ROS-removing nano-medicine for navigating inflammatory microenvironment to enhance anti-epileptic therapy

As a neurological disorder in the brain, epilepsy is not only associated with abnormal synchronized discharging of neurons, but also inseparable from non-neuronal elements in the altered microenvironment. Anti-epileptic drugs (AEDs) merely focusing on neuronal circuits frequently turn out deficient, which is necessitating comprehensive strategies of medications to cover over-exciting neurons, activated glial cells, oxidative stress and chronic inflammation synchronously. Therefore, we would report the design of a polymeric micelle drug delivery system that was functioned with brain targeting and cerebral microenvironment modulation. In brief, reactive oxygen species (ROS)-sensitive phenylboronic ester was conjugated with poly-ethylene glycol (PEG) to form amphiphilic copolymers. Additionally, dehydroascorbic acid (DHAA), an analogue of glucose, was applied to target glucose transporter 1 (GLUT1) and facilitate micelle penetration across the blood‒brain barrier (BBB). A classic hydrophobic AED, lamotrigine (LTG), was encapsulated in the micelles via self-assembly. When administrated and transferred across the BBB, ROS-scavenging polymers were expected to integrate anti-oxidation, anti-inflammation and neuro-electric modulation into one strategy. Moreover, micelles would alter LTG distribution in vivo with improved efficacy. Overall, the combined anti-epileptic therapy might provide effective opinions on how to maximize neuroprotection during early epileptogenesis.

Preparation and applications of the polymeric micelle/hydrogel nanocomposites as biomaterials / 生物医学工程学杂志

Polymeric hydrogels have been widely researched as drug delivery systems, wound dressings and tissue engineering scaffolds due to their unique properties such as good biocompatibility, shaping ability and similar properties to extracellular matrix. However, further development of conventional hydrogels for biomedical applications is still limited by their poor mechanical properties and self-healing properties. Currently, nanocomposite hydrogels with excellent properties and customized functions can be obtained by introducing nanoparticles into their network, and different types of nanoparticles, including carbon-based, polymer-based, inorganic-based and metal-based nanoparticle, are commonly used. Nanocomposite hydrogels incorporated with polymeric micelles can not only enhance the mechanical properties, self-healing properties and chemical properties of hydrogels, but also improve the

Preparation and Preliminary Evaluation of Paclitaxel-loaded TPGS-CR Polymeric Micelles / 中国药学杂志

OBJECTIVE: To prepare paclitaxel loaded D-α-tocopheryl polyethylene glycol 1000 succinate(TPGS)-modified carboxymethyl chitosan-rhein polymeric micelles (PTX/TPGS-CR PMs) and preliminarily evaluate their performance. METHODS: PTX/TPGS-CR PMs was prepared by dialysis method, and the preparation procedure of PTX/TPGS-CR PMs was optimized by single factor with the drug loading, encapsulation rate and particle size as the indicators, then the optimized preparation procedure was verified. The safety of PTX/TPGS-CR PMs was initially investigated by the hemolysis test and the vascular irritation test. The cytotoxicity of PTX/TPGS-CR PMs in Hela cells was studied by MTT assay. Cell uptake experiments were performed by laser confocal microscopy and flow cytometry to investigate the uptake of PTX/TPGS-CR PMs by Hela cells. RESULTS: The particle size and PDI of PTX/TPGS-CR PMs prepared by the optimized preparation were (197.3±4.4) nm and (0.131±0.021), respectively. The Zeta potential was (-31.8±0.5) mV. The drug loading and encapsulation efficiency were (48.20±3.03)% and (87.26±4.91)%, respectively. The hemolytic test results showed that the hemolysis rate was less than 1.71%. No obvious irritation was observed after intravenous injection. The cytotoxicity of PTX/TPGS-CR PMs in Hela cells was concentration-and time-dependent. Cell uptake experiments showed that PTX/TPGS-CR PMs could be efficiently uptake by Hela cells. CONCLUSION: The PTX/TPGS-CR PMs has high drug loading and encapsulation efficiency, good safety. And they exhibite slightly better antitumor activity in vitro than Taxol®.

