Lanthanide-integrated supramolecular polymeric nanoassembly with multiple regulation characteristics for multidrug-resistant cancer therapy.
Cancer treatment can in principle be enhanced by the synergistic effects of chemo- and nucleic acid-based combination therapies but the lack of efficient drug nanocarriers and occurrence of multidrug resistance (MDR) are major obstacles adversely affecting the effectiveness. Herein, a lanthanide-integrated supramolecular polymeric nanoassembly that delivers anticancer drugs and siRNA for more effective cancer therapy is described. This nanotherapeutic system is prepared by loading adamantane-modified doxorubicin (Dox) into polyethylenimine-crosslinked-γ-cyclodextrin (PC) through the supramolecular assembly to form the interior Dox-loaded PC (PCD) followed by electrostatically driven self-assembly of siRNA and PCD to produce the PCD/siRNA nanocomplexes. The PCD/siRNA nanocomplex is further decorated with the exterior neodymium (Nd)-integrated PC (Nd-PC) layer to obtain the PCD/siRNA/Nd-PC nanoassembly in which the interior PC serves as an efficient carrier for simultaneous delivery of Dox and siRNA to the human breast cancer cell line, Dox-resistant MCF-7 (MCF-7/ADR) both in vitro and in vivo. The exterior Nd-PC layer improves the drug sensitivity to the MCF-7/ADR cells as a result of the improved nanoassembly uptake, reduced drug efflux, and enhanced apoptosis, as evidenced by multiple regulation of a series of intracellular proteins related to MDR. Furthermore, in vivo delivery of the PCD/siRNA/Nd-PC nanoassembly is demonstrated to inhibit tumor growth in the mouse model with MCF-7/ADR tumor xenografts as a result of reduced angiogenesis and increased necrosis at the tumor site. This study reveals a simple and universal strategy to transform polymer-based nanoassemblies into advanced organic-inorganic nanotherapeutics suitable for cancer MDR therapy.
Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China.
Weihong
W
Jin
Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou, 310028, China; Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
Qiwen
Q
Wang
Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China; Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou, 310028, China.
Min
M
Wu
Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China; Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou, 310028, China.
Yang
Y
Li
Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China; Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou, 310028, China. Electronic address: tangguping@zju.edu.cn.
Guping
G
Tang
School of Materials Science and Engineering, Nanyang Technological University, Singapore, 639798, Singapore. Electronic address: pingyuan7@gmail.com.
Yuan
Y
Ping
Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China. Electronic address: paul.chu@cityu.edu.hk.
Paul K
PK
Chu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004705:Endocytosis; D005260:Female; D006801:Humans; D028581:Lanthanoid Series Elements / Q000737:chemistry*; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D009354:Neodymium / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D047408:gamma-Cyclodextrins / Q000737:chemistry
D000970:Antineoplastic Agents; D028581:Lanthanoid Series Elements; D011108:Polymers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D047408:gamma-Cyclodextrins; D009354:Neodymium; D004317:Doxorubicin; D011094:Polyethyleneimine; C023792:gamma-cyclodextrin
Chemotherapy; Drug delivery; Nanomedicine; Organic-inorganic hybrid materials; siRNA