title: Octreotide-functionalized and resveratrol-loaded unimolecular micelles for targeted neuroendocrine cancer therapy.
abstract: Medullary thyroid cancer (MTC) is a neuroendocrine tumor (NET) that is often resistant to standard therapies. Resveratrol suppresses MTC growth in vitro, but it has low bioavailability in vivo due to its poor water solubility and rapid metabolic breakdown, as well as lack of tumor-targeting ability. A novel unimolecular micelle based on a hyperbranched amphiphilic block copolymer was designed, synthesized, and characterized for NET-targeted delivery. The hyperbranched amphiphilic block copolymer consisted of a dendritic Boltorn® H40 core, a hydrophobic poly(l-lactide) (PLA) inner shell, and a hydrophilic poly(ethylene glycol) (PEG) outer shell. Octreotide (OCT), a peptide that shows strong binding affinity to somatostatin receptors, which are overexpressed on NET cells, was used as the targeting ligand. Resveratrol was physically encapsulated by the micelle with a drug loading content of 12.1%. The unimolecular micelles exhibited a uniform size distribution and spherical morphology, which were determined by both transmission electron microscopy (TEM) and dynamic light scattering (DLS). Cellular uptake, cellular proliferation, and Western blot analyses demonstrated that the resveratrol-loaded OCT-targeted micelles suppressed growth more effectively than non-targeted micelles. Moreover, resveratrol-loaded NET-targeted micelles affected MTC cells similarly to free resveratrol in vitro, with equal growth suppression and reduction in NET marker production. These results suggest that the H40-based unimolecular micelle may offer a promising approach for targeted NET therapy.
authors.affiliation: Department of Biomedical Engineering, Wisconsin Institutes for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA. sgong@engr.wisc.edu.
authors.forename: Wenjin
authors.initials: W
authors.lastname: Xu
authors.forename: Jocelyn F
authors.initials: JF
authors.lastname: Burke
authors.forename: Srikanth
authors.initials: S
authors.lastname: Pilla
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
authors.forename: Renata
authors.initials: R
authors.lastname: Jaskula-Sztul
authors.forename: Shaoqin
authors.initials: S
authors.lastname: Gong
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D014408:Biomarkers, Tumor / Q000378:metabolism; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D008823:Micelles; D050997:Nanomedicine; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015282:Octreotide / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; D013267:Stilbenes; D011092:Polyethylene Glycols; C033616:poly(lactide); D000077185:Resveratrol; D015282:Octreotide