Research progress on new drug delivery system of triptolide for anticancer therapy / 中草药

Triptolide had broad-spectrum and high-efficient anti-cancer activity, however, its clinical application was limited by the poor water solubility, in vivo rapid elimination, and strong toxicities and side effects. New drug delivery system was the ideal vehicle for targeted delivery of triptolide, which can effectively deliver triptolide to the cancer tissue, and increase the efficiency of tumor therapy. New drug delivery system had great application prospect in improving solubility of triptolide, reducing side effect, and increasing bioavailability. This article reviewed the research progress of new drug delivery system of triptolide based on liposome, polymer micelle and nanoparticle in the past decade, providing some references for the development and application of new drug delivery system of triptolide.

The preparation and study on drug release of a triply-responsive (redox/thermo/pH) cross-linked polymeric micelle as anti-cancer drug carrier / 生物医学工程学杂志

A multiple-stimuli-responsive drug-conjugated cross-linked micelles was prepared by radical copolymerization. The chemical structure, morphology, and size of the cross-linked micelles were characterized, and the drug loading of the micelle was calculated. The experimental results indicated that the hydrodynamic size of the drug-loaded micelles were about 100 nm, and the as prepared micelles could be degraded and swelled in presence of reducing glutathione (GSH). The low critical solution temperature (LCST) of the micelle was around 39.4℃. According to the experimental results, the micelles will shrink at temperature above the LCST. Subsequently, the accumulative drug release rate was up to 91.78% under acidic (pH 5.0), reductive (GSH 10 mmol/L) and high temperature (42.0℃) conditions mimicking the tumor microenvironment, while a relatively low release rate of 1.12% was observed without stimulation. The drug-conjugated cross-linked micelles showed a strong cell uptake behavior. In the cytotoxicity assay, the micelles exhibited effective anti-cancer activity and excellent biocompatibility. In brief, the experimental results show that the as-prepared drug-conjugated cross-linked micelle exhibits multiple stimuli-responsiveness, which holds great promise for anti-cancer drug delivery.

An Open-Label, Randomized, Parallel, Phase III Trial Evaluating the Efficacy and Safety of Polymeric Micelle-Formulated Paclitaxel Compared to Conventional Cremophor EL-Based Paclitaxel for Recurrent or Metastatic HER2-Negative Breast Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Genexol-PM is a Cremophor EL–free formulation of low-molecular-weight, non-toxic, and biodegradable polymeric micelle-bound paclitaxel. We conducted a phase III study comparing the clinical efficacy and toxicity of Genexol-PM with conventional paclitaxel (Genexol). MATERIALS AND METHODS: Patients were randomly assigned (1:1) to receive Genexol-PM 260 mg/m² or Genexol 175 mg/m² intravenously every 3 weeks. The primary outcome was the objective response rate (ORR). RESULTS: The study enrolled 212 patients, of whom 105 were allocated to receive Genexol-PM. The mean received dose intensity of Genexol-PM was 246.8±21.3 mg/m² (95.0%), and that of Genexol was 168.3±10.6 mg/m² (96.2%). After a median follow-up of 24.5 months (range, 0.0 to 48.7 months), the ORR of Genexol-PM was 39.1% (95% confidence interval [CI], 31.2 to 46.9) and the ORR of Genexol was 24.3% (95% CI, 17.5 to 31.1) (p(non-inferiority)=0.021, p(superiority)=0.016). The two groups did not differ significantly in overall survival (28.8 months for Genexol-PM vs. 23.8 months for Genexol; p=0.52) or progression-free survival (8.0 months for Genexol-PM vs. 6.7 months for Genexol; p=0.26). In both groups, the most common toxicities were neutropenia, with 68.6% occurrence in the Genexol-PM group versus 40.2% in the Genexol group (p < 0.01). The incidences of peripheral neuropathy of greater than grade 2 did not differ significantly between study treatments. CONCLUSION: Compared with standard paclitaxel, Genexol-PM demonstrated non-inferior and even superior clinical efficacy with a manageable safety profile in patients with metastatic breast cancer.

