Thermosensitive magnetic liposomes with doxorubicin cell-penetrating peptides conjugate for enhanced and targeted cancer therapy

To specifically deliver cytotoxic drug to tumor cells and enhance cellular uptake is the key for effective cancer therapy. In this paper, we described a novel drug targeting system, which is designed to combine features of biological (cell-penetrating peptides, CPPs) and physical (magnetic) drug targeting for use in the magnetic hyperthermia-triggered release. A doxorubicin–CPPs conjugate (DOX-CPPs) was loaded into thermosensitive magnetic liposomes (TSMLs) (DOX-CPPs/TSMLs), and in vitro DOX-CPPs thermosensitive release activity, anti-proliferation effect, in vivo targeted delivery as well as in vivo antitumor activity were determined. The results demonstrated that the DOX-CPPs/TSMLs showed good physicochemical properties, effective anti-proliferation effect in MCF-7 cells in vitro. Additionally, in vivo study, DOX-CPPs/TSMLs under AC magnetic field displayed superior in vivo targeted delivery efficacy, antitumor efficacy in an MCF-7 xenograft murine model. In conclusion, the application of DOX-CPPs/TSMLs under AC magnetic field may provide a strategy for the selective and efficient delivery of drug.     

In-vivo pharmacokinetics, tissue distribution and anti-tumour effect of hydroxycamptothecin delivered in oil-in-water submicron emulsions

Objectives The aim of this study was to investigate the pharmacokinetics, tissue distribution and anti‐tumour effect of hydroxycamptothecin submicron emulsions (HCPT‐SEs). Methods HCPT‐SEs or HCPT injection (HCPT‐I) was administered intravenously into the tail vein of rats or S180 tumour‐bearing mice. Key findings HCPT‐SEs increased the plasma concentration of HCPT compared with HCPT‐I at all time points. The AUC_0‐∞, elimination half‐life and mean residence time of anionic submicron emulsions containing HCPT (HCPT‐ASEs) and cationic submicron emulsions containing HCPT (HCPT‐CSEs) were significantly greater than those of HCPT‐I (P < 0.01). Especially, a prolonged elimination half‐life was found for HCPT‐CSEs. HCPT‐CSEs and HCPT‐ASEs resulted in a 7.9‐fold and 3.1‐fold increase in AUC_0‐6h of tumour compared with HCPT‐I, respectively. The targeting efficiency (T_e) of HCPT‐ASEs and HCPT‐CSEs indicated their selectivity to tumour and the T_e of HCPT‐CSEs was significantly higher than that of HCPT‐ASEs (P < 0.01). The anti‐tumour effect studies showed that HCPT‐SEs improved the therapeutic efficiency of HCPT compared with HCPT‐I. The percentage of tumour growth suppression rate of mice treated with HCPT‐CSEs (2.0 mg HCPT eq./kg) increased 2.1 fold compared with that of HCPT‐I. Conclusions Submicron emulsions can alter the pharmacokinetic characteristics and tissue distribution of HCPT, and enhance tumour targeting and anti‐tumour activity.     

Modified hydrolysis kinetics of the active lactone moiety of 10-hydroxycamptothecin by liposomal encapsulation

The key structural requirement for the antitumor activity of 10-hydroxycamptothecin (HCPT) is the intact lactone moiety which is always instability and suffered from pH-dependent hydrolysis. The aim of this study was to evaluate the protection effects of liposomal encapsulation on the labile lactone ring. Mono-modal dispersed quasi-spherical liposomes with mean diameter of 145?nm and high drug entrapment efficiency of 90% were obtained under optimal conditions. The in vitro hydrolysis kinetics behaviors of lactone were studied in varied pH buffers. Compared to that of free HCPT in solution formulation, both the hydrolysis half-life and observed equilibrium constant of liposomal HCPT were increased significantly along with the decreased apparent hydrolysis rate constant. The plasma pharmacokinetics was studied by assessing the lactone stability versus time profiles in vivo following intravenous administration of free and liposomal HCPT. The liposomal encapsulation led to a twofold increase in the AUC values and significant decrease in the plasma clearance of lactone (P?<?0.05). There was a good correlation between in vitro and in vivo stability of HCPT-lactone. These results suggested a potential application of the novel liposome formulation for the stable delivery system of HCPT.     

