Kwak, Gijung Jo, Sung Duk Kim, Dongkyu Kim, Hyosuk Kim, Myung Goo Kim, Kwangmeyung Kwon, Ick Chan Kim, Sun Hwa 2024-01-20T00:00:45Z 2024-01-20T00:00:45Z 2021-09-03 2017-12-10 0168-3659 https://pubs.kist.re.kr/handle/201004/121926 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. English ELSEVIER SCIENCE BV CHEMOTHERAPY CANCER ANGIOGENESIS ANTIBODY CYCLOPHOSPHAMIDE XENOGRAFTS RESISTANCE EFFICACY GROWTH CELLS Synergistic antitumor effects of combination treatment with metronomic doxorubicin and VEGF-targeting RNAi nanoparticles Article 10.1016/j.jconrel.2017.08.015 1 JOURNAL OF CONTROLLED RELEASE, v.267, pp.203 - 213 JOURNAL OF CONTROLLED RELEASE 267 203 213 scie scopus 000417328600019 2-s2.0-85028456150 Chemistry, Multidisciplinary Pharmacology & Pharmacy Chemistry Pharmacology & Pharmacy Article; Proceedings Paper CHEMOTHERAPY CANCER ANGIOGENESIS ANTIBODY CYCLOPHOSPHAMIDE XENOGRAFTS RESISTANCE EFFICACY GROWTH CELLS Low-dose metronomic chemotherapy Drug resistance Anti-angiogenesis siRNA Combination therapy VEGF