title: KE108-conjugated unimolecular micelles loaded with a novel HDAC inhibitor thailandepsin-A for targeted neuroendocrine cancer therapy.
abstract: Neuroendocrine (NE) cancers can cause significant patient morbidity. Besides surgery, there are no curative treatments for NE cancers and their metastases, emphasizing the need for the development of other forms of therapy. In this study, multifunctional unimolecular micelles were developed for targeted NE cancer therapy. The unimolecular micelles were formed by multi-arm star amphiphilic block copolymer poly(amidoamine)-poly(valerolactone)-poly(ethylene glycol) conjugated with KE108 peptide and Cy5 dye (abbreviated as PAMAM-PVL-PEG-KE108/Cy5). The unimolecular micelles with a spherical core-shell structure exhibited a uniform size distribution and excellent stability. The hydrophobic drug thailandepsin-A (TDP-A), a recently discovered HDAC inhibitor, was physically encapsulated into the hydrophobic core of the micelles. KE108 peptide, a somatostatin analog possessing high affinity for all five subtypes of somatostatin receptors (SSTR 1-5), commonly overexpressed in NE cancer cells, was used for the first time as an NE cancer targeting ligand. KE108 exhibited superior targeting abilities compared to other common somatostatin analogs, such as octreotide, in NE cancer cell lines. The in vitro assays demonstrated that the TDP-A-loaded, KE108-targeted micelles exhibited the best capabilities in suppressing NE cancer cell growth. Moreover, the in vivo near-infrared fluorescence imaging on NE-tumor-bearing nude mice showed that KE108-conjugated micelles exhibited the greatest tumor accumulation due to their passive targeting and active targeting capabilities. Finally, TDP-A-loaded and KE108-conjugated micelles possessed the best anticancer efficacy without detectable systemic toxicity. Thus, these novel TDP-A-loaded and KE108-conjugated unimolecular micelles offer a promising approach for targeted NE cancer therapy.
authors.affiliation: Department of Materials Science and Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
authors.forename: Guojun
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Renata
authors.initials: R
authors.lastname: Jaskula-Sztul
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: Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Wenjin
authors.initials: W
authors.lastname: Xu
authors.affiliation: University of Texas Health Sciences Center San Anto-Division, San Antonio, TX 76107, USA.
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA. Electronic address: herbchen@uab.edu.
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Materials Science and Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: shaoqingong@wisc.edu.
authors.forename: Shaoqin
authors.initials: S
authors.lastname: Gong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D057446:Hydrodynamics; D008297:Male; D008819:Mice, Nude; D008823:Micelles; D058990:Molecular Targeted Therapy; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000473:pathology; D010316:Particle Size; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D066244:Proton Magnetic Resonance Spectroscopy; D017481:Receptors, Somatostatin / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D008823:Micelles; D010456:Peptides, Cyclic; D011108:Polymers; D017481:Receptors, Somatostatin; C473958:Tyr(0)-(cyclo-D-Dab-Arg-Phe-Phe-D-Trp-Lys-Thr-Phe); C574693:thailandepsin A
keywords: HDAC inhibitor; KE108 peptide; Neuroendocrine cancers; Somatostatin receptor; Targeted drug delivery; Unimolecular micelles