TY - JOUR
T1 - Thailandepsin A-loaded and octreotide-functionalized unimolecular micelles for targeted neuroendocrine cancer therapy
AU - Jaskula-Sztul, Renata
AU - Xu, Wenjin
AU - Chen, Guojun
AU - Harrison, April
AU - Dammalapati, Ajitha
AU - Nair, Renu
AU - Cheng, Yiqiang
AU - Gong, Shaoqin
AU - Chen, Herbert
N1 - Funding Information:
This project was financially supported by grants NIH ( R01 CA121115 to H. Chen and 1K25CA166178 to S. Gong), 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), and Caring for Carcinoids Foundation and AACR ( 14-60-33-CHEN ). The authors 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 - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
KW - Histone deacetylase inhibitor
KW - Neuroendocrine cancer
KW - Octreotide
KW - Targeted drug delivery
KW - Thailandepsin A
KW - Unimolecular micelles
UR - http://www.scopus.com/inward/record.url?scp=84961928059&partnerID=8YFLogxK
U2 - 10.1016/j.biomaterials.2016.03.010
DO - 10.1016/j.biomaterials.2016.03.010
M3 - Article
C2 - 26994874
AN - SCOPUS:84961928059
SN - 0142-9612
VL - 91
SP - 1
EP - 10
JO - Biomaterials
JF - Biomaterials
ER -