KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
J Control Release. 2017 Dec 10;267:203-213. doi: 10.1016/j.jconrel.2017.08.015. Epub 2017 Aug 16.
Conventional cancer treatment strategies have been aimed at eradicating all cancer cells. To this end, standard chemotherapeutic approaches have relied on the maximum tolerated dose (MTD) of cytotoxic drugs with a long off-therapy interval, leading to heavy toxic side effects accompanied by drug resistance. To avoid the problems associated with the traditional MTD chemotherapy, metronomic chemotherapy with relatively low dose continuous treatments of cytotoxic drugs has been proposed as an alternative to the predominant paradigm of directly killing all cancer cells. Low-dose metronomic (LDM) chemotherapy is expected to have not only antitumor effects without toxicity and drug resistance, but also beneficial anti-angiogenic effects by causing selective apoptosis of tumor endothelial cells. In an attempt to keep the drug resistance under control and halt exponential tumor growth, herein, we combined LDM chemotherapy with a second anti-angiogenic strategy. The selective blockade of vascular endothelial growth factor (VEGF) in combination with metronomic doxorubicin (Dox) induced synergistic antitumor effects mainly through an antiangiogenic mechanism. For specific VEGF suppression, VEGF-targeting siRNA was delivered to tumor tissue using polymerized siRNA/thiolated glycol chitosan (poly-siVEGF/tGC) nanoparticles, leading to efficient VEGF gene knockdown in tumor tissue with a sequence-specific manner. Although the single treatment with metronomic Dox and poly-siVEGF/tGC nanoparticles alone showed some antitumor activity, notably, the combination of the two therapies resulted in superb tumor regression without causing systemic toxicity or drug resistance. Thus, these results suggest that the VEGF-targeted RNAi using poly-siRNA/tGC nanoparticles in combination with LDM chemotherapy could be a promising synergistic strategy for controlling tumor growth by enhancing the efficacy of anti-angiogenesis while minimizing toxicity and drug resistance.
传统的癌症治疗策略旨在消灭所有癌细胞。为此，标准的化疗方法依赖于最大耐受剂量（MTD）的细胞毒性药物，并辅以较长的治疗间歇期，导致严重的毒性副作用和耐药性。为了避免传统 MTD 化疗带来的问题，提出了低剂量节拍化疗（LDM）作为直接杀死所有癌细胞的主要模式的替代方法。低剂量节拍（LDM）化疗有望不仅具有抗肿瘤作用而无毒性和耐药性，而且通过选择性诱导肿瘤内皮细胞凋亡还具有有益的抗血管生成作用。为了控制耐药性并阻止肿瘤的指数级生长，我们尝试将 LDM 化疗与第二种抗血管生成策略相结合。联合使用血管内皮生长因子（VEGF）选择性阻断剂和节拍多柔比星（Dox）诱导了协同的抗肿瘤作用，主要是通过抗血管生成机制。为了特异性抑制 VEGF，使用聚合 siRNA/巯基化乙二醇壳聚糖（poly-siVEGF/tGC）纳米粒将 VEGF 靶向 siRNA 递送至肿瘤组织，从而以序列特异性方式有效地在肿瘤组织中敲低 VEGF 基因。虽然单独使用 LDM 多柔比星和 poly-siVEGF/tGC 纳米粒进行单一治疗显示出一定的抗肿瘤活性，但两种治疗方法的联合应用可显著抑制肿瘤生长而不会引起全身毒性或耐药性。因此，这些结果表明，使用 poly-siRNA/tGC 纳米粒的 VEGF 靶向 RNAi 联合 LDM 化疗可能是一种很有前途的协同策略，可以通过增强抗血管生成的疗效同时最小化毒性和耐药性来控制肿瘤生长。