Nanoformulations of the vascular inhibitors: Combretastatin A4 and combretastatin A4 phosphate / 国际药学研究杂志

Combretastatin A4 (CA4), a vascular inhibitor, can target tubulin and inhibit tubulin polymerization, thus it can inhibit the tumor blood vessels and has antitumor effect. But it is insoluble in water and has low bioavailability. CA4 phosphate (CA4P), the derivative of CA4, can improve the solubility of CA4 and convert into CA4. CA4P is undergoing phase II/III clinical trials abroad. However, CA4P has several undesirable side effects and relative short half-life in vivo. Nanoformulations can increase the dissolution and absorption of the drug and obtain controlled release and targeting, prolong the efficacy and reduce side effects. Working on the physical and chemical characteristics and biological pharmacy defects of CA4 and CA4P nanoformulations may change the dissolution, absorption and distribution of the drug. This paper reviews the current nanoformulations of CA4 and CA4P, including den-drimer, polymeric micelle (PM), nanoparticles (NP), long-circulating liposome (LCL), and discusses the prospects of their nanoformulations.

Nanoformulations of the vascular inhibitors:combretastatin A4 and combretastatin A4 phosphate / 国际药学研究杂志

Combretastatin A4(CA4),a vascular inhibitor,can target tubulin and inhibit tubulin polymerization,thus it can inhibit the tumor blood vessels and has antitumor effect. But it is insoluble in water and has low bioavailability. CA 4 phosphate (CA4P),the derivative of CA4,can improve the solubility of CA4 and convert into CA4. CA4P is undergoing phaseⅡ/Ⅲclinical tri?als abroad. However,CA4P has several undesirable side effects and relative short half-life in vivo. Nanoformulations can increase the dissolution and absorption of the drug and obtain controlled release and targeting,prolong the efficacy and reduce side effects. Work?ing on the physical and chemical characteristics and biological pharmacy defects of CA4 and CA4P,nanoformulations may change the dissolution,absorption and distribution of the drug. This paper reviews the current nanoformulations of CA4 and CA4P,including den?drimer,polymeric micelle(PM),nanoparticles(NP),long-circulating liposome(LCL),and discusses the prospects of their nanofor?mulations.

New polymer micelles and its application in cancer therapy / 中国药学杂志

The current prevalence of cancer chemotherapy drugs is inefficient and highly toxic, thus selecting the appropriate new forms of cancer treatment has become one of the important tasks. On the basis of domestic and foreign research literature, cutline the composition, characteristics and main preparation methods of polymeric micelles. Introduced varieties of stimuli-responsive polymer micelles, as well as targeted polymeric micelles used as an anticancer drug carrier. By making use of inside microenvironment of tumor cells, the preparation of various of new intelligent polymeric micelles with slight side effects and good treatment in virto and in vivo, can achieve effective control of drug release, which has great development and prospect in application.

The application of reduction-sensitive polymeric micelles in tumor targeting drug delivery / 中国药学杂志

OBJECTIVE: To introduce the application of reduction-sensitive polymeric micelles in the field of tumor targeting drug delivery. METHODS: In the past decades, tumor targeted drug delivery systems have become important research area because they promise to resolve several key therapeutical issues including low treatment efficacy and significant side effects. On the basis of published literatures, the recent developments in reduction-sensitive polymeric micelles used for tumor targeting drug delivery were reviewed, with an emphasis on their structure characteristics as well as their biomedical applications from the cellular level and animal level, respectively. RESULTS AND CONCLUSION: As a novel intelligent drug delivery system, reduction-sensitive polymeric micelles can effectively control drug release with low side effects and high therapeutic effects both in vitro and in vivo. It has great potential in tumor targeting drug delivery.

Development, characterization and in vitro evaluation of docetaxel-loaded polymeric micelles / 中国药学杂志

OBJECTIVE: To employ PEG-PCL diblock copolymers to prepare DTX-loaded polymeric micelles (PEG-PCL-DTX micelles, DTX-PMs) which addressed the issue of DTX's drug loading capacity, encapsulation efficiency and in vitro release. We also studied its effectiveness for the cytotoxicity on prostate cancer. METHODS: The polymeric micelles were screened by its shape using transmission electron microscope and were also characterized in terms of particle size, Zeta potential, drug loading efficiency, in vitro release and cytotoxicity by using laser particle size analyzer and HPLC. Cytotoxicity against LNCap-C4-2B prostate cancer cells of the DTX-PMs and commercial product of Duopafei® were evaluated by MTT assay. RESULTS: The average particle size and Zeta potential of DTX-PMs were found to be 25.1 nm and 0.64 mV. The micelles' drug loading and encapsulation efficiency were 8.72% and 98.1%, respectively. Cytotoxicity assay showed that DTX-PMs exerted significant anti-proliferation activity on LNCap-C4-2B prostate cancer cells. CONCLUSION: Slightly soluable DTX successfully formulated into the PEG-PCL micells, exhibiting small partical size and good stability. Delayed release in vitro and maintained quite a constant concentration in plasma for a long period, which was favorable for its clinic application. In conclusion, DTX-PMs developed here sufficiently solubilized DTX and increase the concentration of DTX in aqueous phase, offering a sustained in vitro release and effective cytotoxicity on LNCap-C4-2B prostate cancer.

