A folate receptor-targeted lipid nanoparticle formulation for a lipophilic paclitaxel prodrug

Purpose. The anticancer drug paclitaxel has poor aqueous solubility and is difficult to formulate in a lipid-based formulation due to its limited lipid solubility. Pactitaxel-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 glycol-cholesterol (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. Conclusion. FR-targeted LNs containing Tax-Chol are a promising novel formulation for the treatment of FR(+) tumors and further preclinical studies are warranted.