Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in Ovarian Cancer Treatment.
Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in Ovarian Cancer Treatment.
复制标题
DOI：
10.1158/0008-5472.can-16-3119
复制
发表时间：
2017-06-15
期刊：
影响因子：
11.2
通讯作者：
Luo J
中科院分区：
文献类型：
--
作者：
Wang L;Shi C;Wright FA;Guo D;Wang X;Wang D;Wojcikiewicz RJH;Luo J
我们已经开发出多功能纳米颗粒（NP），用于共同递送硼替佐米（BTZ）和阿霉素（DOX），以同步它们的药代动力学特征并协同它们在实体肿瘤治疗中的活性，这一需求在临床仍未得到满足。胶束NP是由一个空间分离的线性枝状远端分子形成的，它包含三个部分：亲水性聚乙二醇（PEG）、btz偶联中间体和枝状dox亲和内部。btz偶联的端突分子与DOX自组装成单分散胶束（NP(BTZ-DOX)），粒径较小（20~30 nm），用于双重药物递送。NP（BTZ-DOX）表现出良好的载药能力和稳定性，最大限度地减少了药物过早泄漏和药物同步释放。酸性pH显著加速BTZ的释放，促进了药物在酸性肿瘤微环境中的可用性。体外观察了BTZ和DOX联合抗多发性骨髓瘤和卵巢癌细胞的协同抗癌作用。NP（BTZ-DOX）延长有效载荷循环，有效靶向肿瘤，肿瘤与正常器官的信号比优越。体外和体内蛋白酶体抑制分析和生物分布研究表明，纳米制剂降低了BTZ和DOX的毒性，并有效地在肿瘤内传递。NP（BTZ- dox）在SKOV-3异种移植小鼠模型中，与游离药物及其联合用药（包括BTZ和Doxil）相比，具有显著改善卵巢癌治疗效果。综上所述，肿瘤靶向和同步给药系统具有增强的抗癌作用，值得在临床中进一步发展。
We have developed multifunctional nanoparticles (NP) for co-delivery of bortezomib (BTZ) and doxorubicin (DOX) to synchronize their pharmacokinetic profiles and synergize their activities in solid tumor treatment, a need still unmet in the clinic. Micellar NP was formed by a spatially segregated, linear-dendritic telodendrimer containing three segments: a hydrophilic polyethylene glycol (PEG), a BTZ-conjugating intermediate, and a dendritic DOX-affinitive interior. BTZ-conjugated telodendrimers, together with DOX, self-assembled into monodispersed micelles (NP(BTZ-DOX)) with small particle sizes (20~30 nm) for dual drug delivery. NP(BTZ-DOX) displayed excellent drug loading capacity and stability, which minimized premature drug leakage and synchronized drug release profiles. BTZ release was accelerated significantly by acidic pH, facilitating drug availability in the acidic tumor microenvironment. Synergistic anticancer effects of combined BTZ and DOX were observed in vitro against both multiple myeloma and ovarian cancer cells. NP(BTZ-DOX) prolonged payload circulation and targeted tumors in vivo efficiently with superior signal ratios of tumor to normal organs. In vitro and in vivo proteasome inhibition analysis and biodistribution studies revealed decreased toxicity and efficient intratumoral BTZ and DOX delivery by nanoformulation. NP(BTZ-DOX) exhibited significantly improved ovarian cancer treatment in SKOV-3 xenograft mouse models in comparison with free drugs and their combinations, including BTZ and Doxil. In summary, tumor-targeted and synchronized delivery system elicits enhanced anticancer effects and merits further development in the clinical setting.