Targeted doxorubicin nanotherapy strongly suppressing growth of multidrug resistant tumor in mice.
The rational design of nanomedicine to treat multidrug resistant (MDR) tumors in vivo is described in the study. We prepared multifunctionalized Pluronic micelles that are already well-established to be responsive to low pH and redox in order to systemically deliver doxorubicin (DOX) to MDR tumors. Folic acids (FAs) were introduced on the micelle surface as tumor-targeting molecules. In vitro, the DOX-loaded micelles exerted high cytotoxicity in the DOX-resistant cells by bypassing MDR efflux. Cellular uptake studies clearly demonstrated that FA-conjugated DOX micelles (FA/DOX micelles) were efficiently internalized and accumulated in the MDR cells. In vivo studies indicated significant efficacy of FA/DOX micelles for MDR tumors in mice, and that the volume of tumors was 3 times smaller in this group than that of tumors in the free DOX group, and 8 times smaller than the tumors in the saline group. To the best of our knowledge, this methodology has been recognized to have significantly high efficacy, compared to previously reported DOX nanoparticle formulations. This superior anti-tumor efficacy of FA/DOX micelles in MDR tumor-bearing mice can be attributed to FA-targeted and -mediated endocytosis, inhibition of MDR effect, and subsequent DOX release triggered by dual stimuli (low pH and redox) inside the tumor. Given the promise of the multifunctional micelle mediated delivery on inhibition of MDR tumor growth, FA/DOX micelle platform is a much sought after goal for cancer chemotherapy, especially for cancers resistant to anticancer drugs.
Department of Molecular Science and Technology, Ajou University, 5 Woncheon, Yeoungtong, Suwon 443-749, Republic of Korea.
Dai Hai
DH
Nguyen
Biomedical Engineering, Yale University, CT 06511, USA.
Jung Seok
JS
Lee
Department of Molecular Science and Technology, Ajou University, 5 Woncheon, Yeoungtong, Suwon 443-749, Republic of Korea.
Jin Woo
JW
Bae
Department of Molecular Science and Technology, Ajou University, 5 Woncheon, Yeoungtong, Suwon 443-749, Republic of Korea.
Jong Hoon
JH
Choi
Department of Molecular Science and Technology, Ajou University, 5 Woncheon, Yeoungtong, Suwon 443-749, Republic of Korea.
Yunki
Y
Lee
Department of Molecular Science and Technology, Ajou University, 5 Woncheon, Yeoungtong, Suwon 443-749, Republic of Korea.
Joo Young
JY
Son
Department of Molecular Science and Technology, Ajou University, 5 Woncheon, Yeoungtong, Suwon 443-749, Republic of Korea. Electronic address: kdp@ajou.ac.kr.
Ki Dong
KD
Park
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D005492:Folic Acid / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry*; D010084:Oxidation-Reduction; D020442:Poloxamer / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D020442:Poloxamer; D011092:Polyethylene Glycols; D004317:Doxorubicin; D005492:Folic Acid
Doxorubicin; Multidrug-resistant tumor; Pluronic micelles; Redox-sensitive; pH-sensitive; targeted chemotherapy