Influence of formulation parameters on gadolinium entrapment and tumor cell uptake using folate-coated nanoparticles.

Emulsifying wax and polyoxyl 2 stearyl ether (Brij 72) nanoparticles (2 mg/ml) containing high concentrations of gadolinium hexanedione (GdH) (0-3 mg) have been engineered from oil-in-water microemulsion templates. Solid nanoparticles were cured by cooling warm microemulsion templates (prepared at 55 degrees C) to room temperature in one vessel. Nanoparticles were characterized by transmission electron microscopy (TEM), photon correlation spectroscopy (PCS) and gel permeation chromatography (GPC). To obtain folate-coated nanoparticles, a folate ligand was added to either the microemulsion templates or nanoparticle suspensions at 25 degrees C. Since the concentration of Gd in the tumor is critical to the success of Gd-neutron capture therapy (NCT), the effects of various formulation factors on GdH entrapment in nanoparticles as well as tumor-targeting were studied. GdH entrapment in nanoparticles was affected mostly by the method of GdH incorporation and surfactant concentration used in preparing the microemulsion templates. Cell uptake studies were carried out in KB cells (human nasopharyngeal epidermal carcinoma cell line). The method of adding folate ligand to the formulations did not significantly affect nanoparticle cell uptake (P>0.11; t-test). However, the concentration of folate ligand added to nanoparticles had the greatest influence on nanoparticle uptake (P<0.01; t-test). The results showed that GdH entrapment and cell uptake were optimized and suggested that engineered folate-coated nanoparticles may serve as effective carrier systems for Gd-NCT of tumors.

[1]  P. Low,et al.  Delivery of liposomes into cultured KB cells via folate receptor-mediated endocytosis. , 1994, The Journal of biological chemistry.

[2]  M. Sc,et al.  Targeted drug delivery for boron neutron capture therapy , 1996 .

[3]  Chen,et al.  Selective boron drug delivery to brain tumors for boron neutron capture therapy. , 1997, Advanced drug delivery reviews.

[4]  D. Tzemach,et al.  Nuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance efflux pump. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[5]  M. Schäfer-Korting,et al.  Solid lipid nanoparticles as drug carriers for topical glucocorticoids. , 2000, International journal of pharmaceutics.

[6]  D Needham,et al.  Increased microvascular permeability contributes to preferential accumulation of Stealth liposomes in tumor tissue. , 1993, Cancer research.

[7]  J. Kreuter,et al.  Gelatin nanoparticles by two step desolvation--a new preparation method, surface modifications and cell uptake. , 2000, Journal of microencapsulation.

[8]  Y. Sakurai,et al.  Gadolinium neutron-capture therapy using novel gadopentetic acid-chitosan complex nanoparticles: in vivo growth suppression of experimental melanoma solid tumor. , 2000, Cancer letters.

[9]  R. Mumper,et al.  Gadolinium-Loaded Nanoparticles Engineered from Microemulsion Templates , 2002, Drug development and industrial pharmacy.

[10]  R. Müller,et al.  Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art. , 2000, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[11]  T. Matsumoto.  Transport calculations of depth-dose distributions for gadolinium neutron capture therapy. , 1992, Physics in medicine and biology.

[12]  Leaf Huang,et al.  Folate-targeted, Anionic Liposome-entrapped Polylysine-condensed DNA for Tumor Cell-specific Gene Transfer (*) , 1996, The Journal of Biological Chemistry.

[13]  Y. Akine,et al.  Radiation effect of gadolinium-neutron capture reactions on the survival of Chinese hamster cells. , 1990, Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al].

[14]  Y. Cai,et al.  Body distribution in mice of intravenously injected camptothecin solid lipid nanoparticles and targeting effect on brain. , 1999, Journal of controlled release : official journal of the Controlled Release Society.

[15]  J. Behr,et al.  Conjugation of Folate via Gelonin Carbohydrate Residues Retains Ribosomal-inactivating Properties of the Toxin and Permits Targeting to Folate Receptor Positive Cells* , 2001, The Journal of Biological Chemistry.

[16]  R. Reisfeld,et al.  Determination of gadolinium in sodium borate glasses. , 1970, Talanta.

[17]  P. Low,et al.  Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro. , 1995, Biochimica et biophysica acta.

[18]  B. Kamen,et al.  Properties of a folate binding protein (FBP) isolated from porcine kidney. , 1986, Biochemical pharmacology.

[19]  B. Allen,et al.  Induction of double-strand breaks following neutron capture by DNA-bound 157Gd. , 1988, International journal of radiation biology.

[20]  P. Couvreur,et al.  Design of folic acid-conjugated nanoparticles for drug targeting. , 2000, Journal of pharmaceutical sciences.

[21]  Biodistribution of gadolinium incorporated in lipid emulsions intraperitoneally administered for neutron-capture therapy with tumor-bearing hamsters. , 1999, Biological & pharmaceutical bulletin.

[22]  Gordon L. Amidon,et al.  The Mechanism of Uptake of Biodegradable Microparticles in Caco-2 Cells Is Size Dependent , 1997, Pharmaceutical Research.

[23]  T. Allen,et al.  A new strategy for attachment of antibodies to sterically stabilized liposomes resulting in efficient targeting to cancer cells. , 1995, Biochimica et biophysica acta.

[24]  Robert J. Lee,et al.  Boron-containing folate receptor-targeted liposomes as potential delivery agents for neutron capture therapy. , 2002, Bioconjugate chemistry.

[25]  L R Coney,et al.  Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. , 1992, Cancer research.

[26]  M. Schäfer-Korting,et al.  Vitamin A loaded solid lipid nanoparticles for topical use: occlusive properties and drug targeting to the upper skin. , 2000, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[27]  R. Müller,et al.  Solid lipid nanoparticles (SLN) : an alternative colloidal carrier system for controlled drug delivery , 1995 .

[28]  R. Brugger,et al.  Gadolinium as a neutron capture therapy agent. , 1992, Medical physics.

[29]  H. Ichikawa,et al.  Chitosan-Gadopentetic Acid Complex Nanoparticles for Gadolinium Neutron-Capture Therapy of Cancer: Preparation by Novel Emulsion-Droplet Coalescence Technique and Characterization , 1999, Pharmaceutical Research.

[30]  Y. Akine,et al.  Preparation of lecithin microcapsules by a dilution method using the Wurster process for intraarterial administration in gadolinium neutron capture therapy. , 1999, Chemical & pharmaceutical bulletin.

[31]  P. Low,et al.  Folate-mediated targeting of antineoplastic drugs, imaging agents, and nucleic acids to cancer cells. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[32]  R. Barth,et al.  Boron neutron capture therapy of primary and metastatic brain tumors , 1994, Molecular and chemical neuropathology.

[33]  Y. Akine,et al.  Comparison of Radiation Effects of Gadolinium and Boron Neutron Capture Reactions , 2000, Strahlentherapie und Onkologie.

[34]  R. Mumper,et al.  Engineering tumor-targeted gadolinium hexanedione nanoparticles for potential application in neutron capture therapy. , 2002, Bioconjugate chemistry.

[35]  S. Gohla,et al.  Production of solid lipid nanoparticles (SLN): scaling up feasibilities , 2002, Journal of microencapsulation.