Au Kin Man, Satterlee Andrew, Min Yuanzeng, Tian Xi, Kim Young Seok, Caster Joseph M, Zhang Longzhen, Zhang Tian, Huang Leaf, Wang Andrew Z
Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Biomaterials. 2016 Mar;82:178-93. doi: 10.1016/j.biomaterials.2015.12.018. Epub 2015 Dec 20.
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 this 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 80-85% in vivo through inhibition of tumor neovasculature, and inhibiting cell proliferation and inducing apoptosis.
唑来膦酸（Zol）是一种第三代双膦酸盐，被广泛用作抗吸收剂来治疗癌症骨转移。虽然临床前数据表明，诸如Zol之类的双膦酸盐对癌细胞具有直接细胞毒性作用，但这种作用在临床环境中尚未得到确凿证实。这可能是由于静脉注射（i.v.）给药后双膦酸盐被骨骼快速吸收所致。在此，我们报告了利用纳米技术对Zol进行的重新配方，并评估了这种新型的Zol纳米级金属有机框架（nMOFs）配方作为抗癌剂的效果。nMOF配方由唑来膦酸钙（CaZol）核心和聚乙二醇（PEG）表面组成。为了将CaZol nMOFs优先递送至肿瘤以及促进Zol的细胞摄取，我们在nMOFs上引入了叶酸（Fol）靶向配体。已知叶酸受体（FR）在包括头颈癌、前列腺癌和非小细胞肺癌在内的几种肿瘤类型中过表达。我们证明了这些靶向CaZol nMOFs在生理条件下具有出色的化学和胶体稳定性。在nMOF内吞过程中，包裹在nMOFs中的Zol在中晚期内体中释放。体外毒性研究表明，在过表达FR的H460非小细胞肺癌和PC3前列腺癌细胞中，叶酸靶向的CaZol nMOFs在抑制细胞增殖和诱导凋亡方面比小分子Zol更有效。我们的研究结果在使用H460和PC3小鼠异种移植模型的体内实验中得到了进一步验证。我们证明了叶酸靶向的CaZol nMOFs是有效的抗癌剂，并且通过抑制肿瘤新生血管、抑制细胞增殖和诱导凋亡，在体内使Zol的直接抗肿瘤活性提高了80 - 85%。
