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已发表论文
顺利获得主动定位和分子靶向组合，叶酸受体靶向脂质体增强伊马替尼的抗肿瘤效力
Authors Ye P, Zhang W, Yang T, Lu Y, Lu M, Gai Y, Ma X, Xiang G
Published Date May 2014 Volume 2014:9(1) Pages 2167—2178
DOI http://dx.doi.org/10.2147/IJN.S60178
Received 6 January 2014, Accepted 11 March 2014, Published 7 May 2014
Purpose: Imatinib inhibits platelet-derived growth factor receptor (PDGFR), and evidence shows that PDGFR participates in the development and progression of cervical cancer. Although imatinib has exhibited preclinical activity against cervical cancer, only minimal clinical therapeutic efficacy was observed. This poor therapeutic efficacy may be due to insufficient drug delivery to the tumor cells and plasma protein binding. Therefore, the purpose of this study was to explore a novel folate receptor (FR)-targeted delivery system via imatinib-loaded liposomes to enhance drug delivery to tumor cells and to reduce plasma protein binding.
Methods: Imatinib was remote-loaded into FR-targeted liposomes which were prepared by thin film hydration followed by polycarbonate membrane extrusion. Encapsulation efficiency, mean size diameter, and drug retention were characterized and cellular uptake, cell cytotoxicity, and cell apoptosis on cervical cancer HeLa cells were evaluated. Comparative pharmacokinetic studies were also carried out with FR-targeted imatinib liposomes, simple imatinib liposomes, and free imatinib.
Results: High encapsulation efficiency (>90%), appropriate mean particle size (143.5 nm), and zeta potential (–15.97 mV) were obtained for FR-targeted imatinib liposomes. The drug release profile showed minimal imatinib leakage (<5%) in phosphate-buffered saline (PBS) at pH =7.4 within 72 hours of incubation, while more leakage (>25%) was observed in PBS at pH =5.5. This indicates that these liposomes possess a certain degree of pH sensitivity. Cytotoxicity assays demonstrated that the FR-targeted imatinib liposomes promoted a six-fold IC50 reduction on the non-targeted imatinib liposomes from 910 to 150 µM. In addition, FR-targeted imatinib liposomes enhanced HeLa cell apoptosis in vitro compared to the non-targeted imatinib liposomes. Pharmacokinetic parameters indicated that both targeted and non-targeted liposomes exhibited long circulation properties in Kunming mice.
Conclusion: These findings indicate that the nano-sized FR-targeted PDGFR antagonist imatinib liposomes may constitute a promising strategy in cervical cancer therapy through the combination of active targeting and molecular targeting.
Keywords: liposomes, imatinib, folate receptor, tumor targeting, PDGFR
Methods: Imatinib was remote-loaded into FR-targeted liposomes which were prepared by thin film hydration followed by polycarbonate membrane extrusion. Encapsulation efficiency, mean size diameter, and drug retention were characterized and cellular uptake, cell cytotoxicity, and cell apoptosis on cervical cancer HeLa cells were evaluated. Comparative pharmacokinetic studies were also carried out with FR-targeted imatinib liposomes, simple imatinib liposomes, and free imatinib.
Results: High encapsulation efficiency (>90%), appropriate mean particle size (143.5 nm), and zeta potential (–15.97 mV) were obtained for FR-targeted imatinib liposomes. The drug release profile showed minimal imatinib leakage (<5%) in phosphate-buffered saline (PBS) at pH =7.4 within 72 hours of incubation, while more leakage (>25%) was observed in PBS at pH =5.5. This indicates that these liposomes possess a certain degree of pH sensitivity. Cytotoxicity assays demonstrated that the FR-targeted imatinib liposomes promoted a six-fold IC50 reduction on the non-targeted imatinib liposomes from 910 to 150 µM. In addition, FR-targeted imatinib liposomes enhanced HeLa cell apoptosis in vitro compared to the non-targeted imatinib liposomes. Pharmacokinetic parameters indicated that both targeted and non-targeted liposomes exhibited long circulation properties in Kunming mice.
Conclusion: These findings indicate that the nano-sized FR-targeted PDGFR antagonist imatinib liposomes may constitute a promising strategy in cervical cancer therapy through the combination of active targeting and molecular targeting.
Keywords: liposomes, imatinib, folate receptor, tumor targeting, PDGFR
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