title: Fusion of cell-penetrating peptides to thermally responsive biopolymer improves tumor accumulation of p21 peptide in a mouse model of pancreatic cancer.
abstract: Current therapies for the treatment of pancreatic cancer are limited. The limitations of this type of treatment are abundant. The majority of chemotherapeutic agents used in clinics are highly toxic to both tumor cells and normal tissues due to the lack of specificity. Resistance can develop due to overexposure of these agents. To address these issues, these agents must be made more exclusive toward the tumor site. We have developed a macromolecular carrier based on the sequence of the biopolymer elastin-like polypeptide (ELP) that is able to aggregate upon reaching the externally heated tumor environment. This carrier is specific to the tumor as it only aggregates at the heated tumor site. ELP is soluble below its transition temperature but will aggregate when the temperature is raised above its transition temperature. ELP was modified by p21, a cell cycle inhibitory peptide, and the addition of Bac, a cell-penetrating peptide with nuclear localization capabilities. In this study, p21-ELP-Bac and its control, ELP-p21, were used in cell proliferation studies using the pancreatic cancer cell lines Panc-1, MiaPaca-2, and S2013. ELP-p21 had little effect on proliferation, while the half maximal inhibitory concentration of p21-ELP-Bac was ∼30 μM. As translocation across the plasma membrane is a limiting step for delivery of macromolecules, these polypeptides were utilized in a pancreatic xenograft model to study the plasma clearance, biodistribution, tumor accumulation, and tumor reduction capabilities of the polypeptide with and without a cell-penetrating peptide.
authors.affiliation: Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Walker
authors.affiliation: Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Jung Su
authors.initials: JS
authors.lastname: Ryu
authors.affiliation: Department of Neurosurgery, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Eddie
authors.initials: E
authors.lastname: Perkins
authors.affiliation: Division of Hematology and Oncology, University of Louisville, Louisville, KY, USA.
authors.forename: Lacey R
authors.initials: LR
authors.lastname: McNally
authors.affiliation: Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Drazen
authors.initials: D
authors.lastname: Raucher
mesh_terms: D000818:Animals; D001704:Biopolymers / Q000008:administration & dosage / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000737:chemistry*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000737:chemistry / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013329:Structure-Activity Relationship; D013696:Temperature; D014407:Tumor Cells, Cultured
chemical_list: D001704:Biopolymers; D057846:Cell-Penetrating Peptides; D050759:Cyclin-Dependent Kinase Inhibitor p21
keywords: elastin-like polypeptide; macromolecule; peptide; targeted drug delivery