Synergistic antitumor effects of combination treatment with metronomic doxorubicin and VEGF-targeting RNAi nanoparticles

Gijung Kwak, Sung Duk Jo, Dongkyu Kim, Hyosuk Kim, Myung Goo Kim, Kwang Meyung Kim, Ick Chan Kwon, Sun Hwa Kim

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalJournal of Controlled Release
DOIs
Publication statusAccepted/In press - 2017

Fingerprint

RNA Interference
Nanoparticles
Doxorubicin
Vascular Endothelial Growth Factor A
Drug Resistance
Neoplasms
Drug Therapy
Small Interfering RNA
Therapeutics
Maximum Tolerated Dose
Gene Knockdown Techniques
Poisons
Growth
Drug-Related Side Effects and Adverse Reactions
Pharmaceutical Preparations
Endothelial Cells
Apoptosis

Keywords

  • Anti-angiogenesis
  • Combination therapy
  • Drug resistance
  • Low-dose metronomic chemotherapy
  • SiRNA
  • VEGF

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Synergistic antitumor effects of combination treatment with metronomic doxorubicin and VEGF-targeting RNAi nanoparticles. / Kwak, Gijung; Jo, Sung Duk; Kim, Dongkyu; Kim, Hyosuk; Kim, Myung Goo; Kim, Kwang Meyung; Kwon, Ick Chan; Kim, Sun Hwa.

In: Journal of Controlled Release, 2017.

Research output: Contribution to journalArticle

Kwak, Gijung ; Jo, Sung Duk ; Kim, Dongkyu ; Kim, Hyosuk ; Kim, Myung Goo ; Kim, Kwang Meyung ; Kwon, Ick Chan ; Kim, Sun Hwa. / Synergistic antitumor effects of combination treatment with metronomic doxorubicin and VEGF-targeting RNAi nanoparticles. In: Journal of Controlled Release. 2017.
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AB - 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.

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