Intraperitoneal siRNA Nanoparticles for Augmentation of Gemcitabine Efficacy in the Treatment of Pancreatic Cancer.
Intraperitoneal siRNA Nanoparticles for Augmentation of Gemcitabine Efficacy in the Treatment of Pancreatic Cancer.
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用于增强吉西他滨治疗胰腺癌疗效的腹腔注射小干扰RNA纳米颗粒
DOI：
10.1021/acs.molpharmaceut.1c00653
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发表时间：
2021-12-06
影响因子：
4.9
通讯作者：
Oupicky, David
中科院分区：
文献类型：
--
作者：
Tang, Siyuan;Hang, Yu;Ding, Ling;Tang, Weimin;Yu, Ao;Zhang, Chuhan;Sil, Diptesh;Xie, Ying;Oupicky, David
胰腺导管腺癌是一种致命的疾病，由于诊断晚和对常规化疗的抵抗，治疗选择有限。在新兴的治疗靶点中，CXCR 4趋化因子受体和polo样激酶1（PLK 1）在胰腺癌的进展、转移和化疗耐药性中起关键作用。在这里，我们测试了这样的假设，即通过聚合CXCR 4拮抗剂PAMD-CHOL抑制CXCR 4与通过siRNA敲低PLK 1相结合，将增强吉西他滨在转移性胰腺癌原位模型中的治疗效果。我们用胆固醇修饰的PAMD和siPLK 1配制纳米颗粒，并在鼠和人胰腺癌细胞系中与吉西他滨体外治疗组合时发现强烈的协同作用。原位胰腺癌模型中纳米颗粒的生物分布显示在原发性和转移性肿瘤中有很强的积累，肝脏分布有限。含胆固醇的纳米颗粒不仅显示出比缺乏胆固醇的对照组增加的肿瘤积聚，而且还显示出更深的肿瘤渗透。在体内治疗研究中，PAMD-CHOL/siPLK 1和吉西他滨的三重组合与单重和双重组合对照相比显示出上级抗癌活性。总之，PAMD-CHOL/siPLK 1纳米颗粒协同增强吉西他滨在胰腺癌中的抗癌活性，并代表了一种有希望的治疗手段。
Pancreatic ductal adenocarcinoma is a deadly disease with limited treatment options due to late diagnosis and resistance to conventional chemotherapy. Among emerging therapeutic targets, the CXCR4 chemokine receptor and polo-like kinase 1 (PLK1) play critical roles in the progression, metastasis and chemoresistance of pancreatic cancer. Here, we tested the hypothesis that combining CXCR4 inhibition by a polymeric CXCR4 antagonist PAMD-CHOL with PLK1 knockdown by siRNA, will enhance the therapeutic effect of gemcitabine in orthotopic model of metastatic pancreatic cancer. We formulated nanoparticles with cholesterol-modified PAMD and siPLK1 and found strong synergism when combined with gemcitabine treatment in vitro in both murine and human pancreatic cancer cell lines. Biodistribution of the nanoparticles in orthotopic pancreatic cancer models revealed strong accumulation in primary and metastatic tumors, with limited hepatic disposition. The cholesterol-containing nanoparticles showed not only increased tumor accumulation than the cholesterol-lacking control but also deeper penetration to the tumors. In a therapeutic study in vivo, the triple combination of PAMD-CHOL/siPLK1 and gemcitabine showed superior anticancer activity when compared with single and dual combination controls. In conclusion, PAMD-CHOL/siPLK1 nanoparticles synergistically enhance anticancer activity of gemcitabine in pancreatic cancer and represent a promising addition to the treatment arsenal.
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影响因子：
3.8
作者：
Morimoto M;Matsuo Y;Koide S;Tsuboi K;Shamoto T;Sato T;Saito K;Takahashi H;Takeyama H
通讯作者：
Takeyama H
影响因子：
5.7
作者：
Lo JH;Hao L;Muzumdar MD;Raghavan S;Kwon EJ;Pulver EM;Hsu F;Aguirre AJ;Wolpin BM;Fuchs CS;Hahn WC;Jacks T;Bhatia SN
通讯作者：
Bhatia SN
影响因子：
29.4
作者：
Saur, D;Seidler, B;Schmid, RM
通讯作者：
Schmid, RM
影响因子：
4.3
作者：
Li, Jie;Wang, Ruixin;Liu, Xiaoqi
通讯作者：
Liu, Xiaoqi
影响因子：
14
作者：
Li, Jing;Oupicky, David
通讯作者：
Oupicky, David