Promoting Antitumor Activities of Hydroxycamptothecin by Encapsulation into Acid-Labile Nanoparticles Using Electrospraying

Purpose

Acid-labile nanoparticles are proposed to enhance the tumor targeting and anti-tumor therapy of hydroxycamptothecin (HCPT) in response to the acidic microenvironment within cells and tumor tissues.

Methods

HCPT was entrapped into matrix polymers containing acid-labile segments and galactose moieties (PGBELA) through an electrospraying technique. The antitumor activities of HCPT-loaded nanoparticles were evaluated both on HepG2 cells and after intravenous injection into H22 tumor-bearing mice.

Results

The electrosprayed nanoparticles were obtained with enhanced loading efficiency and extended release of HCPT compared with other nanoparticle preparation methods. The acid-lability and targeting capability of PGBELA nanoparticles resulted in a 5 times higher inhibitory activity after incubation in pH 6.8 media compared to that of pH 7.4. Animal studies indicated that both the blood circulation time and tumor distribution of PGBELA nanoparticles were significantly increased. HCPT/PGBELA nanoparticles indicated a superior in vivo antitumor activity and fewer side effects than other treatments on the basis of tumor growth, animal survival rate, tissue necrosis and cell apoptosis evaluation.

Conclusion

Biodegradable PGBELA nanoparticles are capable of achieving site-specific drug delivery by active targeting and triggered release by acidic pH both in tumor tissues and after internalization within tumor cells, thereby providing a novel strategy for cancer treatment.     

雾化吸入羟基喜树碱在小鼠体内的药代动力学研究

目的:研究雾化吸入羟基喜树碱(HCPT)在小鼠体内和肺中以及其他脏器中的药代 动力学特征.方法:采用HPLC法测定不同时间点小鼠血浆和肺组织以及其他脏器组织中羟基喜树碱的内酯和盐型的浓度,并对雾化吸入给药后的血浆和各个脏器组织中的药物浓度数据进行药代动力学分析.结果:雾化吸入给药后,肺组织中的浓度远远高于血浆和其他器官组织,血浆和其他器官组织中药物浓度较低,并且在肺组织中,内酯型比例较高.结论:雾化吸入羟基喜树碱在肺癌中能达到靶器官中的高浓度和血浆中的低浓度,两者的药物动力学规律有所不同.     

Intracellular target delivery of 10-hydroxycamptothecin with solid lipid nanoparticles against multidrug resistance

The main objective of this study was to design a suitable drug delivery system for 10-hydroxycamptothecin (HCPT). In this study, HCPT-loaded solid lipid nanoparticle (HCPT-loaded SLN) was successfully prepared. The HCPT-loaded SLN was characterized by size, entrapment efficiency and drug release manner. The cytotoxicity of HCPT-loaded SLN was assessed in vitro using HepG2/HCPT cells and in vivo utilizing human tumor xenograft nude mouse model. HCPT-loaded SLN indicated the ability to target HepG2/HCPT cells and accumulated higher drug content in HepG2/HCPT cells. HCPT-loaded SLN enhanced the cytotoxicity of HCPT in a concentration-dependent manner. Based on these results, HCPT-loaded SLN suggested being a promising vehicle for liver-targeted drug delivery. Moreover, it can be of clinical interest to overcome multidrug resistance (MDR) effectively.     