Preparation of coumarin 6 micelles and uptake and transport study of micelles across epithelial cell monolayer / 中国药学杂志

OBJECTIVE: To investigate the uptake and transport properties of micelles across Madin Darby canine kidney (MD-CK) cells. METHODS: Coumarin 6 loaded PEG-PLA (PEG3000-PLA3000) micelles were prepared by solvent evaporation method, and the HPLC determination method of coumarin 6 was constructed. Competition uptake of blank micelles with coumarin 6 micelles was studied. Temperature and inhibitors effect on transport of micelles across MDCK cell monolayer were studied, the concentration of Ca and EGTA were also studied. RESULTS: Coumarin 6 micelles could be internalized into cells very quickly, and the uptake of micelles could be inhibited by blank micelles. The transport of micelles was affected by temperature and inhibitors, which means that this process is an active and energy-dependent process. The concentration of Ca2+ and EGTA could affect the transport of the micelles, which means micelles could transport across the cell monolayer via paracellular pathway. The amount of transported coumarin 6 micelles was rather limited compared with coumarin 6 micelles added to the apical side. CONCLUSION: Micelles transport across MDCK cell monolayer via both paracellular and transcellular pathway at the same time.

Preparation and characterization of polymeric micelles with chemical conjugation of doxorubicin (DOX-P) / 中国药学杂志

OBJECTIVE: Poloxamer-doxorubicin polymer (DOX-P) was prepared through covalent binding mode via an amide bond, DOX-P can be self-assemble to form nanoscale Characterization and anti-tumor activity of chemical conjugation of doxorubicin (DOX) in polymeric micelles were investigated. METHODS: Succinic anhydride activated Poloxamer188 was first synthesized and the primary amine group in doxorubicin was conjugated to the terminal carboxyl of Poloxamerl88 via a amide. The resulting polymeric micelles in aqueous solution were characterized by measurement of size, ℰ-potential, drug loading and critical micelle concentration. RESULTS: DOX-P micelles had superiorities over physically-loaded DOX micelles in loading efficiency, diameter and CMC value. From drug release experiment in vitro, DOX-P micelles reached a sustained release profile for DOX with 10 d while physically-loaded DOX only 2 d. CONCLUSION: With low CMC value, high loading efficiency, nanometer diameter and controlled release behaviour, DOX-P micelles might be developed as a new cancer targeted delivery system.

Pharmacokinetics and tissue distribution of mitomycin amphiphilic chitosan polymeric micelles in rats / 中国药学杂志

OBJECTIVE: To investigate the pharmacokinetics and tissue distribution of mitomycin amphiphilic chitosan polymeric micelles (MMC-ACPM) in rats. METHODS: Mitomycin injection (MMC-INJ) and MMC-ACPM were administered to rats through tail vein at the dosage of 0. 5 mg · kg-1. An ultra-fast liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method was established to determine the concentration of mitomycin (MMC) in plasma and tissues of rats. RESULTS: The t1/2(β) of MMC-INJ and MMC-ACPM in plasma were estimated to be (0.67 ± 0.36) and (3.33 ± 1.47) h, respectively. The AUC0→∞ were calculated to be (120.94 ± 13.77) and (140.95 ± 11.56) ng · mL-1 · h-1, respectively. The MRT were (0.83 ±0.13) and (1.56 ± 0.22) h, and CL were (0.005 ± 0.001) and (0.003 ± 0.001) L · h-1 · kg-1, respectively. Compared with MMC-INJ group, MMC-ACPM group had lower concentrations of MMC in heart, liver, spleen, lung, and kidney of rats. CONCLUSION: MMC-ACPM can prolong the circulation of MMC in vivo, improve its bioavailability, and reduce the accumulation in liver and kidney, which can improve curative effects and reduce toxicity.