A Stable Irinotecan Liposome with Enhanced Antitumor Activity in a Range of Tumor Models.

PURPOSE: This study aimed to prepare a stable irinotecan liposome (CPT-11 liposome) and evaluate its antitumor efficacy in a range of tumor models. METHODS: CPT-11 liposome was prepared with a Z-average particle size of 110 ~ 120 nm and high entrapment efficiency (> 95%) and had a good stability within 18 months. Then the antitumor efficacy was studied in human colon (Ls-174t), gastric (NCI-N87), pancreatic (BxPC-3) and small cell lung (NCI-H526) cancer xenograft models. The toxicity of high-dose CPT-11 liposome was also evaluated in Beagle dogs. RESULTS: The results showed that the anti-tumor effects of CPT-11 liposome were markedly superior (at least 10 times higher) to those of the CPT-11 injection group in all four xenograft models. The tissue distribution test in the Ls-174t model further demonstrated that the CPT-11 liposome could alter the plasma and tissue distribution of CPT-11, increase the exposure level of its active metabolite SN-38 in tumor, and ultimately improve antitumor efficiency. Meanwhile, CPT-11 liposome showed a much less toxicity than CPT-11 injection in beagle dogs. CONCLUSIONS: Overall, the CPT-11 liposome may be developed as a new clinical alternative for the cancer patients.

Mapping the evolution of inhaled drug delivery research: Trends, collaborations, and emerging frontiers.

Inhaled drug delivery is a unique administration route known for its ability to directly target pulmonary or brain regions, facilitating rapid onset and circumventing the hepatic first-pass effect. To characterize current global trends and provide a visual overview of the latest trends in inhaled drug delivery research, bibliometric analysis of data acquired from the Web of Science Core Collection database was performed via VOSviewer and CiteSpace. Inhaled drug delivery can not only be utilized in respiratory diseases but also has potential in other types of diseases for both fundamental and clinical applications. Overall, we provide an overview of present trends, collaborations, and newly discovered frontiers of inhaled drug delivery.

Preparation and antitumor activity of bFGF-mediated active targeting doxorubicin microbubbles.

Characterization and antitumor activity of basic fibroblast growth factor-mediated active targeting doxorubicin microbubbles (bFGF-DOX-MB) were investigated. Pluronic F68 with chemical conjugation of doxorubicin (DOX-P) and peptide KRTGQYKLC-conjugated DSPE-PEG2000 were prepared. bFGF-DOX-MB had a normal distribution of particle size, with average particle size of 2.7 µm. Using A549 mouse model, bFGF-DOX-MB combined ultrasound showed the best inhibition effect on tumor volume growth among all the test groups. Similar conclusion was obtained from experimental measurements of tumor weight change and blood cell count. From the results, chemotherapeutic drug inhibition on tumor growth could be enhanced by local ultrasound combined with active targeting bFGF-DOX-MB, which might provide a potential application for ultrasound-mediated chemotherapy.

Construction and application of biotin-poloxamer conjugate micelles for chemotherapeutics.

Biotin was conjugated on poloxamer to prepare biotin-poloxamer (BP) conjugate micelles for chemotherapeutics. Epirubicin (EPI) was encapsulated in BP micelles. The EPI-loaded BP micelles were characterized in terms of size, ζ-potential, morphology, drug loading, drug encapsulation and drug release. Marrow leukemic HL-60 cells were used for evaluating the in vitro cytotoxicity of EPI-loaded BP micelles. Nude mice were axillainoculated subcutaneously HL-60 cells to establish tumour model for investigating the inhibition effects of EPI-loaded BP micelles. From the results, the sizes of these nanoparticles were about 100 nm. Fluorescence microscope observation supported the enhanced cellular uptake of the micelles. The order of the inhibition on tumour volume growth was: EPI-loaded BP micelles >EPI-loaded MATP micelles >EPI-loaded poloxamer micelles >EPI. BP micelles showed significant antitumour activity and low toxicity, compared with the non-targeted micelles. With the advantage of EPR effect and tumour-targeting potential, BP conjugate micelles might be developed as a new system for chemotherapeutics.

Preclinical evaluation of albumin-bound docetaxel nanoparticles as potential anti-cancer products.

