Kim Myung Goo, Jo Sung Duk, Yhee Ji Young, Lee Beom Suk, Lee So Jin, Park Sung Gurl, Kang Sun-Woong, Kim Sun Hwa, Jeong Ji Hoon
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, 5, Hwarang-ro, 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea; School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon 16410, Republic of Korea.
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, 5, Hwarang-ro, 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
Biochem Biophys Res Commun. 2017 Jul 15;489(1):35-41. doi: 10.1016/j.bbrc.2017.05.103. Epub 2017 May 19.
A variety of VEGF inhibitors have been reported to treat cancers by suppressing tumor angiogenesis. Bevacizumab, a monoclonal VEGF antibody, was the first FDA approved anti-angiogenic agent for cancer treatments. However, bevacizumab shows modest therapeutic efficiency and often cause resistant problem in significant populations of cancer patients. To solve these problem, we investigated the therapeutic efficacy of siRNA drugs targeting VEGF and combination of the RNAi drug with bevacizumab for cancer treatments. For efficient VEGF siRNA delivery, chemically polymerized siRNAs were complexed with thiolated-glycol chitosan (psi(VEGF)/tGC). The poly-VEGF siRNA and thiolated-glycol chitosan formed stable nanoparticles via electrostatic interaction and chemical crosslinking, and showed high accumulation in tumor tissues resulting in efficient gene silencing. Both VEGF siRNA nanoparticles and bevacizumab had efficient therapeutic effects in tumor xenograft mouse models. Interestingly, most pronounced therapeutic efficacy was observed when the two distinct VEGF inhibitors were treated in combination revealing synergistic effects. The results showed that the psi(VEGF)/tGC nanoparticle mediated knockdown of VEGF exerts anti-tumor effects and the combination treatments with bevacizumab can extend the treatments options to conventional bevacizumab treatments for cancer therapy.
据报道，多种VEGF抑制剂可通过抑制肿瘤血管生成来治疗癌症。贝伐单抗是一种单克隆VEGF抗体，是首个获得美国食品药品监督管理局（FDA）批准用于癌症治疗的抗血管生成药物。然而，贝伐单抗的治疗效果一般，并且在相当一部分癌症患者中常常会引发耐药问题。为了解决这些问题，我们研究了靶向VEGF的siRNA药物以及该RNAi药物与贝伐单抗联合用于癌症治疗的疗效。为了实现高效的VEGF siRNA递送，将化学合成的siRNAs与巯基化的壳聚糖（psi(VEGF)/tGC）复合。聚VEGF siRNA与巯基化的壳聚糖通过静电相互作用和化学交联形成稳定的纳米颗粒，并在肿瘤组织中高度富集，从而实现有效的基因沉默。VEGF siRNA纳米颗粒和贝伐单抗在肿瘤异种移植小鼠模型中均具有有效的治疗作用。有趣的是，当联合使用这两种不同的VEGF抑制剂时，观察到了最显著的治疗效果，显示出协同作用。结果表明，psi(VEGF)/tGC纳米颗粒介导的VEGF基因敲除具有抗肿瘤作用，并且与贝伐单抗联合治疗可为癌症治疗的传统贝伐单抗治疗提供更多的治疗选择。
