AIMTo study the pharmaceutical characterization and pharmacokinetics of long-circulating liposomes containing daunorubicin.

METHODSThe morphology of daunorubicin long-circulating liposome was surveyed under the transmission electron microscope. The size of daunorubicin long-circulating liposomes was determined by laser scatter method. The entrapment efficiency and accelerative experiment stability of the daunorubicin long-circulating liposomes were examined. Visible spectrophotometry and the HPLC method were established for determination of the daunorubicin in the long-circulating liposomes. The percent release of daunorubicin from long-circulating liposomes in HBS (pH 7.5) and rat serum at 37 degrees C were examined. The pharmacokinetics in rats were studied.

RESULTSThe high entrapment efficiency (> 85%) and stabilized long-circulating liposomes could be achieved. The drug was slowly released from the daunorubicin long-circulating liposomes. The drug released from liposomes was less than 10% in 24 h. The T1/2 alpha and AUC of long-circulating liposome were higher than those in injections.

CONCLUSIONThe long-circulating liposomes prepared by us have high encapsulation efficiency and the pharmaceutical characterization showed good stability, they can be used for clinical purpose.

Animals ; Antibiotics, Antineoplastic ; administration & dosage ; pharmacokinetics ; Daunorubicin ; administration & dosage ; pharmacokinetics ; Delayed-Action Preparations ; Drug Carriers ; Liposomes ; Male ; Phosphatidylethanolamines ; Polyethylene Glycols ; chemistry ; Random Allocation ; Rats ; Rats, Wistar

AIMTo prepare the mitoxantrone long circulating liposomes (LCL) and to observe the residence behavior of the mitoxantrone LCL in rabbits.

METHODSThe long circulating mitoxantrone liposomes were prepared by ethanol injection combined with the ammonium sulphate gradients method. Amphipathic polyethylene glycol-distearoyl phosphatidylethanolamine (PEG-DSPE) was added to modify the membrane of the liposomes. The column-switching system of RP-HPLC was utilized to determine mitoxantrone concentration in rabbit plasma.

RESULTSThe mean diameter of the long circulating mitoxantrone liposomes was 60 nm, with the entrapping efficiency of 93.6%. With the same dosage (2 mg.kg-1) i.v. in rabbits, the mean residence time (MRT) of the long circulating mitoxantrone liposomes was 9.8 h, while that of the normal liposomes was 3.6 h, and the AUC of the former is 6.4 fold greater than of the latter. It showed that the long circulating mitoxantrone liposomes prolonged the resident time of the drug in the blood circulating system and they reduced the uptake by the reticuloendothelial system, simultaneously.

CONCLUSIONLiposomes with high entrapping efficiency and small particle size could be prepared by ethanol injection combined with the ammonium sulphate gradients method, and the liposomes modified by PEG-DSPE could raise the AUC and prolonged the resident time of the drug in the blood circulating system.

Animals ; Antineoplastic Agents ; administration & dosage ; pharmacokinetics ; Area Under Curve ; Chemistry, Pharmaceutical ; Delayed-Action Preparations ; Drug Carriers ; Female ; Liposomes ; Male ; Mitoxantrone ; administration & dosage ; pharmacokinetics ; Phosphatidylethanolamines ; Polyethylene Glycols ; Rabbits

PURPOSE: Bisphophonates are drugs used to suppress osteoclastic activity and to treat osteoporosis, Paget's disease of bone and bone metastasis. The purpose of this report is to review the literatures on bisphopsphonates use that could affect bone healing and cause osteonecrosis of the jaws. MATERIALS AND METHODS: Medline research was carried out to find relevant articles on bisphophonates and osteonecrosis of the jaw. RESULTS: Oral administration of bisphopsphonates is reported to decrease the risk of adverse bone outcomes. On the contrary, IV bisphopsphonates is known to significantly increase the risk. Prevention of the osteonecrosis of the jaw is primary concern before usage. If the adverse bone reaction takes place, proper management and treatments are required to alleviate pain of patients and prevent further progression of necrosis. CONCLUSION: Case reports of bisphosphonates induced osteonecrosis of the jaw are increasing. Dentists and physicians should be aware of the higher frequency of osteonecrosis of the jaw in patients receiving IV bisphopsphonates and be prepared to prevent and cope with adverse bone reaction.
Administration, Oral ; Dentists ; Diphosphonates ; Humans ; Hypogonadism ; Jaw ; Mitochondrial Diseases ; Necrosis ; Neoplasm Metastasis ; Ophthalmoplegia ; Osteitis Deformans ; Osteoclasts ; Osteonecrosis ; Osteoporosis ; Phosphatidylethanolamines ; Risk Assessment

AIMTo investigate the possibility of using stealth liposomes modified with arginine-glycine-aspartic acid (RGD) mimetic as the targeted carriers to achieve increased accumulation in tumor and enhanced intracellular delivery for the encapsulated anticancer drugs.

