This study is to evaluate the sustained-release effect of the thermosensitive in situ gel for injection of boanmycin hydrochloride (BAM) by bioluminescence imaging in nude mice. BAM was labeled with fluorescein isothiocyanate (FITC). The FITC-labeled BAM (FITC-BAM) was purified by dialysis and Sephadex G25 gel column, and then was identified by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF). The model of experimental hepatoma HepG-2 nude mice was established, and the optical imaging system was applied to evaluate the distribution of FITC-BAM in vivo. Results of MALDI-TOF proved that the major molecular ratio of BAM : FITC was 1 : 1 or 1 : 2. Bioluminescence imaging showed that the diffusion of FITC-BAM in situ gel group was significantly delayed compared with the negative control group. This study demonstrated that the thermosensitive in situ gel can effectively delay the release of boanmycin hydrochloride, and extend the retention time in vivo.
Animals ; Antibiotics, Antineoplastic ; administration & dosage ; chemistry ; pharmacokinetics ; Bleomycin ; administration & dosage ; analogs & derivatives ; chemistry ; pharmacokinetics ; Delayed-Action Preparations ; Drug Carriers ; chemistry ; Female ; Fluorescein-5-isothiocyanate ; administration & dosage ; chemistry ; pharmacokinetics ; Gels ; chemistry ; Hep G2 Cells ; Humans ; Injections ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Temperature ; Tissue Distribution ; Viscosity

Poloxamer F127, poloxamer F68 and hydroxypropyl methylcellulose K4M were used to prepare the thermosensitive in situ gel of boanmycin hydrochloride for injection. Its gelation temperature, rheological behavior, texture characteristics, scanning electron microscopy, in vitro and in vivo drug release were evaluated. These results showed that the formulation was a fluid solution at room temperature, which could become semisolid at the temperature of 37 degrees C, and the thermally induced sol-gel transition allowed to be injectable and in situ setting. The formulation was constructed into a tridimensional network at gelation temperature. The drug release was controlled by the diffusion of the drug and the erosion of the gelmatrix. The pharmacokinetics indicated that the drug could be released slowly for up to 48 hours after subcutaneous administration in rats.
Animals ; Antibiotics, Antineoplastic ; administration & dosage ; pharmacokinetics ; Bleomycin ; administration & dosage ; analogs & derivatives ; pharmacokinetics ; Diffusion ; Drug Delivery Systems ; Gels ; Hypromellose Derivatives ; Injections, Subcutaneous ; Male ; Methylcellulose ; analogs & derivatives ; chemistry ; Microscopy, Electron, Scanning ; Poloxamer ; chemistry ; Rats ; Rats, Sprague-Dawley ; Rheology ; Temperature ; Viscosity

To develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of epirubicin hydrochloride (EPI) in rat plasma, daunorubicin hydrochloride was used as internal standard. The plasma samples were deproteinated with methanol, and separation was performed on a reversed-phase CAPCELL PAK C18 column (3.0 mm x 50 mm, 3 microm). The mobile phase contained methanol-0.1% formic acid (80:20). Detection was carried out by multiple reaction monitoring on a HP1200-6410 QQQ LC/MS system. Different preparations of EPI solution, EPI-LIP (EPI-liposome) and EPI-LTSL (EPI-thermosensitive liposome) was administered in rats by i.v with the same dosage (12 mg kg(-1)). The pharmacokinetic model and parameters were fitted and calculated by the DAS ver2.0 software. The calibration curve was linear in the range of 0.01-50 microg mL(-1). The limit of quantification was 0.01 microg mL(-1). RSDs of intra- and interbatch precisions were all less than 11.9%. The average extract recovery was 89.3% and 92.1%, respectively. The pharmacokinetics of EPI in rats with all preparations were fitted to three compartments, which all fast distributed and slowly eliminated. The t1/2 alpha, t1/2 beta, t1/2 gamma, AUC(0-infinity), and MRT(0-infinity) of EPI-LTSL group were 7.5, 1.3, 12.6, 12.9, 3.7 times those of EPI solution group; and 1.6, 1.4, 12.3, 2.9, 2.6 times those of EPI-LIP group. Moreover, the CL of the latter two groups was about 13.4 times of the former EPI-LTSL group. EPI-LTSL can significantly improve AUC and prolong the circulation time of EPI in rat plasma.
Animals ; Antibiotics, Antineoplastic ; administration & dosage ; blood ; pharmacokinetics ; Area Under Curve ; Chromatography, Liquid ; Drug Carriers ; Epirubicin ; administration & dosage ; blood ; pharmacokinetics ; Liposomes ; blood ; pharmacokinetics ; Male ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results ; Sensitivity and Specificity ; Tandem Mass Spectrometry

