Abstract | 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. 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. CONCLUSION: FR-targeted LNs containing Tax-Chol are a promising novel formulation for the treatment of FR(+) tumors and further preclinical studies are warranted.
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Authors | Phillip J Stevens, Masaru Sekido, Robert J Lee |
Journal | Pharmaceutical research
(Pharm Res)
Vol. 21
Issue 12
Pg. 2153-7
(Dec 2004)
ISSN: 0724-8741 [Print] United States |
PMID | 15648245
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Carrier Proteins
- Folate Receptors, GPI-Anchored
- Liposomes
- Prodrugs
- Receptors, Cell Surface
- Paclitaxel
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Topics |
- Animals
- CHO Cells
- Carrier Proteins
(metabolism)
- Cell Line, Tumor
- Chemistry, Pharmaceutical
- Cricetinae
- Drug Delivery Systems
(methods)
- Drug Screening Assays, Antitumor
(methods)
- Female
- Folate Receptors, GPI-Anchored
- Humans
- Liposomes
- Mice
- Mice, Inbred BALB C
- Nanostructures
- Paclitaxel
(administration & dosage, metabolism)
- Prodrugs
(administration & dosage, metabolism)
- Receptors, Cell Surface
(metabolism)
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