METHODSRGD mimetic (RGDm) as a ligand for integrins was synthesized and covalently conjugated to the active PEGylated phospholipids (DSPE-PEG-BTC) to form RGDm conjugate (DSPE-PEG-RGDm). Then RGDm-modified SL (RGDm-SL) containing DOX (RGDm-SL-DOX) and SL containing DOX (SL-DOX) were prepared by film dispersion followed by ammonium sulfate gradient method. The pH-sensitive probe, BCECF-AM, was used to study the binding of melanoma cells to DSPE-PEG-RGDm. Flow cytometry and confocal microscopy were performed to evaluate the cellular association or DOX uptake for RGDm-SL-DOX or SL-DOX in vitro.

RESULTSThe melanoma cells A375 and B16 showed enhanced binding to the immobilized DSPE-PEG-RGDm. The cells treated with RGDm-SL-DOX showed remarkable increase in cellular association or DOX uptake compared with SL-DOX.

CONCLUSIONThe RGDm-modified SL could be as the targeted carriers to facilitate the delivery of the encapsulated anti-cancer drugs into tumor cells by receptor-mediated way.

Animals ; Antibiotics, Antineoplastic ; administration & dosage ; metabolism ; Cell Adhesion ; Cell Line, Tumor ; Cell Nucleus ; metabolism ; Doxorubicin ; administration & dosage ; metabolism ; Drug Carriers ; Drug Delivery Systems ; Humans ; Liposomes ; Melanoma, Experimental ; metabolism ; pathology ; Oligopeptides ; Phosphatidylethanolamines ; Polyethylene Glycols

AIMTo prepare long-circulating solid lipid nanoparticles containing paclitaxel with stearic acid, and investigate the in vitro and in vivo characterization of nanoparticles.

METHODSThe method of "emulsion evaporation-solidification at low temperature" was used to prepare the stearic acid solid lipid nanoparticles containing paclitaxel. Its morphology was examined by transmission electron microscope. The HPLC method for determination of paclitaxel in nanoparticles or serum samples was established. The release of paclitaxel in vitro and the pharmacokinetics after i.v. bolus injection to mice were studied.

RESULTSThe mean diameter of Brij78-SLN and F68-SLN is (103.5 +/- 29.2) nm and (220 +/- 98) nm, respectively. The nanoparticles release paclitaxel slowly and linearly, within 24 h, Brij78-SLN and F68-SLN release 8% and 20% of total drug, respectively. Long-circulation nanoparticles was found to stay in the blood circulation, with T 1/2 beta 10.1 h of F68-SLN, and T 1/2 beta 4.88 h of Brij78-SLN more than one commercialized paclitaxel injection, T 1/2 beta 1.3 h.

CONCLUSIONStearic acid might be a new drug carrier material in the future.

Animals ; Antineoplastic Agents, Phytogenic ; administration & dosage ; pharmacokinetics ; Chemistry, Pharmaceutical ; Delayed-Action Preparations ; Drug Carriers ; Mice ; Nanotechnology ; Paclitaxel ; administration & dosage ; pharmacokinetics ; Particle Size ; Phosphatidylethanolamines ; Polyethylene Glycols ; Random Allocation ; Stearic Acids ; chemistry

AIMTo investigate the biodistribution and the hepatocytes targeting of cationic liposome containing 3beta[N-( N',N'-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol) and surface-modified liposomes with sterylglucoside (SG) and polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE).

METHODSCationic liposomes (CL) composed of DC-Chol and dipalmitoylphosphatidylcholine (DPPC), SG/PEG modified cationic liposome (SG/PEG-CL), both contained trace 3H-cholesterol (3H-Chol) as radiolabel, were prepared. The liposomes encapsulating 125I-labled antisense oligodeoxynucleotide (125I-asODN) (SG/PEG-CL-asODN) were also prepared. The biodistribution of CL, SG/PEG-CL, SG/PEG-C2-asODN as well as 125I-asODN solution, were studied. The radioactivities in hepatocytes and non-hepatocytes after administration of CL and SG/PEG-CL were determined by infuseing method.