BACKGROUND AND OBJECTIVEResearch has shown that 5-bromotetrandrine (BrTet) can effectively reverse multidrug resistance (MDR). Imatinib plays an important role in cell proliferation. This study explored the efficacy of the combination of imatinib and BrTet on reversing MDR of tumor cells and its mechanism.

METHODSCytoxicity was assessed by MTT assay. Apoptosis of K562/A02 cells was analyzed by flow cytometry. The expressions of mdr1 mRNA and P-glycoprotein (P-gp) were detected using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis.

RESULTSAfter 48 h of treatment with 0.0625 micromol/L imatinib, 0.5 micromol/L BrTet, or both, the 50% inhibition concentration (IC50) of daunorubicin (DNR) for the K562/A02 cells were 5.69 mg/L, 5.41 mg/L, and 2.19 mg/L, respectively. The gray-scale values of mdr1 mRNA expression in the K562/A02 cells were 0.65+/-0.02, 0.64+/-0.01, and 0.25+/-0.03, respectively. The expression levels of P-gp were 0.74+/-0.02, 0.52+/-0.02, and 0.29+/-0.02, respectively. All decreased significantly in the K562/A02 cells treated with both imatinib and BrTet compared to cells treated with imatinib and BrTet alone (P<0.05). The apoptosis rates of the K562/A02 cells increased without a significant difference after treatment with DNR, imatinib, or BrTet (P>0.05), while increased significantly after treatment with DNR combined with imatinib, BrTet, or both (P<0.05).

CONCLUSIONSThe MDR of K562/A02 cells may be partially reversed by imatinib or BrTet, and the mechanism may be related to the downregulation of mdr1 mRNA and P-gp expression and the upregulation of the rate of apoptosis in K562/A02 cells. Imatinib combined with BrTet showed a synergistic effect on K562/A02 cells.

ATP Binding Cassette Transporter, Sub-Family B ; ATP-Binding Cassette, Sub-Family B, Member 1 ; genetics ; metabolism ; Antibiotics, Antineoplastic ; pharmacokinetics ; pharmacology ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Benzamides ; Benzylisoquinolines ; pharmacology ; Cell Proliferation ; drug effects ; Daunorubicin ; pharmacokinetics ; pharmacology ; Down-Regulation ; Drug Resistance, Multiple ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Drug Synergism ; Gene Expression Regulation, Leukemic ; Humans ; Imatinib Mesylate ; K562 Cells ; drug effects ; Piperazines ; pharmacology ; Pyrimidines ; pharmacology ; RNA, Messenger ; metabolism

It is generally believed that liposomes modified with polyethylene glycol (PEG) have no or lower immunogenicity. However, based on many recent literatures, when the PEGylated liposomes were repeatedly applied to the same animal, the immune responses occurred. The first injection of PEGylated liposomes resulted in a reduction in the circulation time and an increase in hepatic and splenic accumulation of the second dose of PEGylated liposomes in a time-interval, which was called "accelerated blood clearance (ABC)" phenomenon. Such immunogenicity of PEGylated liposomes presents a barrier in the research of liposomal formulations and their use in the clinics. This review focused on the definition, the method of verification, the development of the reason for ABC phenomenon, influencing factors of ABC phenomenon, and discussed if other PEGylated nanocarriers also induce ABC phenomenon.
Animals ; Antibiotics, Antineoplastic ; administration & dosage ; pharmacokinetics ; Doxorubicin ; administration & dosage ; pharmacokinetics ; Drug Carriers ; Immunoglobulin M ; biosynthesis ; blood ; Liposomes ; administration & dosage ; blood ; pharmacokinetics ; Liver ; metabolism ; Metabolic Clearance Rate ; Particle Size ; Polyethylene Glycols ; administration & dosage ; metabolism ; pharmacokinetics ; Serum Albumin, Bovine ; pharmacokinetics ; Spleen ; immunology ; metabolism

