Low-density lipoprotein-coupled N-succinyl chitosan nanoparticles co-delivering siRNA and doxorubicin for hepatocyte-targeted therapy.
Developing safe and effective carriers of small interference RNA (siRNA) is a significant demand for the systemic delivery of siRNA. In this study, low-density lipoprotein (LDL) was isolated from human plasma and loaded with cholesterol-conjugated siRNA to silence the multidrug resistant gene of tumors. Chol-siRNA/LDL-coupled N-succinyl chitosan nanoparticles loaded with doxorubicin (Dox-siRNA/LDL-SCS-NPs) were then prepared and characterised. The Dox-siRNA/LDL-SCS-NPs had average particle size of 206.4 ± 9.2 nm, entrapment efficiency of 71.06% ± 1.42%, and drug-loading amount of 12.35% ± 0.87%. In vitro antitumor activity revealed that cell growth was significantly inhibited. The accumulation of Dox by fluorescence microscopy and flow cytometry showed that LDL-coupled nanoparticles were more easily taken up than Dox-SCS-NPs. Results of confocal microscopy and reverse transcription-PCR revealed the highly efficient uptake of siRNA and the decrease in mdr1 mRNA expression. LDL-coupled nanoparticles protected siRNA from macrophage phagocytosis by dynamic observation using live cell station. In vivo tumor-targeting suggested that Cy7-labelled Dox-LDL-SCS-NPs were markedly accumulated in an analyzed in situ liver tumor model. Results indicated that LDL-SCS-NPs were effective tumor-targeting vectors and that the preparation form may provide a new strategy for co-delivering siRNA and antitumor drugs.
Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
Qiao-ling
QL
Zhu
Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China; The Children's Hospital, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi 214023, People's Republic of China.
Yi
Y
Zhou
Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China; Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing 210029, People's Republic of China.
Min
M
Guan
College of Radiological Medicine and Protection, Soochow University, Suzhou 215123, People's Republic of China.
Xiao-feng
XF
Zhou
Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
Shu-di
SD
Yang
Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
Yang
Y
Liu
Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
Wei-liang
WL
Chen
Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
Chun-ge
CG
Zhang
Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
Zhi-qiang
ZQ
Yuan
Suzhou Municipal Hospital Affiliated to Nanjing Medical University, Suzhou 215001, People's Republic of China.
Chun
C
Liu
Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.
Ai-jun
AJ
Zhu
Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China. Electronic address: zhangxuenong@163.com.
Xue-nong
XN
Zhang
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D048271:Chitosan / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage*; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000737:chemistry*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008077:Lipoproteins, LDL; C118639:N-succinyl-chitosan; D034741:RNA, Small Interfering; D004317:Doxorubicin; D048271:Chitosan
Co-delivery; Low-density lipoprotein; Multidrug resistance; Nanoparticles; Tumor-targeting therapy; siRNA