Zhang Jinming, Li Jingjing, Shi Zhi, Yang Yang, Xie Xi, Lee Simon MingYuen, Wang Yitao, Leong Kam W, Chen Meiwan
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China.
Acta Biomater. 2017 Aug;58:349-364. doi: 10.1016/j.actbio.2017.04.029. Epub 2017 Apr 26.
Co-delivery of multiple drugs with complementary anticancer mechanisms by nano-carriers offers an effective strategy to treat cancer. The combination of drugs with pro-apoptotic and anti-angiogenic activities is potentially effective in treating human hepatocellular carcinoma (HCC). Herein, we developed a co-delivery system for doxorubicin (Dox), a pro-apoptotic drug, and curcumin (Cur), a potent drug for antiangiogenesis, in pH-sensitive nanoparticles (NPs) constituted with amphiphilic poly(β-amino ester) copolymer. Dox & Cur co-loaded NPs ((D+C)/NPs) were prepared with optimized drug ratio, showing low polydispersity, high encapsulation efficiency, and enhanced release in the acidic environment of cancer cells. Furthermore, enhanced cellular internalization of cargoes delivered from (D+C)/NPs were observed in human liver cancer SMMC 7721 cells and human umbilical vein endothelial cells (HUVECs) compared to the use of free drugs. The (D+C)/NPs induced a high rate of apoptosis in SMMC 7721 cells through decreased mitochondrial membrane potential. Additionally, (D+C)/NPs exhibited stronger anti-angiogenic effects including inhibition of HUVEC proliferation, migration, invasion, and tube formation mediated VEGF pathway modulation in vitro and in vivo. Taken together, encapsulation of the pro-apoptotic drug Dox and antiangiogenic agent Cur in pH-sensitive NPs provides a promising strategy to effectively inhibit HCC progression in a synergistic manner.
The combination of multiple drugs has been demonstrated to be more effective than single treatment. However, the different physicochemical and pharmacokinetic profiles of each drug render optimal delivery challenging. In view of the great delivery advantage of nanocarriers to unify the multiple drugs in vivo, stimulus-responsive nano-carriers are more crucial to increase efficacy and reduce toxicity from off-target exposure. Therefore, herein the pH-sensitive nanoparticles, composed by d-α-tocopheryl polyethylene glycol 1000-block-poly (β-amino ester) (TPGS-PAE) polymers, have been fabricated for doxorubicin (Dox) and curcumin (Cur) co-delivery, which exhibited diverse anticancer approaches, i.e. pro-apoptosis and antiangiogenesis. The precise intracellular target site and effective drug combination concentration result in the enhanced antitumor efficiency and the reduced systematic toxicity of Dox. The co-encapsulation of the pro-apoptotic drug and antiangiogenic agent in pH-sensitive NPs provides a promising strategy to effectively inhibit malignant neoplasm progression in a synergistic manner.
通过纳米载体共同递送具有互补抗癌机制的多种药物为治疗癌症提供了一种有效策略。具有促凋亡和抗血管生成活性的药物联合使用可能对治疗人类肝细胞癌（HCC）有效。在此，我们开发了一种共递送系统，用于在由两亲性聚（β-氨基酯）共聚物构成的pH敏感纳米颗粒（NPs）中递送促凋亡药物阿霉素（Dox）和强效抗血管生成药物姜黄素（Cur）。制备了具有优化药物比例的Dox与Cur共负载纳米颗粒（（D + C）/ NPs），其显示出低多分散性、高包封率，并在癌细胞的酸性环境中增强释放。此外，与使用游离药物相比，在人肝癌SMMC 7721细胞和人脐静脉内皮细胞（HUVECs）中观察到从（D + C）/ NPs递送的货物的细胞内化增强。（D + C）/ NPs通过降低线粒体膜电位在SMMC 7721细胞中诱导了高凋亡率。此外，（D + C）/ NPs在体外和体内均表现出更强的抗血管生成作用，包括抑制HUVEC增殖、迁移、侵袭以及通过VEGF途径调节介导的管形成。综上所述，将促凋亡药物Dox和抗血管生成剂Cur封装在pH敏感NPs中提供了一种有前景的策略，以协同方式有效抑制HCC进展。
多种药物联合使用已被证明比单一治疗更有效。然而，每种药物不同的物理化学和药代动力学特征使得优化递送具有挑战性。鉴于纳米载体在体内统一多种药物方面具有巨大的递送优势，刺激响应性纳米载体对于提高疗效和降低脱靶暴露的毒性更为关键。因此，在此制备了由d-α-生育酚聚乙二醇1000-嵌段-聚（β-氨基酯）（TPGS-PAE）聚合物组成的pH敏感纳米颗粒，用于阿霉素（Dox）和姜黄素（Cur）的共递送，其表现出多种抗癌方法，即促凋亡和抗血管生成。精确的细胞内靶位点和有效的药物组合浓度导致增强的抗肿瘤效率和降低的Dox全身毒性。将促凋亡药物和抗血管生成剂共封装在pH敏感NPs中提供了一种有前景的策略，以协同方式有效抑制恶性肿瘤进展。