Pectin, a polysaccharide extracted from the cell wall of plants, was used as the drug carrier to synthesize the pectin-adriamycin conjugates (P(A)n). The structure of the conjugates was confirmed by UV and IR. The degree of esterification (DE) of the pectin was assessed, and it was found that DE significantly influenced the carboxy group contents, inherent viscosity and galacturonic acid contents of the pectin. The results of drug release test in vitro showed that the conjugate was stable in normal saline, but was gradually enzymolyzed to release the adriamycin in blood plasma and in lymph nodes. The results of lymphatic targeting study of P(A), demonstrated that the modification of DE or drug coupling capacity of pectin significantly influenced the lymphatic targeting characteristics of P (A)n. The adriamycin concentration of lymph nodes was 208 times higher than that of plasma after local injection of the P(A)n, of which the adriamycin content was 27.9% and the pectin was deesterificated 120 minutes by the use of hypothermy alkaline deesterification method.
Animals ; Antibiotics, Antineoplastic ; administration & dosage ; pharmacokinetics ; Doxorubicin ; administration & dosage ; pharmacokinetics ; Drug Carriers ; chemistry ; Esterification ; Lymph Nodes ; metabolism ; Pectins ; administration & dosage ; pharmacokinetics ; Rabbits

OBJECTIVETo study relationship between daunorubicin (DNR) pharmacokinetics and efficacy and toxicity in children with acute leukemia.

METHODS(1) The concentration of DNR in plasma of children with acute leukemia was determined by high performance liquid chromatography (HPLC)-fluorescence detection method. Plasma was sampled frequently from the start of the infusion till the end of 24 h. DNR pharmacokinetics was studied by determination of the concentrations. (2) Efficacy and toxicity were monitored in each period after chemotherapy. Laboratory studies included examination of bone marrow, white blood cell count, electrocardiogram, echocardiogram, myocardial enzymogram, the liver and kidney function.

RESULTS(1) DNR was eliminated from plasma in a two-compartment manner. The maximum concentration was seen 1 - 3 h after infusion. Cmax was 63.50 microg/L. Tmax was 1.45 h. The concentration decreased quickly to a low level of about 11.52 microg/L from the end of 2 hours infusion. There was a large inter-individual difference in pharmacokinetic parameters of DNR. The difference of CL was 9-fold, AUC was 8-fold, Cmax was 5-fold. (2) CL of male patients [57.99 L/(h.m(2))] was significantly lower than that of female patients [93.71 L/(h.m(2))] (P < 0.05). Tmax of children older than 6 years was 1.1 h, and that of children younger than 6 years was 1.8 h (P < 0.05); Cmax of children older than 6 years was 90.77 microg/L, younger than 6 years was 57.44 microg/L (P < 0.05).

CONCLUSION(1) There is a large inter-individual difference in pharmacokinetic parameters of DNR in children. It may predict individual variety of efficacy and toxicity. Therapeutic drug monitoring is important. (2) Male patients and children older than 6 years had a higher bioavailability and lower metabolism, toxicity may easily occur in such children, therefore they may need lower dose.

Antibiotics, Antineoplastic ; adverse effects ; pharmacokinetics ; therapeutic use ; Child ; Child, Preschool ; Chromatography, High Pressure Liquid ; Daunorubicin ; adverse effects ; pharmacokinetics ; therapeutic use ; Drug Monitoring ; Female ; Humans ; Infant ; Leukemia ; drug therapy ; metabolism ; Male