In-vivo anti-tumor activity of a novel poloxamer-based thermosensitive in situ gel for sustained delivery of norcantharidin

In order to develop a novel norcantharidin (NCTD) delivery system with slow drug release and specific targeting characteristics, we have developed a Poloxamer-based NCTD thermosensitive in situ gel. The evaluation of the characteristics of this system using both in vitro and in vivo methods was previously reported. However, its anti-tumor activity in vivo is still not confirmed. Thus, the potential anti-tumor activity and relative mechanism were investigated in a murine H22 hepatoma model. Tumor-bearing mice were treated with different dose of NCTD thermosensitive in situ gel (3.3?mg/kg, 6.6?mg/kg, and 9.9?mg/kg, respectively by intra-tumor injection once every three days, totaling 5 injections per group. Control groups included untreated or NCTD injection (2.2?mg/kg, qd) or blank in situ gel. The expression of vascular endothelial growth factor (VEGF) and CD44 in tumor tissue was examined by immunohistochemistry (IHC) staining. Treatment with middle or high dose of NCTD thermosensitive in situ gel significantly induced tumor regression, inhibited VEGF and CD44 expression and improved survival of tumor-bearing mice. The efficacy of NCTD thermosensitive in situ gel is higher than that of free NCTD injection. Therefore, NCTD thermosensitive in situ gel is a novel NCTD delivery approach for chemotherapeutic treatment of cancer.     

Plasma Pharmacokinetics of the Lactone and Carboxylate Forms of 20(S)-Camptothecin in Anesthetized Rats

20(S)-Camptothecin exists in equilibrium between its lactone (CPT) and its carboxylate forms (Na-CPT) under simulated physiological conditions, with the equilibrium favoring the carboxylate form. The rates of lactone hydrolysis were studied in plasma, serum albumin, and blood and were found to be faster than in aqueous buffers at equivalent pH values. From mechanistic information and in vivo activity data, the lactone appears to be the active form of the drug. It has been argued, therefore, that if an equilibrium existed between the lactone and the carboxylate, Na-CPT could be used to deliver the lactone effectively. In the present study, plasma pharmacokinetics were performed in sodium pentobarbital-anesthetized rats treated with both CPT (lactone) and the sodium salt of camptothecin (carboxylate, Na-CPT) and the lactone and carboxylate, as well as the total drug, concentration versus time profiles were assessed. It was found that plasma concentrations and AUC values for the lactone were significantly higher after dosing with CPT than after dosing with Na-CPT. After i.v. administration, the ratio of plasma lactone to carboxylate was skewed by the apparent rapid and extensive uptake of the lactone into tissues and the rapid clearance of both species. From our results, it appears that the lower in vivo activity of Na-CPT compared to that from CPT administration might be attributed to the altered conversion of carboxylate into lactone in vivo compared to that predicted from in vitro data.     

Antitumor activities of emulsion electrospun fibers with core loading of hydroxycamptothecin via intratumoral implantation

Emulsion electrospinning was used in the present study to prepare core-sheath structured fibers with core-loading of hydroxycamptothecin (HCPT), and their antitumor activities were evaluated both in vitro on cancer cell lines and in vivo on tumor bearing mice via intratumoral implantation. Compared with our previous investigation on blend electrospun fibers, the addition of 2-hydroxypropyl-β-cyclodextrin (HPCD) and the preferential formation of HPCT/HPCD inclusion complexes resulted in significantly faster HCPT release from and higher degradation rate of emulsion electrospun fibers. The core-sheath structure led to around 93% of lactone form remaining after emulsion electrospinning and incubation in buffer solutions for over one month. In vitro cytotoxicity tests on HCPT-loaded electrospun fibers indicated over 20 times higher inhibitory activity against HepG2 cells than free HCPT during 72h incubation. Hepatoma H22 cells were subcutaneously injected into Kunming mice to form solid tumors for in vivo tests on the antitumor efficacy. Based on the tumor volume, survival rate and body weight changes, HCPT-loaded fibers indicated superior in vivo antitumor activities to and fewer side effects than free HCPT. The histopathological staining and immunohistochemical examinations of caspase-3 expression indicated more necrosis and apoptosis induced by HCPT-loaded fibers. The above results demonstrate the potential use of emulsion electrospun fibers as drug carriers for local treatment of solid tumors.     

