Reversal of multidrug resistance by mitochondrial targeted self-assembled nanocarrier based on stearylamine.

Multidrug resistance (MDR) remains one of the major challenges for successful chemotherapy. Herein, we tried to develope a mitochondria targeted teniposide loaded self-assembled nanocarrier based on stearylamine (SA-TSN) to reverse MDR of breast cancer. SA-TSN was nanometer-sized spherical particles (31.59 ± 3.43 nm) with a high encapsulation efficiency (99.25 ± 0.21%). The MDR in MCF-7/ADR cells was obviously reduced by SA-TSN, which mainly attributed to the markedly reduced expression of P-gp, increased percentages in G2 phase, selectively accumulation in mitochondria, decrease of mitochondrial membrane potential, and greatly improved apoptosis. The plasma concentration of teniposide was greatly improved by SA-TSN, and the intravenously administered SA-TSN could accumulate in the tumor site and penetrate into the inner site of tumor in MCF-7/ADR induced xenografts. In particular, the in vivo tumor inhibitory efficacy of SA-TSN in MCF-7/ADR induced models was more effective than that of teniposide loaded self-assembled nanocarrier without stearylamine (TSN) and teniposide solution (TS), which verified the effectiveness of SA-TSN in reversal of MDR. Thereby, SA-TSN has potential to circumvent the MDR for the chemotherapy of breast cancer.

Determination of teniposide in rat plasma by ultra performance liquid chromatography electrospray ionization tandem mass spectrometry after intravenous administration.

A novel, specific and rapid ultra performance liquid chromatography electrospray ionization tandem mass spectrometry method has been developed and validated for determination of teniposide in rat plasma. A one-step liquid-liquid extraction method was used and the separation was carried out on an Acquity UPLC(TM) BEH C(18) column with gradient elution using a mobile phase composed of acetonitrile and water (containing 0.1% formic acid) at a flow rate of 0.20 mL/min. A triple quadrupole tandem mass spectrometer in multiple-reaction monitoring mode via an electrospray ionization interface was used for the detection of teniposide. The detection was complete within 3.0 min. A linear calibration curve was obtained over the concentration range 10-10,000 ng/mL for teniposide, with a lower limit of quantification of 10 ng/mL. The intra-day precision and inter-day precision (relative standard deviation) were less than 10.23 and 13.09%, respectively. The developed method was applied for the first time to the pharmacokinetic study of teniposide in rats following a single intravenous administration of 4.5 mg/kg teniposide.

Reduction of drug accumulation and DNA topoisomerase II activity in acquired teniposide-resistant human cancer KB cell lines.

We have isolated stable teniposide (VM26)-resistant cell lines from human cancer KB cells by stepwise exposure to increasing doses of the drug. At each step, we have purified VM26-resistant cell lines. KB/VM-a, KB/VM-b, KB/VM-1, KB/VM-2, KB/VM-3, and KB/VM-4 showed 3-, 6-, 12-, 16-, 74-, and 95-fold higher resistance to VM26 than did KB. We have further characterized KB/VM-2 and KB/VM-4 which showed about 15- and 100-fold higher resistance to VM26 or etoposide (VP16) than did KB. Both VM26-resistant cell lines showed 4- to 11-fold higher relative resistance to daunomycin and Adriamycin than did KB. Steady-state levels of the cellular accumulation of radioactive VP16 in KB/VM-2 and KB/VM-4 cells were about 40% of that of KB cells, whereas similar levels of radioactive daunomycin accumulation were observed in KB/VM-2 and KB/VM-4 cells as KB cells. Topoisomerase II activity of nuclear extracts of both KB/VM-2 and KB/VM-4 assayed by decatenation of kinetoplast DNA was consistently two-thirds or less the activity of KB cells. A similar reduction was seen in both immunoblot assays with specific anti-topoisomerase II antibody and Northern blot analysis with specific human DNA topoisomerase II complementary DNA. DNA topoisomerase I activity, however, was similar between the mutants and their parent. Furthermore, cell growth of KB/VM-2 and KB/VM-4 was more thermolabile than that of KB, while KB/VM-b already showed temperature-sensitive growth. KB/VM-1 did show reduced accumulation of VP16 as in KB/VM-2 or KB/VM-4, but it had a normal level of topoisomerase II content as in KB cells. These data suggest that the reduced expression of DNA topoisomerase II, possibly combined with decreased permeability to the drugs, can account for the acquired VM26 resistance of KB/VM-2 and KB/VM-4 cells and also that the temperature-sensitive phenotype might not be obligatorily coupled with the reduced expression of topoisomerase II or the decreased permeability.

