Dynamic disordering of liposomal cocktails and the spatio-temporal favorable release of cargoes to circumvent drug resistance.
Multidrug resistance (MDR) has been a major impediment to the success of cancer chemotherapy. Extensive efforts have been devoted to the development of drug delivery systems using nanotechnology to reverse MDR in cancer. However, the spontaneous release of drug payloads was always a slow process, which leads to the low intracellular drug concentration resulting in consequent drug insensitivity. To circumvent this limitation, we described a liposomal cocktail (LMDHV) constructed by a pH-responsive molecule (i.e., malachite green carbinol base (MG)) and liposome conjugated with Her-2 antibody for codelivery of doxorubicin (DOX) and verapamil (VER) to suppress drug resistance in Her-2 positive breast cancer. MG inserted in the bilayer as pH responders greatly contributed to the destabilization of the vesicle membrane in low pH, followed by the rapid release of the payloads. LMDHV showed 6-fold reversal efficiency in DOX resistant breast cancer owing to the efficient tumor targeting delivery and rapid burst release of drug intracellularly. Compared to tumor inhibition ratio of treated groups by free DOX (32.4 ± 7.4%), our designed kinetically favorable drug release system exhibited significantly (P < 0.01) enhanced tumor inhibition ratio up to 83.9 ± 12.5%, which is attributed to the remarkably increased drug concentration in cells. The spatio-temporal favorable release of drugs resulted in synergistic inhibition of tumor growth in xenografts. We envision that this new type of liposomal cocktail might be potentially utilized to circumvent drug resistance in the future.
College of Marine Life Science, Ocean University of China, No. 5 Yushan Road, Qingdao, China.
Ya
Y
Liu
Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, No. 11 Beiyitiao, Zhongguancun, Beijing, China.
Li-Li
LL
Li
Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, No. 11 Beiyitiao, Zhongguancun, Beijing, China.
Guo-Bin
GB
Qi
College of Marine Life Science, Ocean University of China, No. 5 Yushan Road, Qingdao, China. Electronic address: xgchen@ouc.edu.cn.
Xi-Guang
XG
Chen
Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, No. 11 Beiyitiao, Zhongguancun, Beijing, China. Electronic address: wanghao@nanoctr.cn.
Hao
H
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008081:Liposomes; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology
D000970:Antineoplastic Agents; D008081:Liposomes; D004317:Doxorubicin; D014700:Verapamil
Co-delivery; Drug resistance; Liposome; Spatio-temporal; Supramolecular