Revisiting the nanoformulation design approach for effective delivery of topotecan in its stable form: an appraisal of its in vitro Behavior and tumor amelioration potential

Topotecan (TPT) is indicated against a variety of solid tumors, but has restricted clinical use owing to associated pharmaceutical caveats. This study is focused at formulating a successful TPT PLGA nanosystem which ameliorates the rapid conversion of active lactone form of drug to its inactive carboxylate form and consequently improvises its efficacy. TPT PLGA nanoparticles were formulated by a double emulsion-solvent evaporation technique with sequential optimization to obtain desired particle size, PDI, zeta potential, and entrapment efficiency. Stability of TPT was ensured by maintaining an acidic pH in the drug-containing phase and the system was evaluated for in vitro–in vivo performance including cytotoxic potency. The optimized nanosystem had a particle size of 187.33?±?7.50?nm, a PDI of 0.179?±?0.05, and an entrapment efficiency of 56?±?1.2%. Low pH in the interior of nanoparticles stabilized the drug to remain in its active lactone form and revealed a biphasic release pattern till 15?d. Additionally, an in vitro cytotoxicity testing as well as in vivo antitumor efficacy demonstrated a significant potential of higher proliferation inhibition as compared with neat drug (TPT). Thus, the investigation summarized an innovative simple tool for developing stable TPT NPs for effective delivery for treating solid tumors.     

雾化吸入羟基喜树碱在兔体内分布及肺器官中药代动力学研究

目的　研究雾化吸入羟基喜树碱在兔体内分布及肺器官中药物动力学特点。方法　采用HPLC法测定不同时间点兔血浆和肺组织中羟基喜树碱浓度 ,分析雾化吸入给药后的组织分布特点 ,并对雾化吸入给药后的肺器官中药物浓度数据进行了药物动力学分析。结果　雾化吸入给药后肺组织中的药物含量最高 ,而血浆和其它组织中的含量极低。HCPT在肺组织内浓度随着时间的延长而逐渐降低 ,其药代动力学规律可用二室模型来描述。结论　雾化吸入羟基喜树碱能维持肺中的高浓度 ,其药物动力学规律与血浆药物动力学规律有所不同     

Well-defined hydroxyethyl starch-10-hydroxy camptothecin super macromolecule conjugate: cytotoxicity,pharmacodynamics research,tissue distribution test and intravenous injection safety assessment

10-Hydroxy camptothecin (10-HCPT) is an antitumor agent effective in the treatment of several solid tumors but its use is hampered by poor water solubility, low lactone stability, short plasma half-life and dose-limiting toxicity. These limits of 10-HCPT had been overcome by our group through preparing super macromolecule prodrug: 10-HCPT-hydroxyethyl starch (HES) conjugate. In this study, we mainly evaluated in vitro and in vivo behavior of the prodrug, containing cytotoxicity assay, pharmacodynamics study, vascular irritation test, hemolysis experiment and tissue distribution test of rats. The irritation test results achieved much lower irritation than the commercial injection. The tissue distribution results showed that HES-10-HCPT conjugate increased significantly the 10-HCPT concentration in the tumor, liver and spleen site, whereas decreased the drug concentration in the heart and kidney. The hemolysis effect of the prepared conjugate was not obvious. The pharmacodynamics results indicated that HES-10-HCPT prodrug had a better antitumor efficiency against mice with H22 tumor than the commercial injection, and the inhibition ratio of tumor was 85.2% and 31.1%, respectively at the same dosage. These findings suggest that HES-10-HCPT prodrug is a promising drug delivery system providing improved good injection safety, greater tolerance and antitumor effect.     

