title: A free cysteine prolongs the half-life of a homing peptide and improves its tumor-penetrating activity.
abstract: The accessibility of extravascular tumor tissue to drugs is critical for therapeutic efficacy. We previously described a tumor-targeting peptide (iRGD) that elicits active transport of drugs and macromolecules (covalently coupled or co-administered) across the vascular wall into tumor tissue. Short peptides (iRGD is a 9-amino acid cyclic peptide) generally have a plasma half-life measured in minutes. Since short half-life limits the window of activity obtained with a bolus injection of iRGD, we explored to extend the half-life of the peptide. We show here that addition of a cysteine residue prolongs the plasma half-life of iRGD and increases the accumulation of the peptide in tumors. This modification prolongs the activity of iRGD in inducing macromolecular extravasation and leads to greater drug accumulation in tumors than is obtained with the unmodified peptide. This effect is mediated by covalent binding of iRGD to plasma albumin through a disulfide bond. Our study provides a simple strategy to improve peptide pharmacokinetics and activity. Applied to RGD, it provides a means to increase the entry of therapeutic agents into tumors.
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Pang
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Braun
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: She
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Venkata R
authors.initials: VR
authors.lastname: Kotamraju
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA; Department of Surgery, Columbia University, College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Kazuki N
authors.initials: KN
authors.lastname: Sugahara
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA; Laboratory of Cancer Biology, Centre of Excellence for Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia.
authors.forename: Tambet
authors.initials: T
authors.lastname: Teesalu
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA; Center for Nanomedicine, University of California Santa Barbara, Santa Barbara, CA 93106-9610, USA; Department of Cell, Molecular and Developmental Biology, Bio II, Rm. #3119, University of California Santa Barbara, Santa Barbara, CA 93106-9610, USA. Electronic address: ruoslahti@sanfordburnham.org.
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003545:Cysteine / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D016503:Drug Delivery Systems; D006207:Half-Life; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism*; D009842:Oligopeptides / Q000097:blood / Q000737:chemistry / Q000378:metabolism*
chemical_list: D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D003545:Cysteine
keywords: Albumin; Bystander activity; Extra cysteine; Half-life; Tumor extravasation; iRGD