Folate-targeted paclitaxel-conjugated polymeric micelles inhibits pulmonary metastatic hepatoma in experimental murine H22 metastasis models.
Hepatocellular carcinoma shows low response to most conventional chemotherapies; additionally, extrahepatic metastasis from hepatoma is considered refractory to conventional systemic chemotherapy. Target therapy is a promising strategy for advanced hepatoma; however, targeted accumulation and controlled release of therapeutic agents into the metastatic site is still a great challenge. Folic acid (FA) and paclitaxel (PTX) containing composite micelles (FA-M[PTX]) were prepared by coassembling the FA polymer conjugate and PTX polymer conjugate. The main purpose of this study is to investigate the inhibitory efficacy of FA-M(PTX) on the pulmonary metastasis of intravenously injected murine hepatoma 22 (H22) on BALB/c mice models. The lung metastatic burden of H22 were measured and tissues were analyzed by immunohistochemistry and histology (hematoxylin and eosin stain), followed by survival analysis. The results indicated that FA-M(PTX) prevented pulmonary metastasis of H22, and the efficacy was stronger than pure PTX and simple PTX-conjugated micelles. In particular, the formation of lung metastasis colonies in mice was evidently inhibited, which was paralleled with the downregulated expression of matrix metalloproteinase-2 and matrix metalloproteinase-9. Furthermore, the mice bearing pulmonary metastatic hepatoma in the FA-M(PTX) group gained significantly prolonged survival time when compared with others given equivalent doses of PTX of 30 mg/kg. The enhanced efficacy of FA-M(PTX) is theoretically ascribed to the target effect of FA; moreover, the extensive pulmonary capillary networks may play a role. In conclusion, FA-M(PTX) displayed great potential as a promising antimetastatic agent, and the FA-conjugated micelles is a preferential targeted delivery system when compared to micelles without FA.
Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
Yan
Y
Zhang
Department of Thoracic Surgery, Xuzhou Central Hospital, Xuzhou, Jiangsu, People's Republic of China.
Hui
H
Zhang
Department of Thoracic Surgery, Xuzhou Central Hospital, Xuzhou, Jiangsu, People's Republic of China.
Wenbin
W
Wu
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, People's Republic of China ; Department of Otolaryngology, The First Hospital of Lanzhou University, Lanzhou, Gansu, People's Republic of China.
Fuhong
F
Zhang
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, People's Republic of China.
Shi
S
Liu
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, People's Republic of China.
Rui
R
Wang
Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
Yingchun
Y
Sun
Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
Ti
T
Tong
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, People's Republic of China.
Xiabin
X
Jing
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D004655:Emulsions / Q000737:chemistry; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D058990:Molecular Targeted Therapy / Q000379:methods; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D016896:Treatment Outcome
D000972:Antineoplastic Agents, Phytogenic; D004655:Emulsions; D008823:Micelles; D011108:Polymers; D005492:Folic Acid; D017239:Paclitaxel
folate receptor; paclitaxel; polymer–drug conjugate; pulmonary metastasis; targeted drug delivery