title: EGFR-Targeted Polymeric Mixed Micelles Carrying Gemcitabine for Treating Pancreatic Cancer.
abstract: The objective of this study was to design GE11 peptide (YHWYGYTPQNVI) linked micelles of poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-gemcitabine-graft-dodecanol (PEG-b-PCC-g-GEM-g-DC) for enhanced stability and target specificity of gemcitabine (GEM) to EGFR-positive pancreatic cancer cells. GE11-PEG-PCD/mPEG-b-PCC-g-GEM-g-DC mixed micelles showed EGFR-dependent enhanced cellular uptake, and cytotoxicity as compared to scrambled peptide HW12-PEG-PCD/mPEG-b-PCC-g-GEM-g-DC mixed micelles and unmodified mPEG-b-PCC-g-GEM-g-DC micelles. Importantly, GE11-linked mixed micelles preferentially accumulated in orthotopic pancreatic tumor and tumor vasculature at 24 h post systemic administration. GE11-linked mixed micelles inhibited orthotopic pancreatic tumor growth compared to HW12-linked mixed micelles, unmodified mPEG-b-PCC-g-GEM-g-DC micelles, and free GEM formulations. Tumor growth inhibition was mediated by apoptosis of tumor cells and endothelial cells as determined by immunohistochemical staining. In summary, GE11-linked mixed micelles is a promising approach to treat EGFR overexpressing cancers.
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: Goutam
authors.initials: G
authors.lastname: Mondal
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: Virender
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center , Omaha, Nebraska United States.
authors.forename: Surendra K
authors.initials: SK
authors.lastname: Shukla
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center , Omaha, Nebraska United States.
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: Ram I
authors.initials: RI
authors.lastname: Mahato
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000138:chemical synthesis / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008823:Micelles; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010455:Peptides / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; C572557:GE11 peptide; D008823:Micelles; D010455:Peptides; D011091:Polyesters; D011108:Polymers; C556102:poly(ethylene glycol)-block-poly(2-methyl-2-carboxylpropylene carbonate-graft-dodecanol); D003841:Deoxycytidine; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; C512478:EGFR protein, human; D066246:ErbB Receptors; D000093542:Gemcitabine