Pharmacokinetics of continuous infusion of methotrexate and teniposide in pediatric cancer patients.

Laboratory studies have demonstrated the ability of teniposide to markedly enhance the intracellular accumulation of methotrexate suggesting that combination therapy with these agents may produce clinical benefit. Studies of methotrexate and teniposide were conducted in 19 children with relapsed acute lymphocytic leukemia to evaluate the pharmacokinetics of this previously untested combination of agents given alone or in combination and to demonstrate the feasibility of a Bayesian dose optimization strategy. Patients were randomly assigned to receive intermediate dose methotrexate as a 24-h continuous infusion, administered either simultaneously with continuous infusion teniposide or sequentially with the teniposide infusion beginning 12 h after the end of the methotrexate infusion. Plasma samples were obtained during and after infusions at appropriate times for a comprehensive pharmacokinetic study of each drug. Two measured drug concentrations obtained during the infusion were used to adjust each patient's dose rate to achieve target values of 10 microM for methotrexate and 15 microM for teniposide. Pharmacokinetic parameters for teniposide were not different for patients given simultaneous methotrexate from parameters estimated for patients receiving teniposide 12 h after the end of the methotrexate infusion. Despite similar end of infusion methotrexate concentrations, 24-h postinfusion methotrexate concentrations were lower (0.137 versus 0.235 microM; P less than 0.05) in the patients receiving simultaneous infusions. The patient specific dose regimens yielded acceptably precise, minimally biased steady state drug concentrations. These pharmacokinetic results provide the basis for further clinical studies with this combination of antileukemic agents.

Characterization of the drug resistance and transport properties of multidrug resistance protein 6 (MRP6, ABCC6).

Mutations in human multidrug resistance protein 6 (MRP6, ABCC6), a member of the MRP family of drug efflux pumps, are the genetic basis of Pseudoxanthoma elasticum, a disease that affects elastin fibers in the skin, retina, and blood vessels. However, little is known about the functional characteristics of the protein, including its potential activity as a resistance factor for anticancer agents. Here, we report the results of investigations of the in vitro transport properties and drug resistance activity of MRP6. Using membrane vesicles prepared from Chinese hamster ovary cells transfected with MRP6 expression vector, it is shown that expression of MRP6 is specifically associated with the MgATP-dependent transport of the glutathione S-conjugates leukotriene C(4) and S-(2, 4-dinitrophenyl)glutathione and the cyclopentapeptide BQ123 but not glucuronate conjugates such as 17beta-estradiol 17-(beta-D-glucuronide). Analysis of the drug sensitivity of MRP6-transfected cells revealed low levels of resistance to several natural product agents, including etoposide, teniposide, doxorubicin, and daunorubicin. These results indicate that MRP6 is a glutathione conjugate pump that is able to confer low levels of resistance to certain anticancer agents.

Preparation and evaluation of teniposide-loaded polymeric micelles for breast cancer therapy.

