title: Fine-tuning vitamin E-containing telodendrimers for efficient delivery of gambogic acid in colon cancer treatment.
abstract: Certain natural products such as gambogic acid (GA) exhibit potent antitumor effects. Unfortunately, administration of these natural products is limited by their poor solubility in conventional pharmaceutical solvents. In this study, a series of telodendrimers, composed of linear polyethylene glycol (PEG)-blocking-dendritic oligomer of cholic acid (CA) and vitamin E (VE), have been designed with architectures optimized for efficient delivery of GA and other natural anticancer compounds. Two of the telodendrimers with segregated CA and VE domains self-assembled into stable cylindrical and/or spherical nanoparticles (NPs) after being loaded with GA as observed under transmission electron microscopy (TEM), which correlated with the dynamic light scattering (DLS) analysis of sub-30 nm particle sizes. A very high GA loading capacity (3:10 drug/polymer w/w) and sustained drug release were achieved with the optimized telodendrimers. These novel nanoformulations of GA were found to exhibit similar in vitro cytotoxic activity against colon cancer cells as the free drug. Near-infrared fluorescence small animal imaging revealed preferential accumulation of GA-loaded NPs into tumor tissue. The optimized nanoformulation of GA achieved superior antitumor efficacy compared to GA-Cremophor EL formulation at equivalent doses in HT-29 human colon cancer xenograft mouse models. Given the mild adverse effects associated with this natural compound and the enhanced anticancer effects via tumor targeted telodendrimer delivery, the optimized GA nanoformulation is a promising alternative to the traditional chemotherapy in colon cancer treatment.
authors.affiliation: †Department of Pharmacology and §Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York 13078, United States.
authors.forename: Wenzhe
authors.initials: W
authors.lastname: Huang
authors.affiliation: †Department of Pharmacology and §Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York 13078, United States.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: †Department of Pharmacology and §Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York 13078, United States.
authors.forename: Changying
authors.initials: C
authors.lastname: Shi
authors.affiliation: †Department of Pharmacology and §Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York 13078, United States.
authors.forename: Dandan
authors.initials: D
authors.lastname: Guo
authors.affiliation: †Department of Pharmacology and §Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York 13078, United States.
authors.forename: Gaofei
authors.initials: G
authors.lastname: Xu
authors.affiliation: †Department of Pharmacology and §Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York 13078, United States.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: †Department of Pharmacology and §Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York 13078, United States.
authors.forename: Alexa
authors.initials: A
authors.lastname: Bodman
authors.affiliation: †Department of Pharmacology and §Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York 13078, United States.
authors.forename: Juntao
authors.initials: J
authors.lastname: Luo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D050091:Dendrimers / Q000737:chemistry*; D004337:Drug Carriers / Q000627:therapeutic use; D016503:Drug Delivery Systems; D015195:Drug Design; D005260:Female; D045325:HCT116 Cells; D006461:Hemolysis; D006801:Humans; D008027:Light; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000737:chemistry; D012542:Scattering, Radiation; D012995:Solubility; D014810:Vitamin E / Q000737:chemistry*; D044004:Xanthones / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D050091:Dendrimers; D004337:Drug Carriers; D008823:Micelles; D044004:Xanthones; D014810:Vitamin E; D011092:Polyethylene Glycols; C052659:gambogic acid
keywords: colon cancer therapy; drug delivery; macromolecular architecture; nanoparticles; natural anticancer reagents