Thailandepsin A-loaded and octreotide-functionalized unimolecular micelles for targeted neuroendocrine cancer therapy

详细信息    查看全文

• 作者：Renata Jaskula-Sztul^a ; ¹ ; Wenjin Xu^b ; ¹ ; Guojun Chen^b ; ^c ; April Harrison^a ; Ajitha Dammalapati^a ; Renu Nair^a ; Yiqiang Cheng^d ; Shaoqin Gong^b ; ^c ; ^{shaoqingong@wisc.edu" class="auth_mail" title="E-mail the corresponding author} ; Herbert Chen^e ; ^{herbchen@uab.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Targeted drug delivery ; Unimolecular micelles ; Octreotide ; Neuroendocrine cancer ; Thailandepsin A ; Histone deacetylase inhibitor
• 刊名：Biomaterials
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：91
• 期：Complete
• 页码：1-10
• 全文大小：1836 K

文摘

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.