Preparation, pharmacokinetics and tissue distribution of micelles made of reverse thermo-responsive polymers

New reverse thermo-responsive polymers, poly(ethylene oxide)–poly(propylene oxide) multiblock copolymers (poly(ether-carbonate)s) were synthesized. The micelles made of new reverse thermo-responsive polymers were also prepared loaded with the poorly soluble anticancer drug, hydroxycamptothecin (HCPT). The structure characterization of poly(ether-carbonate)s was determined by ¹H NMR and FT-IR analysis. The critical micelle concentration (CMC), critical micelle temperature (CMT), size distribution and drug release in vitro were determined. The pharmacokinetics and tissue distribution in vivo for novel copolymer micelles were studied. The experimental results showed that the micelles was spherical in appearance and dispersed well. The process of HCPT release from micelles in vitro was composed of two steps, abrupt release and sustained release. After i.v. administration (2 h), the drug concentration of poly(ether-carbonate) micelles group in liver in mice was 3.46 μg/g, while that of HCPT injection group was 0.401 μg/g. Compared with HCPT injection, the elimination half-life of poly(ether-carbonate) micelles group was prolonged remarkably from 1.3 to 12.5 h. The poly(ether-carbonate) micelles showed a combination of liver targeting and sustained drug release in experiments on animals.     

Development,characterization and cancer targeting potential of surface engineered carbon nanotubes

Abstract

The aim of the present study was to assess the in vitro and in vivo potential of doxorubicin-loaded, folic acid appended engineered multi-walled carbon nanotubes (DOX/FA-PEG-MWCNTs) for efficient tumor targeting. The loading efficiency was determined to be 92.0?±?0.92 (DOX/FA-PEG-MWCNTs) in phosphate buffer solution (pH 7.4) ascribed to π–π stacking interaction. The developed nanoconjugates were evaluated for in vitro DOX release, erythrocytes toxicity, ex vivo cytotoxicity and cell uptake studies on MCF-7 (breast cancer cell line). The DOX/FA-PEG-MWCNTs nanoconjugate affords higher efficacy in tumor growth suppression due to its stealth nature and most preferentially taken up by the cultured MCF-7 through caveolae-mediated endocytosis as compared to free DOX. The in vivo studies were performed to determine the pharmacokinetics, biodistribution and antitumor efficacy on tumor bearing female Sprague Dawley rats and improved pharmacokinetics confirm the function of FA-PEG conjugated CNTs. The median survival time for tumor bearing rats treated with DOX/FA-PEG-MWCNTs (30?d) was extended very significantly as compared to free DOX (p?<?0.001). The results concluded that developed water-soluble nano-conjugates might emerge as “safe and effective” nano-medicine in cancer treatment by minimizing the side effects with and Generally Regarded as Safe prominence.     

Development and evaluation of magnetic microemulsion: tool for targeted delivery of camptothecin to BALB/c mice-bearing breast cancer

Abstract

Purpose: Development and evaluation of camptothecin-loaded-microemulsion (ME) and -magnetic microemulsion (MME) for passive/active-targeted delivery to BALB/c mice-bearing breast cancer.

Methods: Based on the pseudo-ternary phase diagrams camptothecin-loaded-MEs and -MMEs were developed using benzyl alcohol:Captex 300 (3:1), TPGS:Tween 80 (2:1) and water. Furthermore, characterized for their droplet size distribution, magnetic susceptibility and effect of droplet size in plasma and evaluated for in vitro and in vivo targeting potential, drug release, haemolytic potential, cytotoxicity, genotoxicity, in vivo biodistribution and lactone ring stability.

Results: Drug-loaded MEs showed uniform droplet distribution, extended drug release (76.07?±?4.30% at 24?h), acceptable level of haemolytic activity (<20%), significant cytotoxicity (129?±?3.9?ng/mL) against MCF-7 cancer cells and low DNA damage in lymphocytes. Targeting potential of MMEs was documented in 4T1 breast cancer-induced BALB/c mice. MMEs were concentrated more at the target tissue on introduction of external magnetic field. In vivo biodistribution study documented the active targeting of 5067.56?±?354.72?ng/gm and passive targeting of 1677.58?±?134.20?ng/gm camptothecin to breast cancer from MME and ME, respectively. Lactone stability study shows around 80% of the lactone stable at 24?h.