Self-assembled polymeric micelles have been widely applied in anticancer drug delivery systems. Teniposide is a broad spectrum and effective anticancer drug, but its poor water-solubility and adverse effects of commercial formulation (VM-26) restrict its clinical application. In this work, teniposide-loaded polymeric micelles were prepared based on monomethoxy-poly(ethylene glycol)-poly(ε-caprolactone-co-d,l- lactide) (MPEG-PCLA) copolymers through a thin-film hydration method to improve the hydrophilic and reduce the systemic toxicity. The prepared teniposide micelles were without any surfactants or additives and monodisperse with a mean particle size of 29.6±0.3nm. The drug loading and encapsulation efficiency were 18.53±0.41% and 92.63±2.05%, respectively. The encapsulation of teniposide in MPEG-PCLA micelles showed a slow and sustained release behavior of teniposide in vitro and improved the terminal half-life (t1/2), the area under the plasma concentration-time curve (AUC) and retention time of teniposide in vivo compared with VM-26. In addition, teniposide micelles also enhanced the cellular uptake by MCF-7 breast cancer cells in vitro and increased the distribution in tumors in vivo. Teniposide micelles showed an excellent safety with a maximum tolerated dose (MTD) of approximately 50mg teniposide/kg body weight, which was 2.5-fold higher than that of VM-26 (about 20mg teniposide/kg body weight). Furthermore, the intravenous application of teniposide micelles effectively suppressed the growth of subcutaneous MCF-7 tumor in vivo and exhibited a stronger anticancer effect than that of VM-26. These results suggested that we have successfully prepared teniposide-loaded MPEG-PCLA micelles with improved safety, hydrophilic and therapeutic efficiency, which are efficient for teniposide delivery. The prepared teniposide micelles may be promising in breast cancer therapy.

A phase II study of combined methotrexate and teniposide infusions prior to reinduction therapy in relapsed childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study.

Teniposide (VM-26) can increase intracellular methotrexate (MTX) and its polyglutamate derivatives in vitro and thus has the potential to improve the therapeutic index of regimens containing MTX. In this phase II study, children and adolescents with acute lymphoblastic leukemia (ALL) in first or second marrow relapse were randomly assigned to receive either simultaneous (n = 11) or sequential (n = 12) continuous infusions of MTX and VM-26 prior to reinduction. Infusions of VM-26 were begun 12 hours after completion of MTX infusion in the sequential group. Dosages were individually adjusted to maintain plasma concentration levels of 10 microns for MTX and 15 microns for VM-26; total infusion times were 24 and 72 hours, respectively. Significant toxicity in the first six patients who received the scheduled 72-hour VM-26 infusion (including one drug-related death) prompted a 50% reduction in infusion duration. The reduced dose was associated with similar but more manageable toxicity. Examination of bone marrow aspirates 10 days after therapy was begun showed one complete and two partial marrow remissions; a fourth patient who had an aplastic marrow on day 10 received no further chemotherapy and had a complete remission (CR) documented on day 31. There was no obvious clinical advantage associated with either infusion schedule, although small sample sizes preclude definitive conclusions. The 17% response rate to the MTX/VM-26 therapeutic window in patients with refractory disease suggests the need for further investigation to evaluate alternative schedules and concomitant therapy for this drug combination.

Escalating teniposide systemic exposure to increase dose intensity for pediatric cancer patients.

PURPOSE: The primary objective for this study was to determine whether controlling pharmacokinetic variability, by designing patient-specific dosage regimens for teniposide using a Bayesian estimation control strategy, would permit an increase in dose intensity without increased toxicity. PATIENTS AND METHODS: Twenty patients with relapsed acute lymphocytic leukemia were given teniposide as part of their induction and maintenance therapy. Before beginning reinduction therapy, an intensive pharmacokinetic study was performed based on 12 measured teniposide plasma concentrations. Doses were determined to achieve a targeted systemic exposure defined by an area under the plasma concentration time curve (AUC) beginning at an AUC consistent with that predicted for a patient with average pharmacokinetic parameters receiving the currently accepted maximal-tolerated dose. The targeted systemic exposure was then escalated in increments of 25% in cohorts of at least three patients until unacceptable toxicity occurred. In 36 follow-up studies, when teniposide was administered during maintenance therapy, a Bayesian strategy based on only three or five measured drug concentrations was evaluated for precision and bias for achieving the targeted systemic exposure against the full pharmacokinetic study. RESULTS: Teniposide clearance varied over a fivefold range (3.7 to 21.6 mL/min/m2). With the use of the patient-specific dosage regimens, the intensity of systemic exposure was increased 50% (1,656 mumol.h v 1,060 mumol/L.h) over that previously possible with standard fixed doses, with no increase in acute, nonhematologic toxicity. Teniposide concentrations (n = 265) were well predicted (R2 = .82) with as few as three measured values from the initial study. CONCLUSION: Targeting systemic exposure is clinically feasible, precise, and allows increased dose intensity for teniposide without increased risk of acute, nonhematologic toxicity, when compared with fixed-dose regimens.

