer Cells and Mouse Models.
abstract: The targeting of therapeutics specifically to diseased tissue is crucial for the development of successful cancer treatments. The approach here is based on the pH(low) insertion peptide (pHLIP) for the delivery of a potent mitotic inhibitor monomethyl auristatin F (MMAF). We investigated six pHLIP variants conjugated to MMAF to compare their efficacy in vitro against cultured cancer cells. While all pHLIP-MMAF conjugates exhibit potent pH- and concentration-dependent killing, their cytotoxicity profiles are remarkably different. We also show that the lead conjugate exhibits significant therapeutic efficacy in mouse models without overt toxicities. This study confirms pHLIP-monomethyl auristatin conjugates as possible new therapeutic options for cancer treatment and supports their further development.
authors.affiliation: Department of Chemistry, Lehigh University , 6 East Packer Avenue, Bethlehem, Pennsylvania 18015, United States.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Burns
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center , 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, United States.
authors.forename: Harvey
authors.initials: H
authors.lastname: Hensley
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center , 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, United States.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Robinson
authors.affiliation: Department of Chemistry, Lehigh University , 6 East Packer Avenue, Bethlehem, Pennsylvania 18015, United States.
authors.forename: Damien
authors.identifier: 0000-0002-1866-0694
authors.initials: D
authors.lastname: Thévenin
mesh_terms: D062365:Aminobenzoates / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018796:Immunoconjugates / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*
chemical_list: D062365:Aminobenzoates; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D009842:Oligopeptides; D010455:Peptides; C543533:auristatin
keywords: cytotoxicity; in vivo efficacy; monomethyl auristatins; peptide drug delivery; targeted drug delivery; tumor acidity