TY - JOUR
T1 - KE108-conjugated unimolecular micelles loaded with a novel HDAC inhibitor thailandepsin-A for targeted neuroendocrine cancer therapy
AU - Chen, Guojun
AU - Jaskula-Sztul, Renata
AU - Harrison, April
AU - Dammalapati, Ajitha
AU - Xu, Wenjin
AU - Cheng, Yiqiang
AU - Chen, Herbert
AU - Gong, Shaoqin
N1 - Funding Information:
This project was financially supported by grants from the NIH ( R01 CA121115 to H. Chen, 1K25CA166178 and R21CA196653 to S. Gong), the American Cancer Society (MEN2 Thyroid Cancer Professorship 120319–RPM–11–080–01–TBG to H. Chen and Research Scholar Award RSGM TBE–121413 to H. Chen), Layton F. Rikkers, MD, Chair in Surgical Leadership Professorship (H. Chen), the Caring for Carcinoids Foundation , and the AACR . The authors would like to thank Dr. Ricardo Lloyd for the pathological assessment of the mice tissues and Dr. Glen Leverson for the statistical analysis.
Publisher Copyright:
© 2016 Elsevier Ltd.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
KW - HDAC inhibitor
KW - KE108 peptide
KW - Neuroendocrine cancers
KW - Somatostatin receptor
KW - Targeted drug delivery
KW - Unimolecular micelles
UR - http://www.scopus.com/inward/record.url?scp=84964907524&partnerID=8YFLogxK
U2 - 10.1016/j.biomaterials.2016.04.029
DO - 10.1016/j.biomaterials.2016.04.029
M3 - Article
C2 - 27156249
AN - SCOPUS:84964907524
SN - 0142-9612
VL - 97
SP - 22
EP - 33
JO - Biomaterials
JF - Biomaterials
ER -