Conclusions: Developed ME and MME may act as a promising nanocarrier for efficient targeting of breast cancer tissues.     

Promoted antitumor activities of acid-labile electrospun fibers loaded with hydroxycamptothecin via intratumoral implantation

The acidosis of tumor microenvironments is one of the universal phenomena of solid tumors, and the increased acidity may be in fact essential intermediates in the progression of tumor growth and several lethal phenotypic traits of tumors, such as invasion and metastasis. Acid-labile polymers PBELA with incorporating acetal groups into biodegradable backbone of poly(d,l-lactide)–poly(ethylene glycol) (PELA) were utilized to load hydroxycamptothecin (HCPT) into electrospun fibers for intratumoral chemotherapy. Compared with that under a simulated physiological condition of pH 7.4, the incubation of PBELA fibers in acidic media resulted in larger mass loss and molecular weight reduction of fiber matrices and enhanced HCPT release from fibers. In vitro cytotoxicity assay of HCPT-loaded PBELA fibers indicated 6-fold higher inhibitory activity against HepG2 cells after incubation in pH 6.8 media than that of pH 7.4, while there was no significant difference for free HCPT and HCPT-loaded PELA fibers. The tumor growth, tumor cell apoptosis, and animal survival rate after intratumoral implantation of HCPT-loaded PBELA fibers indicated a superior in vivo antitumor activity and fewer side effects than other treatment. Therefore, acid-labile electrospun fibers may be promising implants for localized therapy of inoperable tumors and for prevention of post-surgical tumor recurrence.     

Preparation, characterization and biodistribution of the lactone form of 10-hydroxycamptothecin (HCPT)-loaded bovine serum albumin (BSA) nanoparticles

10-Hydroxycamptothecin (HCPT) is insoluble in both water and physiological acceptable organic solvents and tends to change into its carboxylate form, which shows minimal anticancer activity and several unpredictable side effects. The goal of this study is to exploit an appropriate delivery system for HCPT to improve the stability of its lactone form. Bovine serum albumin (BSA) nanoparticles entrapping HCPT were prepared by reformative emulsion-heat stabilization technique. During this process, HCPT transformed from lactone to carboxylate and finally back to lactone form successfully. A simple reversed-phased HPLC method was developed to analyze both lactone and carboxylate forms of HCPT synchronously. Mean particle size and the ratio of lactone and carboxylate forms of HCPT were evaluated to investigate the effects of the formulations and preparation conditions. It was indicated the percentage of lactone form of HCPT in resultant BSA nanoparticles could be improved over 95% through adjusting the concentration of NaOH solution and the stirring time after high-speed emulsification. This drug delivery system was also characterized by dynamic light scattering (DLS) and light microscopy. The investigations on drug loading, in vitro release and body distribution in rats after intravenous (i.v.) administration were also carried out. It was found that the obtained nanoparticles showed spherical shape with the mean particle size of around 600 nm, and drug loading content, encapsulation efficiency and yield achieved 2.21%, 57.5% and 90.5% with the optimal preparation conditions, respectively. The in vitro release behavior exhibited a sustaining release manner and was affected by the trypsin in medium. HCPT could release more than 90% within 20 h in the medium of pH 7.4 PBS containing 750 U/ml trypsin, but only 25% within 40 h in the pure pH 7.4 PBS. The results of body distribution study in rats showed the liver targeting potential of HCPT–BSA nanoparticles that 59.6%, 52.9% and 55.3% of the examined amount of lactone HCPT accumulated in livers at 1, 4 and 24 h after injection, respectively. These results suggest that the HCPT–BSA nanoparticles seem to be a stable delivery system for poorly soluble HCPT or its derivatives.     

A two-step pH-dependent liquid–liquid extraction combined with HPLC-fluorescence method for the determination of 10-hydroxycamptothecin in mouse liver tissue

Context: Liquid–liquid extraction (LLE) shows high efficiency in the plasma sample preparation. However, this extraction method is not optimal for the biological samples containing complex organic interferences, such as liver and brain tissues. Some plant secondary metabolites can be converted between water-insoluble and water-soluble forms by pH adjustment.