Increased teniposide clearance with concomitant anticonvulsant therapy.

PURPOSE: A possible pharmacokinetic interaction between teniposide and anticonvulsant medications was evaluated in pediatric patients. PATIENTS AND METHODS: The systemic clearance of teniposide was determined in six pediatric patients with acute lymphocytic leukemia receiving concomitant therapy with anticonvulsants. Clearance was then compared with a control group of patients treated with the same protocol therapy and matched for age at diagnosis, sex, and race but not receiving anticonvulsants or other agents known to induce hepatic metabolism or alter protein binding of drugs. Eight blood samples were obtained during and after 4-hour infusions of teniposide, and plasma concentrations were measured by a specific high-performance liquid chromatography (HPLC) assay. A two-compartment model was fitted to each subject's data. RESULTS: The mean systemic clearance (range) for the six anticonvulsant-treated patients studied during 22 courses of therapy was 32 mL/min/m2 (range, 21 to 54 mL/min/m2), significantly higher (P less than .001) than the mean value of 13 mL/min/m2 (range, 7 to 17 mL/min/m2) for the control patients studied during 26 courses of therapy. Clearance estimates for control patients were similar to previously published values for pediatric patients. CONCLUSION: These data indicate that the systemic clearance of teniposide is consistently increased two- to three-fold by concomitant phenobarbital or phenytoin therapy. The consequent substantial reduction in systemic exposure may reduce teniposide's efficacy.

Preparation and in vitro-in vivo evaluation of teniposide nanosuspensions.

Teniposide (TEN) is a potent, broad spectrum antitumor agent, especially for cerebroma. But the application in clinic was limited because of its poor solubility. In this paper, teniposide nanosuspensions drug delivery system (TEN-NSDDS) for intravenous administration was developed for the first time. Specifically, TEN nanosuspensions were prepared by an anti-solvent sonication-precipitation method and evaluated in comparison with teniposide injection (VUMON) in vitro and in vivo. TEN nanosuspensions prepared showed rod-like morphology and the size was 151 ± 11 nm with a narrow poly dispersion index 0.138 determined by dynamic light scattering. The obtained TEN nanosuspensions were physically stable at least 10 days at 4°C. And the freeze-drying preparations were stable during 3 months. The cytotoxicity of TEN nanosuspensions were considerable to that of VUMON against U87MG and C6 cells in vitro. When tested in rats bearing C6 tumors, the TEN concentration in the tumors treated by the nanosuspensions was more than 20 times than that by the TEN solution at 2h. The TEN nanosuspensions exhibited significant tumor growth inhibition. Overall, the results suggested that nanosuspensions was an alternative formulation for teniposide to be administered intravenously, and it would be a promising formulation in clinic.

Absolute bioavailability and pharmacokinetics of oral teniposide.

The absolute bioavailability and pharmacokinetics of orally administered teniposide were investigated in 25 patients. All patients received 50 to 60 mg/m2 teniposide intravenously on day 1, before oral administration. Six patients received 60 mg/m2 as a single oral dose on day 8; 5 patients received 60 mg/m2 and 120 mg/m2 as a single oral dose on days 8 and 15, respectively; 5 patients received 120 mg/m2 and 240 mg/m2 as a single oral dose on days 8 and 15, respectively; 6 patients received 60 mg/m2 as a single oral dose on 5 consecutive days from days 8 to 12; and 3 patients received 50 mg/m2 three times a day at 6-hour intervals on day 8. The mean absolute bioavailability was 41.6% +/- 14.2% with a large interindividual variability (range, 19.7% to 71.4%) and a low intraindividual variability (range, 2.8% to 13.9%). At a dose of 240 mg/m2, the bioavailability was decreased, whereas administration of multiple doses on 1 day or 5 consecutive days increased the overall bioavailability. In conclusion, teniposide can be administered orally with a bioavailability comparable with that of etoposide. The schedule dependency of both drugs warrants investigations of oral administration for 21 or more days. A formulation of teniposide capsules of 50 mg or less would be most helpful to facilitate oral administration.

