title: Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China ; Department of Pharmacy, Wuhan University, Renmin Hospital, Wuhan, People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Ye
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Wendian
authors.initials: W
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Tan
authors.initials: T
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Lu
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Miao
authors.initials: M
authors.lastname: Lu
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Yongkang
authors.initials: Y
authors.lastname: Gai
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Ma
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Guangya
authors.initials: G
authors.lastname: Xiang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D001549:Benzamides / Q000008:administration & dosage* / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects*; D003131:Combined Modality Therapy; D004058:Diffusion; D004357:Drug Synergism; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism*; D005492:Folic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006367:HeLa Cells; D006801:Humans; D000068877:Imatinib Mesylate; D008081:Liposomes / Q000737:chemistry*; D058990:Molecular Targeted Therapy / Q000379:methods; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage* / Q000737:chemistry; D011743:Pyrimidines / Q000008:administration & dosage* / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D058973:Folate Receptors, GPI-Anchored; D008081:Liposomes; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D005492:Folic Acid
keywords: PDGFR; folate receptor; imatinib; liposomes; tumor targeting