Docetaxel and Doxorubicin Codelivery by Nanocarriers for Synergistic Treatment of Prostate Cancer
Docetaxel and Doxorubicin Codelivery by Nanocarriers for Synergistic Treatment of Prostate Cancer
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纳米载体联合多西紫杉醇和阿霉素协同治疗前列腺癌
DOI：
10.3389/fphar.2019.01436
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发表时间：
2019-12-18
影响因子：
5.6
通讯作者：
Chen, Xueli
中科院分区：
文献类型：
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作者：
Li, Ke;Zhan, Wenhua;Chen, Xueli
联合化疗已被证明是治疗前列腺癌（PCA）的有效策略。然而，相关药物之间的药代动力学差异是实现其协同抗癌的不可逾越的障碍。为了克服联合化疗治疗PCA的缺点，设计了靶向纳米颗粒（NPs），它可以以最佳协同比例联合输送多西紫杉醇（DOC）和阿霉素（DOX）。在本研究中，DOC 和 DOX 共递送纳米颗粒（DDC NP）是由透明质酸（HA）和阳离子两亲淀粉（CSaSt）通过自组装过程构建的。然后使用人 PCA 细胞系（PC-3、DU-145 和 LNCap）和小鼠模型分别评估体外和体内的递送和抗肿瘤效果。 DDC NPs呈球形，表面粗糙，尺寸和zeta电位分别为68.4±7.1 nm和-22.8±2.2 mV。纳米颗粒中 DOC 和 DOX 的包封率分别为 96.1 ± 2.3% 和 91.4 ± 3.7%，而总载药量为 9.1 ± 1.7%。此外，DDC NPs中DOC与DOX的比例约为1:400，这与药物的最佳协同比例一致。 DDC NPs 表现出优异的负载能力，具有持续的酶促释放，并且在 PBS、培养基和血清中稳定。经过体外研究，DDC NPs 在细胞毒性、抗迁移和凋亡方面与双药组合一样有效。内化结果表明，DDC NPs 可以有效地将有效负载递送并完全释放到 PCA 细胞中，并且该过程是由 HA 与 CD44 蛋白的配体-受体相互作用介导的。通过急性毒性和溶血试验证实体内低毒性。体内分布表明DDC NPs可以增强药物在肿瘤中的积累并减少正常器官中的非特异性积累。更重要的是，DDC NPs显着促进了PCA细胞异种移植小鼠模型中DOC和DOX组合的疗效，表明带有NPs的药物确实具有协同作用。这项研究表明DDC NPs作为PCA临床化疗的发展前景具有显着的潜力。
Combination chemotherapy has been proven to be an efficient strategy for the treatment of prostate cancer (PCA). However, the pharmacokinetic distinction between the relevant drugs is an insurmountable barrier to the realization of their synergistic use against cancer. To overcome the disadvantages of combination chemotherapy in the treatment of PCA, targeted nanoparticles (NPs), which can codeliver docetaxel (DOC) and doxorubicin (DOX) at optimal synergistic proportions, have been designed. In this study, the DOC and DOX codelivery nanoparticles (DDC NPs) were constructed by hyaluronic acid (HA) and cationic amphipathic starch (CSaSt) through a self-assembly process. Human PCA cell lines (PC-3, DU-145, and LNCap) and mouse models were then used for evaluation in vitro and in vivo, respectively, of delivery and antitumor effects. The DDC NPs were spherical with rough surfaces, and the size and zeta potential were 68.4 ± 7.1 nm and -22.8 ± 2.2 mV, respectively. The encapsulation efficiencies of DOC and DOX in the NPs were 96.1 ± 2.3% and 91.4 ± 3.7%, respectively, while the total drug loading was 9.1 ± 1.7%. Moreover, the ratio of DOC to DOX in the DDC NPs was approximately 1:400, which aligned with the optimal synergistic proportions of the drugs. The DDC NPs exhibited excellent loading capacities, performed sustained and enzymatic release, and were stable in PBS, medium, and serum. After investigations in vitro, the DDC NPs were as effective as the dual drug combination in terms of cytotoxicity, antimigration, and apoptosis. Internalization results indicated that the DDC NPs could effectively deliver and fully release the payloads into PCA cells, and the process was mediated by the ligand-receptor interaction of HA with the CD44 protein. Low toxicity in vivo was confirmed by acute toxicity and hemolytic assays. The distribution in vivo showed that DDC NPs could enhance the accumulation of drugs in tumors and decrease nonspecific accumulation in normal organs. More importantly, DDC NPs significantly promoted the curative effect of the DOC and DOX combination in the PCA cell xenograft mouse model, indicating that the drugs with NPs did indeed act synergistically. This study suggests that the DDC NPs possess noteworthy potential as prospects for the development of PCA clinical chemotherapy.