Clinical pharmacology and schedule dependency of the podophyllotoxin derivatives.

Etoposide and teniposide are closely related derivatives of podophyllotoxin, and both have a phase-specific action in the late S and early G2 phases of the cell cycle. Etoposide has attracted more widespread use and study, although no evidence suggests a differing mode of action or spectrum of anticancer activity. The drugs have significant differences in their clinical pharmacology, however. Teniposide exhibits greater protein-binding affinity, has a longer plasma terminal elimination half-life, and has reduced plasma and renal clearances. Little is accurately known about the metabolism of either drug, but the fact that 40% to 60% of administered etoposide is accounted for by excretion or metabolism, whereas the range is only 10% to 25% for teniposide, reflects a further difference between the drugs. Renal dysfunction impairs etoposide excretion, but the effect of hepatic impairment on drug clearance is unclear. A specific oral formulation exists only for etoposide, although the unpalatable intravenous preparations of both drugs can be taken orally. The bioavailability of oral etoposide is about 50% at doses of 200 mg or less and decreases as drug doses increase. There is considerable intrapatient and interpatient variation in etoposide absorption, but the reasons for this are unknown. In vitro, the efficacy of etoposide is highly dependent on the schedule of administration. The superior efficacy without increased toxicity of more prolonged schedules of etoposide administration has been demonstrated recently in patients with small cell lung cancer (SCLC). Although the optimal schedule in any specific tumor is not known, current pharmacodynamic evidence suggests that the efficacy of etoposide, at least in SCLC, is related to the maintenance of prolonged low blood concentrations of drug.

Human autopsy tissue distribution of the epipodophyllotoxins etoposide and teniposide.

Autopsy tissues were collected from ten patients who had received etoposide, 150-3480 mg, from 1 to 412 days antemortem and from five patients who had received teniposide, 234-1577 mg, from 3 to 52 days antemortem. Tissues were assayed for etoposide and teniposide using high-pressure liquid chromatography with electrochemical detection. Etoposide was detectable in tissues of three of four patients dying < 5 days after their last etoposide treatments to cumulative doses of 150-432 (median, 280) mg but was detectable in tissues of only one of six patients dying 7-412 (median, 37) days after their last etoposide treatment to a cumulative dose of 607-3600 (median, 1553) mg. The highest tissue concentrations were in the small bowel, prostate, thyroid, bladder, spleen, and testicle. Intermediate concentrations were found in the lymph node, skeletal muscle, adrenal gland, stomach, tumor, liver, lung, pancreas, and kidney, and the lowest concentrations were found in the heart, brain, diaphragm, vagina, and esophagus. Teniposide was detectable in one patient dying 3 days after a cumulative teniposide dose of 576 mg (spleen, prostate, heart > large bowel, liver, pancreas > thyroid, adrenal, stomach, small bowel, bladder, testicle, and skeletal muscle) but was not detectable in any tissue from four patients dying 5-52 (median, 8) days after their last treatment to a cumulative teniposide dose of 234-1577 (median, 520) mg. The very short tissue half-life contrasts with our previous observations for human autopsy tissue concentrations of mitoxantrone, doxorubicin, menogaril metabolites, diaziquone, and amsacrine. The short tissue half-life may help explain the schedule dependency of epipodophyllotoxin efficacy and may also help explain the lack of visceral toxicity of these compounds.

Pharmacokinetics of continuous-infusion amsacrine and teniposide for the treatment of relapsed childhood acute nonlymphocytic leukemia.