Docetaxel is a highly potent anti-tumor agent which is clinically effective for the treatment of various cancers. However, the clinical application of docetaxel is limited due to its poor solubility. The solvent and cosolvent existing in the complex solvent systems can lead to serious adverse effects in clinical application. This paper aimed to develop a novel formulation of docetaxel with improved aqueous solubility and enhanced anti-tumor efficacy. Novel albumin-bound docetaxel nanoparticles were successfully developed based on the nanoparticle albumin-bound (nabTM) technology platform, showing a perfect particle size of 115.6 nm and high encapsulation efficiency (95.43%). Then the in vivo anti-tumor efficacy, plasma pharmacokinetics, tissue distribution and toxicity profiles of albumin-bound docetaxel nanoparticles were evaluated in comparison with those of Docetaxel Injection. The preclinical study demonstrated that albumin-bound docetaxel nanoparticles exhibited equivalent pharmacokinetic profiles, similar safety profiles and better anti-tumor efficacy on NCI-N87 human gastric carcinoma and BxPC-3 human pancreatic carcinoma compared with those of Docetaxel Injection. These results indicated that such albumin-bound docetaxel nanoparticles are promising in reducing toxicity and enhancing efficacy in clinical applications, showing great potential for developing an advanced drug delivery system for cancer therapy.

Biodegradable poly(D, L-lactide-co-glycolide) (PLGA) microspheres for sustained release of risperidone: Zero-order release formulation.

The preparation and investigation of sustained-release risperidone-encapsulated microspheres using erodible poly(D, L-lactide-co-glycolide) (PLGA) of lower molecular weight were performed and compared to that of commercial Risperdal Consta™ for the treatment of schizophrenia. The research included screening and optimizing of suitable commercial polymers of lower molecular weight PLGA50/50 or the blends of these PLGA polymers to prepare microspheres with zero-order release kinetics properties. Solvent evaporation method was applied here while studies of the risperidone loaded microsphere were carried out on its drug encapsulation capacity, morphology, particle size, as well as in vitro release profiles. Results showed that microspheres prepared using 50504A PLGA or blends of 5050-type PLGAs exerted spherical and smooth morphology, with a higher encapsulation efficiency and nearly zero-order release kinetics. These optimized microspheres showed great potential for a better depot preparation than the marketed Risperdal Consta™, which could further improve the patient compliance.

Effects of formulation parameters on encapsulation efficiency and release behavior of risperidone poly(D,L-lactide-co-glycolide) microsphere.

A 4-week sustained release risperidone biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microsphere for the therapy of schizophrenia, the effects of formulation parameters on encapsulation efficiency and release behavior were studied. The risperidone PLGA microspheres were prepared by O/W solvent evaporation method and characterized by HPLC, SEM, laser particle size analysis, GC and HPLC-MS. The results indicated that the morphology of the risperidone PLGA microspheres presented a spherical shape with smooth surface, the particle size was distributed from 32 to 92 microm and the drug encapsulation efficiency was influenced by homogeneous rotation speed, intrinsic viscosity, carboxylic terminal group, the polymer concentration in the oil phase and the molecular weight of the polymer. These changes were also reflected in drug release. When the Mw of the polymers increased from ca. 28000 to ca. 90000, the initial burst release of risperidone PLGA microspheres decreased from 13 to 0.8% and the sustained-release could be extended to 4 weeks. Pharmacokinetic study on beagle dogs showed that the 4-week sustained release profile of the risperidone loaded microspheres prepared with 75253A was verified. The PLGA 75253A and 75255A show the potential as excipients for the monthly sustained release risperidone PLGA microspheres due to higher encapsulation efficiency and almost zero-order release kinetics of release profile.

Development of near zero-order release PLGA-based microspheres of a novel antipsychotic.

The novel antipsychotic isoperidone, a prodrug of paliperidone, was designed to improve liposolubility for the development of poly(D,L-lactide-co-glycolide) (PLGA)-based microspheres to achieve near zero-order release behaviour in vivo. Microspheres with a smooth surface were obtained using the oil-in-water emulsion solvent evaporation method and yielded a high encapsulation efficiency of 92%. Pharmacokinetic studies in beagle dogs showed a one-week plateau phase followed by a two-week quasi-zero-order release with no burst release. The in vitro release method with a good in vitro-in vivo correlation was also established. Pharmacodynamic evaluation was performed using the MK-801-induced schizophrenic behavioural mouse model, and the sustained suppressive effect lasted two weeks. The pharmacokinetic-pharmacodynamic (PK-PD) relationship of isoperidone microspheres was compared to that of oral administration of free drug. The results revealed a strong correlation between the plasma drug level and the antipsychotic effect. A stable drug plasma concentration was detected in mice both intraday and interday from 8 to 22 d after a single injection of isoperidone microspheres, and a sustained suppressive effect on the schizophrenic model was also observed. In comparison, the mouse group receiving oral daily administration exhibited more dose-dependent effects, and the pharmacological effect diminished rapidly in conjunction with a reduction of the plasma drug levels 8h after the last administration of isoperidone on day 3. The above results confirm the superiority of long-acting release over oral administration and indicate a valuable alternative for the clinical treatment of schizophrenia.

[Single-lung transplantation and contralateral lung volume reduction for emphysema].

