Quercetin Remodels the Tumor Microenvironment To Improve the Permeation, Retention, and Antitumor Effects of Nanoparticles.
Quercetin Remodels the Tumor Microenvironment To Improve the Permeation, Retention, and Antitumor Effects of Nanoparticles.
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DOI：
10.1021/acsnano.7b01522
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发表时间：
2017-05-23
期刊：
影响因子：
17.1
通讯作者：
Huang L
中科院分区：
文献类型：
--
作者：
Hu K;Miao L;Goodwin TJ;Li J;Liu Q;Huang L
我们以前的工作表明，Wnt 16在顺铂损伤的肿瘤相关成纤维细胞中的表达是导致恶性肿瘤顺铂耐药的关键因素。具有低毒性的天然抗纤维化化合物是下调Wnt 16表达的有希望的候选者，从而提高顺铂纳米颗粒的抗肿瘤效果。在筛选几种天然化学物质后，我们发现膳食类黄酮槲皮素显著抑制活化成纤维细胞中Wnt 16的表达。为了促进药物递送，我们制备了由槲皮素的前药组成的靶向脂质/钙/磷酸盐纳米颗粒制剂，即，槲皮素磷酸盐，具有高装载效率（26.6%w/w）。该槲皮素纳米颗粒的粒径约为35 nm，显著提高了母体槲皮素的生物利用度和代谢稳定性。槲皮素磷酸盐从纳米颗粒中释放出来，并在生理条件下转化回母体槲皮素。在富含基质的膀胱癌模型中，全身给予磷酸槲皮素纳米颗粒后，观察到Wnt 16表达显著下调，并进一步产生与顺铂纳米颗粒的协同抗肿瘤作用。联合治疗后，肿瘤内α-SMA阳性成纤维细胞和胶原明显减少。这表明槲皮素诱导的肿瘤微环境重塑在促进协同作用中起着关键作用。事实上，我们的数据进一步证实，槲皮素磷酸盐单独显着重塑肿瘤微环境，并增加了第二波纳米粒子进入肿瘤巢的渗透。总的来说，磷酸槲皮素纳米颗粒可能是一种安全有效的方法，以改善促结缔组织增生性肿瘤的治疗。
Our previous work demonstrated that Wnt16 expression in cisplatin-damaged tumor-associated fibroblasts is a key factor contributing to cisplatin resistance in malignancies. Natural antifibrotic compounds with low toxicities are promising candidates to downregulate Wnt16 expression, improving the antitumor effect of cisplatin nanoparticles. Upon screening several natural chemicals, we found that a dietary flavonoid, quercetin, significantly suppresses Wnt16 expression in activated fibroblasts. To facilitate drug delivery, we have prepared a targeted lipid/calcium/phosphate nanoparticle formulation consisting of a prodrug of quercetin, i.e., quercetin phosphate, with a high loading efficiency (26.6% w/w). This quercetin nanoparticle with a particle size of around 35 nm significantly improved the bioavailability and metabolic stability of the parent quercetin. Quercetin phosphate is released from the nanoparticles and converted back to the parent quercetin under physiological conditions. Following systemic administration of quercetin phosphate nanoparticles, a significant downregulation in Wnt16 expression was observed and further yielded a synergistic antitumor effect with cisplatin nanoparticles in a stroma-rich bladder carcinoma model. The α-SMA-positive fibroblast and collagen within the tumor decreased significantly after combination treatment. This suggests that the remodeling of the tumor microenvironment induced by quercetin plays a critical role in promoting the synergy. Indeed, our data further confirmed that quercetin phosphate alone significantly remodeled the tumor microenvironment and increased the penetration of second-wave nanoparticles into the tumor nests. Collectively, quercetin phosphate nanoparticles may be a safe and effective way to improve therapeutic treatment for desmoplastic tumors.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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