The systemic disposition of both amsacrine and teniposide was determined in children receiving treatment for resistant acute nonlymphocytic leukemia. As part of a phase I-II study, amsacrine and teniposide were given as continuous 72-h i.v. infusions at doses of 75-150 and 150-250 mg m-2 day-1, respectively. Plasma samples obtained during steady state were analyzed for drug concentrations by high-performance liquid chromatography assays specific for each compound. Clearance and systemic exposure values for both amsacrine and teniposide were calculated for 14 patients, and data were available for teniposide alone in an additional 14 subjects. Interpatient variability in clearance was substantial for each drug, producing overlapping systemic exposure across dose levels. No evidence of dose-dependent drug clearance was evident. Clearance values for teniposide given in combination with amsacrine were similar to previous values obtained when teniposide was given in an identical manner but as a single agent. In all, 80% of patients experienced some degree of mucositis after chemotherapy administration. Severe mucositis (Pediatric Oncology Group grades 3-4) occurred in 18% of cases, all of whom showed teniposide steady-state plasma concentrations above the median population value (11.9 micrograms/ml; P less than 0.0001). A comparison of the results of the present study on teniposide combined with amsacrine with those previously obtained for single-agent teniposide suggest that amsacrine produced little additive gastrointestinal toxicity. The evaluation of anti-cancer drug pharmacokinetics in individual patients during combination chemotherapy regimens helps to determine the relative importance of each agent when toxicity patterns are similar.

Pharmacokinetics of VM 26 given intrapericardially or intravenously in patients with malignant pericardial effusion.

Three patients with lung cancer (1 SCLC, 2 NSCLC) and pericardial malignant effusion received 100 mg/m2 Teniposide (VM 26) i.v. and, 1 week later, 50 mg/m2 intrapericardially. Plasma, pericardial, and urine levels of the drug were measured in all patients after the two treatments by a HPLC assay. After intrapericardial administration, a high VM 26 concentration was found in the pericardial cavity and slow systemic drug absorption was observed. Since the drug AUC after intrapericardial administration was approximately 15-21 times that after i.v. administration, it could be that this treatment is more effective against neoplastic deposits localized in the pericardium. Even though this small series does not permit conclusions to be drawn on the efficacy of VM 26 given intrapericardially, the lack of local toxicity, minimal systemic toxicity, and the response observed in two out of three patients given intrapericardial VM 26 suggest that further investigation should be carried out on this method of VM 26 administration.

The vascular compartment hampers accurate determination of teniposide penetration into brain tumor tissue.

After a pre-operative 1-h i.v. infusion of 150 mg/m2 of teniposide (Vumon; VM26), the drug levels were determined in resected brain tumor specimens from three patients with malignant glioma and from three patients with brain metastases. Tissue dissections were performed within 0-2.5 h after drug administration in three patients and after 24 h in the other three patients. Teniposide was quantified by high-performance liquid chromatography and the levels of albumin in the resected tissue samples were quantified by radial immunodiffusion. In addition, albumin levels were quantified in normal brain tissue, in malignant glioma and in metastatic brain tumor tissue obtained post mortem from deceased patients. The albumin levels indicated that a substantial fraction (range: 0.16-0.50) of the resected brain tumor specimens consisted of blood. As the plasma concentration of teniposide during the first hours after infusion is high, the major part of the drug measured in the tumor specimens collected within 2.5 h after drug administration originated from the blood compartment. At 24 h after drug administration, when the plasma level of teniposide had declined to approximately 0.20 microgram/ml, we could discern a real tissue uptake of teniposide ranging from 0.15-0.27 microgram/g wet tissue weight in the resected tumor. Although the number of patients in this study is small, this work clearly illustrates that an accurate determination of the tissue concentration of teniposide is hindered by the high concurrent plasma levels. It is therefore essential that future tissue distribution studies also include a suitable procedure that establishes the contribution of drug originating from the blood compartment.

Targeting of teniposide to the mononuclear phagocytic system (MPS) by incorporation in liposomes and submicron lipid particles; an autoradiographic study in mice.

