Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic.
Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic.
复制标题
DOI：
10.1016/j.biomaterials.2015.12.018
复制
发表时间：
2016-03
期刊：
影响因子：
14
通讯作者：
Wang AZ
中科院分区：
文献类型：
--
作者：
Au KM;Satterlee A;Min Y;Tian X;Kim YS;Caster JM;Zhang L;Zhang T;Huang L;Wang AZ
唑来膦酸盐（Zol）是第三代双膦酸盐，广泛用作治疗癌症骨转移的抗吸收剂。虽然有临床前数据表明双膦酸盐（如Zol）对癌细胞具有直接的细胞毒性作用，但这种作用在临床环境中尚未确定。这可能是由于在静脉内（i. v.）局在此，我们报告了使用纳米技术重新制定Zol和评价Zol作为抗癌剂的新型纳米级金属有机框架（nMOFs）配方。nMOF制剂由唑来膦酸钙（CaZol）核心和聚乙二醇（PEG）表面组成。为了优先将CaZol nM 0 F递送至肿瘤以及促进Zol的细胞摄取，我们在nM 0 F上掺入了叶酸（Fol）靶向配体。已知叶酸受体（FR）在几种肿瘤类型中过表达，包括头颈癌、前列腺癌和非小细胞肺癌。我们证明了这些靶向CaZol nMOFs在生理条件下具有优异的化学和胶体稳定性。在nMOF内吞作用期间，包封的Zol从nMOF的释放发生在中间内体中。体外毒性研究表明，Fol-targeted CaZol nMOFs在FR-过表达的H460非小细胞肺癌和PC 3前列腺癌细胞中抑制细胞增殖和诱导细胞凋亡方面比小分子Zol更有效。我们的研究结果进一步验证了体内使用小鼠异种移植模型H460和PC 3。我们证明，Fol-targeted CaZol nMOFs是有效的抗癌剂，通过抑制肿瘤新生血管、抑制细胞增殖和诱导凋亡，使Zol的体内直接抗肿瘤活性增加80 - 85%。
Zoledronate (Zol) is a third-generation bisphosphonate that is widely used as an anti-resorptive agent for the treatment of cancer bone metastasis. While there is preclinical data indicating that bisphosphonates such as Zol have direct cytotoxic effects on cancer cells, such effect has not been firmly established in the clinical setting. This is likely due to the rapid absorption of bisphosphonates by the skeleton after intravenous (i.v.) administration. Herein, we report the reformulation of Zol using nanotechnology and evaluation of a novel nanoscale metal-organic frameworks (nMOFs) formulation of Zol as an anticancer agent. The nMOF formulation is comprised of a calcium zoledronate (CaZol) core and a polyethylene glycol (PEG) surface. To preferentially deliver CaZol nMOFs to tumors as well as facilitate cellular uptake of Zol, we incorporated folate (Fol)-targeted ligands on the nMOFs. The folate receptor (FR) is known to be overexpressed in several tumor types, including head-and-neck, prostate, and non-small cell lung cancers. We demonstrated that these targeted CaZol nMOFs possess excellent chemical and colloidal stability in physiological conditions. The release of encapsulated Zol from the nMOFs occurs in the mid-endosomes during nMOF endocytosis. In vitro toxicity studies demonstrated that Fol-targeted CaZol nMOFs are more efficient than small molecule Zol in inhibiting cell proliferation and inducing apoptosis in FR-overexpressing H460 non-small cell lung and PC3 prostate cancer cells. Our findings were further validated in vivo using mouse xenograft models of H460 and PC3. We demonstrated that Fol-targeted CaZol nMOFs are effective anticancer agents and increase the direct antitumor activity of Zol by 80 to 85% in vivo through inhibition of tumor neovasculature, and inhibiting cell proliferation and inducing apoptosis.