OBJECTIVE: To report the operation technique, patient selection and curative effect of single-lung transplantation with contralateral lung volume reduction for a patient with end-stage emphysema. METHODS: A 47-year-old male patient who was dependent on mechanical ventilation because of end-stage emphysema received left-lung transplantation on 20 June, 2003. The surgical technique used was similar to that mentioned in the literature. The donor lung was perfused by low-potassium dextran solutions (LPD) with a cold ischemic time of 390 minutes. The patient received contralateral lung volume reduction because of subacute native lung hyperinflation on the 7th day after operation. He was received tracheostomy on 15th day after operation and was weaned from ventilator on the 26th day post-operation. Immunosuppression included cyclosporine, mycophenolate mofetil and corticosteroid. The acute rejection occurred on the 9th and 15th days after operation and was cured successfully. RESULTS: The lung function was improved significantly and the patient was discharged from hospital 71 days after operation. CONCLUSIONS: Single-lung transplantation combined with contralateral lung volume reduction for end-stage emphysema is an effective measure for subacute native lung hyperinflation. Further follow-up is required to assess the long term results of this procedure.

[Single-lung transplantation for end-stage emphysema].

OBJECTIVE: To evaluate operative technique, patient selection and perioperative management of single-lung transplantation for a patients with end-stage emphysema. METHODS: A 56-year-old patient with end-stage emphysema underwent left-lung transplantation on September 28, 2002. The surgical technique used was similar to that mentioned in the literature. The donor lung was perfused by LPD solution with a cold ischemic time of 260 minutes. Cardiopulmonary bypass was not performed. RESULTS: The patient weaned from a ventilator at the 93th hour after operation. Immunosuppressants included cyclosporine, mycophenolate mofetil and corticosteroid. Acute rejection occurred on the ninth day after operation and was cured by bolus methylprednisolone given intravenously. Lung function was improved significantly and the patient was discharged from the hospital on the 47th day after operation. CONCLUSION: Single-lung transplantation for patients with end-stage emphysema is effective for long-term improvement of pulmonary function.

Preparation and characterization of sustained-release rotigotine film-forming gel.

OBJECTIVE: The aim of this study was to develop a film-forming gel formulation of rotigotine with hydroxypropyl cellulose (HPC) and Carbomer 934. To optimize this formulation, we applied the Response Surface Analysis technique and evaluated the gel's pharmacokinetic properties. METHODS: The factors chosen for factorial design were the concentration of rotigotine, the proportion of HPC and Carbomer 934, and the concentration of ST-Elastomer 10. Each factor was varied over three levels: low, medium and high. The gel formulation was evaluated and optimized according to its accumulated permeation rate (Flux) through Franz-type diffusion. A pharmacokinetic study of rotigotine gel was performed with rabbits. RESULTS: The Flux of the optimized formulation reached the maximum (199.17 µg/cm(2)), which was 3% rotigotine and 7% ST-Elastomer 10 with optimal composition of HPC: Carbomer 934 (5:1). The bioavailability of the optimized formulation compared with intravenous administration was approximately 20%. CONCLUSION: A film-forming gel of rotigotine was successfully developed using the response surface analysis technique. The results of this study may be helpful in finding an optimum formulation for transdermal delivery of a drug. The product may improve patients' compliance and provide better efficacy.

Studies on the acute toxicity, pharmacokinetics and pharmacodynamics of paliperidone derivatives--comparison to paliperidone and risperidone in mice and rats.

The objective of this study was to investigate the acute toxicity, pharmacokinetics and pharmacodynamics of paliperidone derivatives (PDs) compared with paliperidone and risperidone. The i.g. LD(50) and i.v. maximum tolerated doses of PD1, PD5 and PD6 were greater than those of paliperidone and risperidone in mice. Pharmacokinetic study showed that PDs were quickly metabolized to paliperidone to take effect in the treatment of schizophrenia in rats after i.g. administration. Only traces of the parent substances were found. Pharmacodynamic study showed that PDs significantly reduced MK-801-induced hyperlocomotion in mice. The electrocardiogram (ECG) was recorded at 0, 5, 10, 15, 20, 25, 30, 45 and 60 min. in anaesthetized rats after i.v. injection of 0.21, 0.59, 1.69 micromol/kg drugs. Heart rate reduction had a linear relation with dose after i.v. injection of PDs, paliperidone and risperidone. No significant change in the ECG parameters was found in all groups after administration of the low dose. Although the reductions in heart rate and the corrected QT interval (QTc) were observed in all drugs at the high dose, PD5 and PD6 were associated with smaller effects on the ECG parameters than other compounds, including paliperidone and risperidone. Therefore, PD5 and PD6 could be potential candidates for the treatment of schizophrenia.