title: Thailandepsin A-loaded and octreotide-functionalized unimolecular micelles for targeted neuroendocrine cancer therapy.
abstract: Due to the overexpression of somatostatin receptors in neuroendocrine (NE) cancers, drug nanocarriers conjugated with somatostatin analogs, such as octreotide (OCT), for targeted NE cancer therapy may offer increased therapeutic efficacies and decreased adverse effects. In this study, OCT-functionalized unimolecular micelles were prepared using individual hyperbranched polymer molecules consisting of a hyperbranched polymer core (Boltorn(®) H40) and approximately 25 amphiphilic polylactide-poly(ethlyene glycol) (PLA-PEG) block copolymer arms (H40-PLA-PEG-OCH3/OCT). The resulting micelles, exhibiting a uniform core-shell shape and an average hydrodynamic diameter size of 66 nm, were loaded with thailandepsin-A (TDP-A), a relatively new naturally produced histone deacetylase (HDAC) inhibitor. In vitro studies using flow cytometry and confocal laser scanning microscopy (CLSM) demonstrated that OCT conjugation enhanced the cellular uptake of the unimolecular micelles. Consequently, TDP-A-loaded and OCT-conjugated micelles exhibited the highest cytotoxicity and caused the highest reduction of NE tumor markers. Finally, the in vivo studies on NE cancer bearing nude mice demonstrated that TDP-A-loaded and OCT-conjugated micelles possessed superior anticancer activity in comparison with other TDP-A formulations or drug alone, while showing no detectable systemic toxicity. Thus, these TDP-A-loaded and OCT-conjugated micelles offer a promising approach for targeted NE cancer therapy.
authors.affiliation: Department of Surgery, University of Wisconsin, Madison, WI, 53705, USA.
authors.forename: Renata
authors.initials: R
authors.lastname: Jaskula-Sztul
authors.affiliation: Department of Biomedical Engineering and Wisconsin Institutes for Discovery, University of Wisconsin-Madison, 1550 Engineering Drive, 3144 Engineering Centers Building, Madison, WI, 53715, USA.
authors.forename: Wenjin
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Biomedical Engineering and Wisconsin Institutes for Discovery, University of Wisconsin-Madison, 1550 Engineering Drive, 3144 Engineering Centers Building, Madison, WI, 53715, USA; Department of Materials Science and Engineering, University of Wisconsin-Madison, Madison, WI, 53715, USA.
authors.forename: Guojun
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Surgery, University of Wisconsin, Madison, WI, 53705, USA.
authors.forename: April
authors.initials: A
authors.lastname: Harrison
authors.affiliation: Department of Surgery, University of Wisconsin, Madison, WI, 53705, USA.
authors.forename: Ajitha
authors.initials: A
authors.lastname: Dammalapati
authors.affiliation: Department of Surgery, University of Wisconsin, Madison, WI, 53705, USA.
authors.forename: Renu
authors.initials: R
authors.lastname: Nair
authors.affiliation: University of Texas Health Sciences Center San Anto-Division, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Biomedical Engineering and Wisconsin Institutes for Discovery, University of Wisconsin-Madison, 1550 Engineering Drive, 3144 Engineering Centers Building, Madison, WI, 53715, USA; Department of Materials Science and Engineering, University of Wisconsin-Madison, Madison, WI, 53715, USA. Electronic address: shaoqingong@wisc.edu.
authors.forename: Shaoqin
authors.initials: S
authors.lastname: Gong
authors.affiliation: Department of Surgery, University of Alabama - Birmingham, Birmingham, 1808 7th Avenue South / Suite 502, 35233, AL, USA. Electronic address: herbchen@uab.edu.
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000627:therapeutic use*; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007773:Lactates / Q000737:chemistry*; D008297:Male; D008819:Mice, Nude; D008823:Micelles; D015282:Octreotide / Q000008:administration & dosage / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047630:Depsipeptides; D004337:Drug Carriers; D056572:Histone Deacetylase Inhibitors; D007773:Lactates; D008823:Micelles; C088513:poly(lactic acid-ethylene glycol); C574693:thailandepsin A; D011092:Polyethylene Glycols; D015282:Octreotide
keywords: Histone deacetylase inhibitor; Neuroendocrine cancer; Octreotide; Targeted drug delivery; Thailandepsin A; Unimolecular micelles