RESULTSCL and SG/PEG CL significantly aggregated in liver. The distribution of SG/PEG CL was significantly higher in hepatocytes (P < 0.01) and lower in non-hepatocytes (P < 0.01) than that of CL. The concentrations of SG/PEG-CL-asODN in liver and spleen were significantly higher than that of asODN solution (P < 0.01).

CONCLUSIONCationic liposome modified with SG/PEG changed the distribution of asODN. Cationic liposome can target hepatocytes more effective after being modified with SG.

1,2-Dipalmitoylphosphatidylcholine ; administration & dosage ; pharmacokinetics ; Animals ; Area Under Curve ; Cholestenes ; administration & dosage ; pharmacokinetics ; Cholesterol ; administration & dosage ; analogs & derivatives ; pharmacokinetics ; Drug Carriers ; Drug Delivery Systems ; Hepatocytes ; metabolism ; Liposomes ; administration & dosage ; pharmacokinetics ; Male ; Mice ; Oligodeoxyribonucleotides, Antisense ; administration & dosage ; pharmacokinetics ; Phosphatidylethanolamines ; administration & dosage ; pharmacokinetics ; Polyethylene Glycols ; administration & dosage ; pharmacokinetics ; Tissue Distribution

AIMTo investigate the enhancing effect on insulin absorption through GI. tract in mice by using the Ulex europaeus agglutinin I (UEA1) modified liposomes as the carrier.

METHODSUEA1 modified phosphatidylethanolamine (PE) was prepared by conjugating method of 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide (EDC), then the modified compound (PE-UEA1) was incorporated into the conventional liposomes of insulin to obtain UEA1 modified liposomes. The agglutination test was performed to examine the UEA1 biological activities after synthesis and modification. When liposomes were applied to healthy mice or diabetic mice at insulin dose of 350 u x kg(-1) orally, the hypoglycemic effect was investigated according to the blood glucose level determination.

RESULTSThe blood glucose levels of the healthy mice reduced by UEA1 modified liposomes were (84 +/- 15)% at 4 h, (78 +/- 11)% at 8 h and (90 +/- 12)% at 12 h after oral administration. The conventional liposomes and saline showed no effect. The blood glucose levels of the diabetic mice reduced by UEA1 modified liposomes were (73 +/- 7)% at 4 h, (74 +/- 9)% at 8 h, (86 +/- 9)% at 12 h after oral administration.

CONCLUSIONThe UEA1 modified liposomes promote the oral absorption of insulin due to the specific-site combination on M cell membrane.

Administration, Oral ; Animals ; Blood Glucose ; metabolism ; Diabetes Mellitus, Experimental ; blood ; Drug Carriers ; Drug Delivery Systems ; Hypoglycemic Agents ; administration & dosage ; pharmacokinetics ; Insulin ; administration & dosage ; pharmacokinetics ; Intestinal Absorption ; drug effects ; Liposomes ; Mice ; Phosphatidylethanolamines ; chemistry ; Plant Lectins ; chemistry ; isolation & purification ; pharmacology ; Plants, Medicinal ; chemistry ; Ulex ; chemistry

AIMTo investigate the enhancing effect on insulin absorption through GI tract in mice by using tomato lectin (TL) modified liposomes as the carrier.

METHODSTL-phosphatidylethanolamine (PE) conjugate (TL-PE) was synthesized by using carbodiimide cross-linking method, then the compound was incorporated into the conventional liposomes of insulin. The agglutination test was performed to examine TL biological activities after synthesis and incorporation. When TL modified liposomes were administrated orally to the normal mice or diabetic mice at insulin dose of 350 u x kg(-1), the hypoglycemic effect was determinated according to the blood glucose level.

RESULTSThe blood glucose levels of the normal mice were reduced by modified liposomes. The glucose levels were (85 +/- 5)% at 4 h, (54 +/- 11)% at 8 h, (57 +/- 6)% at 12 h postdose compared with the glucose levels prior to oral administration respectively. However, the conventional liposomes and saline have no hypoglycemic effect. The blood glucose levels of the diabetic mice were obviously reduced by TL modified liposomes, the glucose levels were (38 +/- 13)% at 4 h, (50 +/- 15)% at 8 h, (50 +/- 16)% at 12 h respectively.

CONCLUSIONTL modified liposomes promote the oral absorption of insulin due to the specific-site combination on GI cell membrane.

