title: Targeted therapy of colorectal neoplasia with rapamycin in peptide-labeled pegylated octadecyl lithocholate micelles.
abstract: Many powerful drugs have limited clinical utility because of poor water solubility and high systemic toxicity. Here, we formulated a targeted nanomedicine, rapamycin encapsulated in pegylated octadecyl lithocholate micelles labeled with a new ligand for colorectal neoplasia, LTTHYKL peptide. CPC;Apc mice that spontaneously develop colonic adenomas were treated with free rapamycin, plain rapamycin micelles, and peptide-labeled rapamycin micelles via intraperitoneal injection for 35days. Endoscopy was performed to monitor adenoma regression in vivo. We observed complete adenoma regression at the end of therapy. The mean regression rate for peptide-labeled rapamycin micelles was significantly greater than that for plain rapamycin micelles, P<0.01. On immunohistochemistry, we observed a significant reduction in phospho-S6 but not β-catenin expression and reduced tumor cell proliferation, suggesting greater inhibition of downstream mTOR signaling. We observed significantly reduced renal toxicity for peptide-labeled rapamycin micelles compared to that of free drug, and no other toxicities were found on chemistries. Together, this unique targeted micelle represents a potential therapeutic for colorectal neoplasia with comparable therapeutic efficacy to rapamycin free drug and significantly less systemic toxicity.
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, MI, USA; School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.
authors.forename: Supang
authors.initials: S
authors.lastname: Khondee
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Emily F
authors.initials: EF
authors.lastname: Rabinsky
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Owens
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Bishnu P
authors.initials: BP
authors.lastname: Joshi
authors.affiliation: Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Xiyu
authors.initials: X
authors.lastname: Duan
authors.affiliation: Department of Statistics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, USA. Electronic address: thomaswa@umich.edu.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Wang
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use*; D001667:Binding, Competitive / Q000187:drug effects; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016503:Drug Delivery Systems; D006801:Humans; D008095:Lithocholic Acid / Q000737:chemistry*; D051379:Mice; D008823:Micelles; D010455:Peptides; D011092:Polyethylene Glycols / Q000737:chemistry*; D020123:Sirolimus / Q000008:administration & dosage* / Q000627:therapeutic use*; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: D000903:Antibiotics, Antineoplastic; D008823:Micelles; D010455:Peptides; D051176:beta Catenin; D011092:Polyethylene Glycols; D008095:Lithocholic Acid; D020123:Sirolimus
keywords: Colorectal cancer; Endoscopy; Micelles; Rapamycin; Targeted therapy