To prepare doxorubicin-loaded N-octyl-N'-succinyl chitosan polymeric micelle (DOX-OSC) and study the biodistribution of DOX-OSC in mice, DOX-OSC was prepared by dialysis method. By using doxorubicin injection (DOX-INJ) as control, DOX-OSC and DOX-INJ were administered to mice through caudal vein at a dose of 5 mg x kg(-1) body weight. The RP-HPLC method was established to determine the DOX levels in the plasma and other tissues of mice. The tissues distribution and targeting efficiency were evaluated by pharmacokinetic parameters (AUC, MRT) and targeting parameters (Re, Ce and Te). The drug loading and entrapment efficiency of DOX-OSC were (35.8 +/- 0.4)% and (75.3 +/- 1.1)%, respectively. The diameter and zeta potential of DOX-OSC were (174 +/- 12) nm and (-37.1 +/- 3.0) mV, respectively. The transmission electron microscope result showed DOX-OSC with spherical shape. The biodistribution results showed that the concentration of DOX of both DOX-OSC and DOX-INJ decreased rapidly in blood after iv administration. While free DOX levels in blood at 12-96 h were not detectable for DOX-INJ, in contrast, DOX level in blood at 96 h was still found for DOX-OSC. In contrast to DOX-INJ group, DOX-OSC showed a higher targeting efficiency in the liver and spleen. The AUCs of DOX in the liver and spleen were 20.0 and 47.4 times and the MRT were 11.2 and 37.2 times, respectively. And the levels of DOX-OSC in the heart and kidney tissues were significantly reduced. And the drug distribution of DOX-OSC in the heart and kidney tissues were 17.0% and 11.4%, respectively. Hence, DOX-OSC shows an excellent drug loading capabilities and a higher targeting efficiency in the liver and spleen. That the levels of DOX-OSC in the heart and kidney tissues are significantly reduced, might improve the treatment efficacy of DOX and decrease the side effects.
Animals ; Antibiotics, Antineoplastic ; administration & dosage ; pharmacokinetics ; Area Under Curve ; Chitosan ; analogs & derivatives ; chemistry ; Doxorubicin ; administration & dosage ; pharmacokinetics ; Drug Carriers ; Drug Delivery Systems ; Female ; Liver ; metabolism ; Male ; Mice ; Micelles ; Particle Size ; Polymers ; Spleen ; metabolism ; Tissue Distribution

In this paper, we address the preparation of the EPC and HEPC sterically stabilized doxorubicin liposomes and report the data collected from further studies on pharmacokinetics in blood for choosing a better carrier in delivering the drugs. The pharmacokinetics of EPC and HEPC sterically stabilized liposomes (EPC-SSL, and HEPC-SSL) in Wistar rats were investigated by HPLC. The results showed that the mean residence time of HEPC-SSL in blood is 23.3 h, while that of EPC-SSL is 12.0 h. In conclusion, HEPC-SSL is a better carrier in delivering the drugs to the extravascular sites when compared with EPC-SSL.
Animals ; Antibiotics, Antineoplastic ; administration & dosage ; pharmacokinetics ; Delayed-Action Preparations ; chemical synthesis ; pharmacokinetics ; Doxorubicin ; administration & dosage ; pharmacokinetics ; Drug Carriers ; chemistry ; Hydrogenation ; Liposomes ; Phosphatidylcholines ; chemistry ; pharmacology ; Rats

OBJECTIVETo evaluate the adsorption and desorption of epirubicin (EADM) by carbon-coated iron nanocrystals (CCIN).

METHODSEADM standard curve was generated. After thorough mixture of CCIN and EADM with sonication, the mixture solution was centrifuged at high speed to obtain dissociated EADM for evaluating the adsorption capacity of CCIN. A dialyzer was used to evaluate the desorption of drug-loaded CCIN particles in different media (PBS, normal saline, or distilled water), at different temperatures, and with different quantities of loaded drug.

RESULTSThe adsorption of EADM by CCIN presented linear adsorption before saturation and saturation adsorption, with an adsorption saturation point of about 160 microg/mg. The desorption of EADM from CCIN particles was affected by such factors as the extraction media, temperature, and quantity of the loaded drug. Compared to distilled water, PBS and normal saline improved the release rate of EADM from the drug-loaded CCIN particles. Higher temperature also contributed to higher release rate of EADM. Higher release rate of EADM occurred after the CCIN particles adsorbed greater amount of EADM.

CONCLUSIONCCIN shows an EADM adsorption pattern of Langmuir isotherm adsorption. Such factors as higher temperature, PBS solution, higher speed of medium replacement, and more drug adsorbed all contribute to a higher release rate of EADM.

Adsorption ; Antibiotics, Antineoplastic ; chemistry ; pharmacokinetics ; Carbon ; chemistry ; Delayed-Action Preparations ; chemistry ; pharmacokinetics ; Drug Carriers ; Drug Delivery Systems ; Epirubicin ; chemistry ; pharmacokinetics ; Iron ; chemistry ; Nanoparticles ; chemistry