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.

常规的癌症治疗策略旨在消除所有癌细胞。为此，标准的化学治疗方法依赖于具有较长的非治疗间隔的细胞毒性药物的最大耐受剂量（MTD），从而导致严重的毒性副作用以及耐药性。为了避免与传统MTD化疗相关的问题，有人提出采用相对低剂量连续治疗细胞毒性药物的节律化疗作为直接杀死所有癌细胞的主要范例的替代方法。低剂量节律（LDM）化学疗法不仅具有无毒性和抗药性的抗肿瘤作用，而且通过引起肿瘤内皮细胞的选择性凋亡，还具有有益的抗血管生成作用。为了保持耐药性在控制范围内并阻止指数性肿瘤生长，在本文中，我们将LDM化疗与第二种抗血管生成策略相结合。选择性阻断血管内皮生长因子（VEGF）与节律性阿霉素（Dox）的结合主要通过抗血管生成机制诱导协同抗肿瘤作用。对于特定的VEGF抑制，使用聚合的siRNA /硫醇化的壳聚糖（poly-siVEGF / tGC）纳米颗粒将靶向VEGF的siRNA递送至肿瘤组织，从而以序列特异性方式在肿瘤组织中有效地敲低VEGF基因。尽管单独使用节律性Dox和poly-siVEGF / tGC纳米颗粒进行的单次治疗显示出一定的抗肿瘤活性，但值得注意的是，两种疗法的结合导致了极好的肿瘤消退，而没有引起全身毒性或耐药性。因此，这些结果表明，使用聚-siRNA / tGC纳米粒子与LDM化疗相结合的靶向VEGF的RNAi可能是通过增强抗血管生成的功效同时将毒性和耐药性降至最低来控制肿瘤生长的有前景的协同策略。