Supercooled smectic nanoparticles: influence of the matrix composition and in vitro cytotoxicity.

Cholesteryl nonanoate (CN), myristate (CM), palmitate (CP) and oleate (CO) alone or in combination were evaluated as matrix lipids for the preparation of supercooled smectic nanoparticles with a high stability against recrystallization during storage. The phase behavior of the cholesterol esters in the bulk was studied by polarizing light microscopy, differential scanning calorimetry (DSC) and small angle X-ray scattering (SAXS). Colloidal dispersions with pure and mixed cholesterol ester matrices were prepared by high-pressure melt homogenization and characterized by photon correlation spectroscopy, laser diffraction combined with polarizing intensity differential scattering, DSC and SAXS. The morphology of selected formulations was studied by freeze-fracture electron microscopy. All smectic nanoparticles with a mixed cholesterol ester matrix were stable against recrystallization when stored at room temperature. Nanoparticles with a pure CN and mixed CM/CN matrix with a high fraction of CN (60% of the whole lipid matrix) could even be stored at 4 degrees C for at least 18 months without any recrystallization. As smectic nanoparticles are studied especially with regard to parenteral administration of lipophilic drugs, the cytotoxicity of selected formulations was compared with that of a clinically used colloidal fat emulsion (Lipofundin MCT) in the murine fibroblast cell line L929 using the sulforhodamine B assay. The supercooled smectic nanoparticle formulations display a good overall cell compatibility although in some cases their cytotoxicity was slightly higher than that of Lipofundin MCT.

[1]  D. Scudiero,et al.  New colorimetric cytotoxicity assay for anticancer-drug screening. , 1990, Journal of the National Cancer Institute.

[2]  M. Hashida,et al.  Long circulating emulsion carrier systems for highly lipophilic drugs. , 1994, Biological & pharmaceutical bulletin.

[3]  Y. Pathak,et al.  Nanoparticulate Drug Delivery Systems , 2007 .

[4]  A. Scanu,et al.  Serum lipoproteins structure and function. , 1972, Annual review of biochemistry.

[5]  H. Bunjes,et al.  Influence of preparation conditions and heat treatment on the properties of supercooled smectic cholesteryl myristate nanoparticles. , 2007, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[6]  R. Porter,et al.  Heats of transition for some cholesteryl esters by differential scanning calorimetry , 1967 .

[7]  G. Ginsburg,et al.  Physical properties of cholesteryl esters. , 1986, Progress in lipid research.

[8]  W Mehnert,et al.  Solid lipid nanoparticles (SLN) for controlled drug delivery--drug release and release mechanism. , 1998, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[9]  H. Bunjes,et al.  Crystallization behavior of supercooled smectic cholesteryl myristate nanoparticles containing phospholipids as stabilizers. , 2005, Colloids and surfaces. B, Biointerfaces.

[10]  H. Bunjes,et al.  Supercooled Smectic Nanoparticles , 2007 .

[11]  H. Bunjes,et al.  Physicochemical characterization of lipid nanoparticles and evaluation of their drug loading capacity and sustained release potential , 1997 .

[12]  R. Porter,et al.  Phase Studies on Binary Systems of Cholesteryl Esters A. Two Aliphatic Ester Pairs , 1973 .

[13]  P. Morlière,et al.  The role of the low density lipoprotein receptor pathway in the delivery of lipophilic photosensitizers in the photodynamic therapy of tumours. , 1991, Journal of photochemistry and photobiology. B, Biology.

[14]  J. Barnard,et al.  A Crystallographic Examination of 14 Straight Chain Alkyl Esters of Cholesterol , 1974 .

[15]  Y. Carpentier,et al.  Advances in Intravenous Lipid Emulsions , 2000, World Journal of Surgery.

[16]  G. Shipley,et al.  Structure and interactions of lipids in human plasma low density lipoproteins. , 1977, The Journal of biological chemistry.

[17]  S. Benita,et al.  A new in vitro technique for the evaluation of drug release profile from colloidal carriers - ultrafiltration technique at low pressure , 1993 .

[18]  H. Bunjes,et al.  Supercooled Smectic Nanoparticles: A Potential Novel Carrier System for Poorly Water Soluble Drugs , 2004, Pharmaceutical Research.

[19]  T. Hosokawa,et al.  Evaluation of the carrier potential for the lipid dispersion system with lipophilic compound. , 2003, Biological & pharmaceutical bulletin.

[20]  R. Maranhão,et al.  Pharmacokinetics and tumor uptake of a derivatized form of paclitaxel associated to a cholesterol-rich nanoemulsion (LDE) in patients with gynecologic cancers , 2006, Cancer Chemotherapy and Pharmacology.

[21]  J. Wendorff,et al.  The Structure of Mesophases of Cholesteryl Esters , 1973 .

[22]  G. Ginsburg,et al.  Microemulsions of phospholipids and cholesterol esters. Protein-free models of low density lipoprotein. , 1982, The Journal of biological chemistry.

[23]  T. Takino.  Pharmacokinetic disposition analysis of lipophilic drugs injected with various lipid carriers in the single-pass rat liver perfusion system , 1995 .

[24]  C. Washington,et al.  Release rate measurements of model hydrophobic solutes from submicron triglyceride emulsions , 1995 .

[25]  N. Gershfeld.  Handbook of lipid research, vol. 4, the physical chemistry of lipids: From alkanes to phospholipids: D. M. Small, Plenum, New York/London, 1985. 672 pp., $89.50 , 1987 .

[26]  S. Tamilvanan,et al.  Oil-in-water lipid emulsions: implications for parenteral and ocular delivering systems. , 2004, Progress in lipid research.

[27]  S. Davis,et al.  The production of parenteral feeding emulsions by microfluidizer , 1988 .

[28]  K. Mäder,et al.  Solid lipid nanoparticles: production, characterization and applications. , 2001, Advanced drug delivery reviews.