Objective: A two-step pH-dependent LLE method was introduced in this study to eliminate both water-soluble and lipidic interferences using the properties of pH-dependent interconvertible forms of analytes during sample preparation. A sensitive and reliable method using a reverse-phase HPLC coupled with a fluorescence detector was developed and validated.

Materials and methods: 10-Hydroxycamptothecin (HCPT) with internal standard camptothecin and liver tissues were used as model compounds and biological samples. The lactone form of HCPT was converted to the water-soluble carboxylate form under moderate alkaline conditions, and the water-insoluble interferences were extracted with a nonpolar solvent. Afterward, the water-insoluble lactone form of HCPT was regenerated by acidification and then extracted using an organic solvent in a second LLE step.

Results: The calibration curve was linear (r² > 0.999) for HCPT concentrations ranging from 2.5 to 160?ng/mL. The mean recoveries of HCPT were 114.94?±?3.98, 104.30?±?2.44 and 95.90?±?1.40% (n?=?6) at concentrations of 2.5, 10 and 80?ng/mL, respectively. The stability determination data showed that no significant degradation occurred under the experimental conditions. This method was successfully applied to liver tissue distribution study of HCPT in mice.

Discussion and conclusion: This two-step LLE can be applied to distribution studies of compounds with pH-dependent interconvertible forms in other biological matrices.     

Effect of sodium caprate on the oral absorptions of danshensu and salvianolic acid B

The current study aims to investigate the effect of sodium caprate on the intestinal absorption and bioavailabilities of danshensu and salvianolic acid B, the major active components in Salvia miltiorrhiza Bge (Danshen). Biopharmaceutics and pharmacokinetics properties of the two compounds have been characterized by in vitro, in situ models as well as in vivo in rats. Based on the identified biopharmaceutics characteristics of the two compounds, effect of sodium carparate as absorption enhancer on the intestinal absorption and pharmacokinetics of danshensu and salvianolic acid B in pure compound form as well as extract form were investigated both in vitro and in vivo. Both danshensu and salvianolic acid B demonstrated very limited intestinal permeabilities, leading to oral bioavailabilities of only 11.09% and 3.90% in rats, respectively. Results from both in vitro and in vivo studies consistently indicated that sodium caprate could significantly enhance intestinal permeabilities as well as the in vivo bioavailabilities of both danshensu and salvianolic acid B. The current findings not only identified the usefulness of sodium caprate for the improved delivery of Danshen product but also demonstrated the importance of biopharmaceutics characterization in the dosage form development of traditional Chinese medicine.     

Excretion Into Gastrointestinal Tract of Irinotecan Lactone and Carboxylate Forms and Their Pharmacodynamics in Rodents

Purpose. To investigate the excretion of irinotecan hydrochloride (CPT-11) and its active metabolite, SN-38, into the gastrointestinal lumen via the biliary and/or intestinal membrane route after dosing with lactone and carboxylate forms of CPT-11, and to evaluate the toxic and antitumor effects of the two forms. Methods. The excretions of CPT-11 and SN-38 were investigated by the in situ perfusion technique using rats. The incidence of delayed diarrhea was evaluated after i.v. dosing (60 mg/kg) with CPT-11 lactone and carboxylate forms for 4 days. Antitumor activity and changes in body weight were investigated in mice with Meth A tumors. Results. The excretion of CPT-11 into bile was greater in dosing with CPT-11 carboxylate than that with its lactone form, whereas the exsorption across intestinal membrane was greater in dosing with CPT-11 lactone than that with its carboxylate form. Dosing with CPT-11 lactone dose-dependently inhibited the increase in tumor weights in Meth A tumor mice, whereas the dosing with its carboxylate form reduced the antitumor effect. Conclusions. The decreased antitumor effect caused by dosing with the CPT-11 carboxylate form could be due to less accumulation in the tissue including tumor cells resulting from the rapid elimination of the form in the body.