Liposomal quercetin efficiently suppresses growth of solid tumors in murine models.
OBJECTIVE
Quercetin is a potent chemotherapeutic drug. Clinical trials exploring different schedules of administration of quercetin have been hampered by its extreme water insolubility. To overcome this limitation, this study is aimed to develop liposomal quercetin and investigate its distribution in vivo and antitumor efficacy in vivo and in vitro.


METHODS
Quercetin was encapsulated in polyethylene glycol 4000 liposomes. Biodistribution of liposomal quercetin i.v. at 50 mg/kg in tumor-bearing mice was detected by high-performance liquid chromatography. Induction of apoptosis by liposomal quercetin in vitro was tested. The antitumor activity of liposomal quercetin was evaluated in the immunocompetent C57BL/6N mice bearing LL/2 Lewis lung cancer and in BALB/c mice bearing CT26 colon adenocarcinoma and H22 hepatoma. Tumor volume and survival time were observed. The mechanisms underlying the antitumor effect of quercetin in vivo was investigated by detecting the microvessel density, apoptosis, and heat shock protein 70 expression in tumor tissues.


RESULTS
Liposomal quercetin could be dissolved in i.v. injection and effectively accumulate in tumor tissues. The half-time of liposomal quercetin was 2 hours in plasma. The liposomal quercetin induced apoptosis in vitro and significantly inhibited tumor growth in vivo in a dose-dependent manner. The optimal dose of liposomal quercetin resulted in a 40-day survival rate of 40%. Quantitative real-time PCR showed that liposomal quercetin down-regulated the expression of heat shock protein 70 in tumor tissues. Immunohistochemistry analysis showed that liposomal quercetin inhibited tumor angiogenesis as assessed by CD31 and induced tumor cell apoptosis.


CONCLUSIONS
Our data indicated that pegylated liposomal quercetin can significantly improve the solubility and bioavailability of quercetin and can be a potential application in the treatment of tumor.
Yuan
Zhi-ping
ZP
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, People's Republic of China.
Chen
Li-juan
LJ
Fan
Lin-yu
LY
Tang
Ming-hai
MH
Yang
Guang-li
GL
Yang
Han-su
HS
Du
Xiao-bo
XB
Wang
Guo-qing
GQ
Yao
Wen-xiu
WX
Zhao
Qu-mei
QM
Ye
Bin
B
Wang
Rui
R
Diao
Peng
P
Zhang
Wei
W
Wu
Hong-bin
HB
Zhao
Xia
X
Wei
Yu-quan
YQ
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004337:Drug Carriers; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D007275:Injections, Intravenous; D008081:Liposomes; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols; D011794:Quercetin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012995:Solubility; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D004337:Drug Carriers; D018840:HSP70 Heat-Shock Proteins; D008081:Liposomes; D011092:Polyethylene Glycols; D011794:Quercetin