Administration, Oral ; Animals ; Blood Glucose ; metabolism ; Delayed-Action Preparations ; Diabetes Mellitus, Experimental ; blood ; metabolism ; Drug Carriers ; Drug Delivery Systems ; Hypoglycemic Agents ; administration & dosage ; pharmacokinetics ; pharmacology ; Insulin ; administration & dosage ; pharmacokinetics ; pharmacology ; Intestinal Absorption ; drug effects ; Intestine, Small ; metabolism ; Liposomes ; Mice ; Phosphatidylethanolamines ; chemistry ; Plant Lectins ; chemistry ; pharmacology ; Technology, Pharmaceutical ; methods

AIMTo prepare the PEGylated liposomes modified with cell penetrating peptides, which protect siRNA from nuclease degradation and deliver efficiently siRNA into cells to facilitate silencing of target gene.

METHODSThe purity of R8-PEG-PE and pNP-PEG-PE was detected by HPLC; the quantity of R8, PEG-DPPE modified R8, and R8 attached to the out membrane surface of the liposomal siRNA by transfer from R8-PEG-DPPE micelles to the liposomes was tested by fluorescence; Size and size distribution of siRNA loaded liposomes with and without attached R8 were determined by Zetasizer 5000; A comparison of mediated siRNA transfection efficiency between R8-liposomes and lipofectamine 2000 was examined by individual inside cell fluorescence intensity; The growth inhibition of small cell lung carcinoma NCI-H446 cells treated with R8-liposomal hdm2-siRNA or lipofectamine 2000-hdm2-siRNA complex was tested by MTT assay.

RESULTSThe retention times of PEG-DPPE and R8-PEG-DPPE were 9.0 min and 7.8 min, respectively. Fluorescence scanning indicated that lipids composed of liposomes and siRNAs didn't interfere to the determination of R8 when it was attached to the liposomal siRNA. The cells treated with R8-liposomal hdm2-siRNA significantly enhanced the cellular uptake of hdm2-siRNA and facilitated the functions of hdm2-siRNA through silencing of target gene which, in turn, inhibited tumor cell growth, compared with lipofectamine 2000.

CONCLUSIONThe R8 attached liposomes are shown to be powerful carriers for delivery siRNAs into cell to silence targeted gene.

Carcinoma, Small Cell ; metabolism ; pathology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Gene Silencing ; Gene Targeting ; Humans ; Liposomes ; Lung Neoplasms ; metabolism ; pathology ; Oligopeptides ; administration & dosage ; pharmacology ; Phosphatidylethanolamines ; Polyethylene Glycols ; Proto-Oncogene Proteins c-mdm2 ; genetics ; metabolism ; RNA, Small Interfering ; administration & dosage ; metabolism ; pharmacology ; Transduction, Genetic

AIMSome surfactants such as DSPE-PEG, Tween 80 and Brij 35 were used to modify the amphotericin B liposome, improve the stability, optimize the tissue distribution and decrease the toxicity of amphotericin B liposome.

METHODSThe amphotericin B liposome was prepared by the film-supersound method. The effects of cholesterol and amphotericin B on the encapsulation percentage were studied. The diameter, leakage percentage in phosphate buffer solution(PBS) and calf blood serum, and tissue distributions of amphotericin B liposome in the rat were determined.

RESULTSThe top encapsulation percentage of amphotericin B liposome is (91.2 +/- 1.6)%. After modification with DSPE-PEG, Tween 80 and Brij 35, the encapsulation percentages were improved, the average diameters were decreased and the stabilities were improved, the amphotericin B concentrations in the liver, spleen and kidney were decreased, and the amphotericin B concentrations in the brain were increased, especially in the AmB-L-Tween 80 group.

CONCLUSIONDSPE-PEG and Brij 35 could decrease the clearing of reticuroendothelial systems(RES) to the amphotericin B liposome and Tween 80 could facilitate the transporting of amphotericin B liposome into the brain.

Amphotericin B ; administration & dosage ; pharmacokinetics ; Animals ; Antifungal Agents ; administration & dosage ; pharmacokinetics ; Brain ; metabolism ; Drug Carriers ; Drug Delivery Systems ; Drug Interactions ; Liposomes ; chemistry ; Particle Size ; Phosphatidylethanolamines ; pharmacology ; Polyethylene Glycols ; pharmacology ; Polysorbates ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Surface-Active Agents ; pharmacology ; Tissue Distribution