title: A folate receptor-targeted lipid nanoparticle formulation for a lipophilic paclitaxel prodrug.
abstract: OBJECTIVE
  The anticancer drug paclitaxel has poor aqueous solubility and is difficult to formulate in a lipid-based formulation due to its limited lipid solubility. Paclitaxel-7-carbonyl-cholesterol (Tax-Chol), a prodrug of paclitaxel with increased lipophilicity, was therefore synthesized and evaluated for incorporation into a lipid nanoparticle (LN) formulation, which also contained folate-polyethylene glycolcholesterol (f-PEG-Chol) as a ligand that targets the tumor marker folate receptor (FR). This novel formulation was designed for prolonged systemic circulation and selective targeting of tumor cells with amplified FR expression.
  
  
  METHODS
  Tax-Chol was synthesized. FR-targeted LNs, composed of distearoyl phosphatidylcholine (DSPC)/triolein/Chol oleate/PEG-Chol/f-PEG-Chol (40:40:18:2.0:0.5, mole/mole), were then prepared by solvent dilution followed by diafiltration. FR-targeted LNs containing Tax-Chol were then evaluated for cytotoxicity in KB, a human oral carcinoma cell line, and M109, a murine lung carcinoma cell line, both of which are FR(+) and in FR(-) Chinese hamster ovary (CHO) cells. Furthermore, tumor growth inhibition and animal survival in response to treatment with FR-targeted LNs and control formulations were evaluated in BALB/c mice bearing subcutaneously engrafted M109 tumors.
  
  
  RESULTS
  The LNs had a mean diameter of 130 nm and Tax-Chol incoporation efficiency of greater than 90% and exhibited excellent colloidal stability. FR-targeted LNs showed greater uptake and cytotoxicity in FR(+) KB and M109 cells than nontargeted LNs. Furthermore, treatment of mice bearing M109 tumors with FR-targeted LNs resulted in significantly greater tumor growth inhibition and animal survival compared to treatment with nontargeted LNs or paclitaxel formulated in Cremophor EL.
  
  
  CONCLUSIONS
  FR-targeted LNs containing Tax-Chol are a promising novel formulation for the treatment of FR(+) tumors and further preclinical studies are warranted.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Stevens
authors.forename: Masaru
authors.initials: M
authors.lastname: Sekido
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D006224:Cricetinae; D016503:Drug Delivery Systems / Q000379:methods*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D006801:Humans; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D049329:Nanostructures; D017239:Paclitaxel / Q000008:administration & dosage* / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D008081:Liposomes; D011355:Prodrugs; D011956:Receptors, Cell Surface; D017239:Paclitaxel