Liposomes are concentrated in the mononuclear phagocytic system in vivo and may therefore be of value as carriers of drugs when treating diseases involving phagocytic cells. Teniposide (VM-26) is a potent and lipophilic cytotoxic drug. Teniposide was incorporated in large unilamellar liposomes (LUVs) consisting of egg phosphatidylcholine and dioleoyl phosphatidic acid and into the novel submicron lipid particles containing cholesteryl oleate, cholesteryl palmitate and soybean lecithin, in order to evaluate the drug targeting effect. Radiolabelled teniposide and lipids were used and the organ distribution in mice was studied with whole-body autoradiography 20 and 90 min post i.v. injection. When the commercial formulation of teniposide (Vumon) was administered, teniposide accumulated in the liver where the drug is metabolized. Biliary excretion was rapid and considerable already after 20 min. The liposomal formulation enhanced liver uptake of teniposide slightly. The distribution of radiolabelled phosphatidyl choline differed from that of teniposide indicating instability of the liposomes in circulation. Despite this, the splenic uptake of the drug was significantly enhanced by administration in liposomes. In the red pulp of the spleen the teniposide level was 23 times higher 90 min post injection, using the liposomal formulation as compared to free drug. The submicron lipid particles were mainly accumulated in the liver and to a lesser extent in the spleen. The study shows that liposomes and lipid particles enhance splenic and liver uptake and can be used to target teniposide to the MPS.

A pharmacokinetic model for intraperitoneal administration of drugs: application to teniposide in humans.

A pharmacokinetic study of teniposide after ip administration with a 4-h dwell time was performed in patients suffering from abdominal malignant ascites. A three-compartment open model was developed to fit together the data obtained in plasma and peritoneum. The pharmacokinetic parameters obtained by the model agreed with those obtained by model-independent analysis, and the fitting correctly depicted the plasma and peritoneal concentration decays. According to the results, such a model could be applied to ip administration of anticancerous drugs.

Production of rubusoside from stevioside by using a thermostable lactase from Thermus thermophilus and solubility enhancement of liquiritin and teniposide.

Solubility is an important factor for achieving the desired plasma level of drug for pharmacological response. About 40% of drugs are not soluble in water in practice and therefore are slowly absorbed, which results in insufficient and uneven bioavailability and GI toxicity. Rubusoside (Ru) is a sweetener component in herbal tea and was discovered to enhance the solubility of a number of pharmaceutically and medicinally important compounds, including anticancer compounds. In this study, thirty-one hydrolyzing enzymes were screened for the conversion of stevioside (Ste) to Ru. Recombinant lactase from Thermus thermophiles which was expressed in Escherichia coli converted stevioside to rubusoside as a main product. Immobilized lactase was prepared and used for the production of rubusoside; twelve reaction cycles were repeated with 95.4% of Ste hydrolysis and 49 g L(-1) of Ru was produced. The optimum rubusoside synthesis yield was 86% at 200 g L(-1), 1200 U lactase. The purified 10% rubusoside solution showed increased water solubility of liquiritin from 0.98 mg mL(-1) to 4.70±0.12 mg mL(-1) and 0 mg mL(-1) to 3.42±0.11 mg mL(-1) in the case of teniposide.

A self-assembled nanocarrier loading teniposide improves the oral delivery and drug concentration in tumor.

We attempted to improve the oral delivery of lipophilic teniposide to achieve higher drug concentration in tumor by self-assembled nanocarrier for further oral chemotherapy. The teniposide loaded self-assembled nanocarrier (TSN) was spherical nanometric particles with narrow size distribution. The intestinal absorption of teniposide from TSN was obviously improved 4.09- and 6.35-fold in duodenum and jejunum at 0.5h after oral administration, then significantly decreased with the prolongation of time. The cellular uptake of TSN in Caco-2 cell monolayer was significantly enhanced over 3 folds and increased with incubation time. Moreover, TSN could be internalized into Caco-2 cell monolayer through clathrin-mediated endocytosis pathway, and then mainly transported into the systemic circulation via portal vein and intestinal lymphatic pathway. The pharmacokinetic results indicated that the AUC(0-t) value of TSN in rats was significantly improved 5.41-fold than that of teniposide solution, moreover, the teniposide concentration in tumor from TSN was obviously improved over 7-fold in tumor bearing mice. The captured image indicated that the oral administered TSN could specifically accumulate in tumor in the xenograft model. Therefore, the self-assembled nanocarrier was promising to enhance the oral delivery of lipophilic teniposide and its concentration in tumor for oral chemotherapy.