In Vivo Antitumor Activity of Folate-Conjugated Cholic Acid-Polyethylenimine Micelles for the Code livery of Doxorubicin and siRNA to Colorectal Adenocarcinomas
In Vivo Antitumor Activity of Folate-Conjugated Cholic Acid-Polyethylenimine Micelles for the Code livery of Doxorubicin and siRNA to Colorectal Adenocarcinomas
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DOI：
10.1021/acs.molpharmaceut.5b00827
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发表时间：
2015-12-01
影响因子：
4.9
通讯作者：
Iyer, Arun K.
中科院分区：
文献类型：
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作者：
Amjad, Muhammad Wahab;Amin, Mohd Cairul Iqbal Mohd;Iyer, Arun K.
多药耐药给肿瘤治疗带来了巨大挑战。为了提高小干扰RNA（siRNA）和阿霉素的靶向性和共递送能力，并克服多药耐药性，我们将胆酸-聚乙烯亚胺聚合物与叶酸偶联，形成CA-PEI-FA胶束。CA-PEI-FA表现出低临界胶束浓度（80 μ M）、小平均粒径（150 nm）和正zeta电位（+12 mV）。它们显示出对阿霉素的高包封率（61.2 +/-1.7%，w/w），形成D-CA-PEI-FA，以及对siRNA的高包封率，形成D-CA-PEI-FA-S。X射线光电子能谱分析表明，外部FA的存在下，对D-CA-PEI-FA胶束。在pH 7.4下，约25%的阿霉素在24小时内释放，而在pH 5下观察到超过30%的释放。FA的存在增强了胶束的抗肿瘤活性。D-CA-PEI-FA和D-CA-PEI-FA-S胶束在体内抑制肿瘤生长。它们的体外细胞毒活性或体内抗肿瘤作用之间没有观察到显著差异，表明siRNA共辄没有显著增加抗肿瘤活性。组织学分析显示，用D-CA-PEI-FA或D-CA-PEI-FA-S处理的小鼠的肿瘤组织显示出最低的癌细胞密度和最高水平的凋亡和坏死。同样，在所有给药组中，这些小鼠的肝脏显示出最低水平的二氢嘧啶脱氢酶。在使用靶向VEGF的siRNA用D-CA-PEI-FA-S胶束处理的小鼠中观察到最低血清血管内皮生长因子（VEGF）水平（24.4pg/mL）。这些发现表明，开发的CA-PEI-FA纳米缀合物具有实现药物和siRNA的靶向共递送的潜力。
Multidrug resistance poses a great challenge to cancer treatment. In order to improve the targeting and codelivery of small interfering RNA (siRNA) and doxorubicin, and to overcome multidrug resistance, we conjugated a cholic acid-polyethylenimine polymer with folic acid, forming CA-PEI-FA micelles. CA-PEI-FA exhibited a low critical micelle concentration (80 mu M), small average particle size (150 nm), and positive zeta potential (+ 12 mV). They showed high entrapment efficiency for doxorubicin (61.2 +/- 1.7%, w/w), forming D-CA-PEI-FA, and for siRNA, forming D-CA-PEI-FA-S. X-ray photoelectron spectroscopic analysis revealed the presence of external FA on D-CA-PEI-FA micelles. About 25% doxorubicin was released within 24 h at pH 7.4, while more than 30% release was observed at pH 5. The presence of FA enhanced micelle antitumor activity. The D-CA-PEI-FA and D-CA-PEI-FA-S micelles inhibited tumor growth in vivo. No significant differences between their in vitro cytotoxic activities or their in vivo antitumor effects were observed, indicating that the siRNA coloading did not significantly increase the antitumor activity. Histological analysis revealed that tumor tissues from mice treated with D-CA-PEI-FA or D-CA-PEI-FA-S showed the lowest cancer cell density and the highest levels of apoptosis and necrosis. Similarly, the livers of these mice exhibited the lowest level of dihydropyrimidine dehydrogenase among all treated groups. The lowest serum vascular endothelial growth factor level (VEGF) (24.4 pg/mL) was observed in mice treated with D-CA-PEI-FA-S micelles using siRNA targeting VEGF. These findings indicated that the developed CA-PEI-FA nanoconjugate has the potential to achieve targeted codelivery of drugs and siRNA.