ABSTRACT
The efficacy and safety of recombinant tissue plasminogen activator (rtPA) need to be improved due to its low bioavailability and requirement of large dose administration.The purpose of this study was to develop a fibrin-targeted nanoparticle (NP) drug delivery system for thrombosis combination therapy.We conjugated rtPA to poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) nanoparticles (rtPA-NP) and investigated its physicochemical characteristics such as particle size,zeta potential,enzyme activity of conjugated rtPA and its storage stability at 4℃.The thrombolytic activity of rtPA-NP was evaluated in vitro and in vivo as well as the half-life of rtPA-NP,the properties to fibrin targeting and its influences on systemic hemostasis in vivo.The results showed that rtPA-NP equivalent to 10％ of a typical dose of rtPA could dissolve fibrin clots and were demonstrated to have a neuroprotective effect after focal cerebral ischemia as evidenced by decreased infarct volume and improved neurological deficit (P＜0.001).RtPA-NP did not influence the in vivo hemostasis or coagulation system.The half-life of conjugated rtPA was shown to be approximately 18 times longer than that of free rtPA.These experiments suggested that rtPA-conjugated PEG-PCL nanoparticles might be a promising fibrin-targeted delivery system for a combination treatment of thrombosis.
ABSTRACT
The efficacy and safety of recombinant tissue plasminogen activator (rtPA) need to be improved due to its low bioavailability and requirement of large dose administration.The purpose of this study was to develop a fibrin-targeted nanoparticle (NP) drug delivery system for thrombosis combination therapy.We conjugated rtPA to poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) nanoparticles (rtPA-NP) and investigated its physicochemical characteristics such as particle size,zeta potential,enzyme activity of conjugated rtPA and its storage stability at 4℃.The thrombolytic activity of rtPA-NP was evaluated in vitro and in vivo as well as the half-life of rtPA-NP,the properties to fibrin targeting and its influences on systemic hemostasis in vivo.The results showed that rtPA-NP equivalent to 10％ of a typical dose of rtPA could dissolve fibrin clots and were demonstrated to have a neuroprotective effect after focal cerebral ischemia as evidenced by decreased infarct volume and improved neurological deficit (P＜0.001).RtPA-NP did not influence the in vivo hemostasis or coagulation system.The half-life of conjugated rtPA was shown to be approximately 18 times longer than that of free rtPA.These experiments suggested that rtPA-conjugated PEG-PCL nanoparticles might be a promising fibrin-targeted delivery system for a combination treatment of thrombosis.
ABSTRACT
The development of pharmaceuticals has been providing many kinds of novel drug delivery systems, which are important for improving therapeutic effect and one of the most important fields in pharmaceutics. According to their application, we can generally divide the novel drug delivery systems into three categories:quickly performed drug delivery system, long-term drug delivery system and high effective drug delivery system. Some diseases, such as asthma, angina pectoris and migraine, require therapeutics urgently, and the drugs have to be absorbed in several minutes. Therefore, quickly performed drug delivery systems are developed, such as oral disintegrating tablets and nasal spray. For normal tablets and capsules, especially the drugs with short blood half life, the drug concentration in blood shows obvious peak-valley phenomenon, which reduces the therapeutic effect and requires multiple administration. To solve this problem, sustained drug release system was developed, which could release the drugs slowly and sustainably even in zero-order kinetics. The pulse drug delivery system was developed that can delayed and pulsed release drug for one or several times. This system is especially useful in the management of asthma and heart disease, which are often found in midnight or early morning when patients are in bed. Transdermal drug delivery system could release drugs sustainably and deliver the drugs through skin to blood circulation, providing long term activity. The water-insoluble drugs are difficult for pharmaceutical development, thus many methods were developed to improve the solubility and bioavailability of drugs. Although biopharmaceuticals are important for disease treatment, the application shadows by the poor stability and low bioavailability. Thus the biopharmaceutical delivery system was developed, which mainly focused on structure modification and encapsulation by carriers. Considering therapeutic effect requires interaction between drugs and their targets, it is important to deliver drugs to their targets. Therefore, targeting delivery systems were developed, which mainly based on the nanoparticles. Furthermore, on-demand release drug delivery systems are also developed with the property of environment-triggered drug release. In conclusion, the novel drug delivery systems were reviewed in this study.
ABSTRACT
Tumor is one of the most serious threats for human being. Although many anti-tumor drugs are approved for clinical use, the treatment outcome is still modest because of the poor tumor targeting efficiency and low accumulation in tumor. Therefore, it is important to deliver anti-tumor drug into tumor efficiently, elevate drug concentration in tumor tissues and reduce the drug distribution in normal tissues. And it has been one of the most attractive directions of pharmaceutical academy and industry. Many kinds of strategies, especially various nanoparticulated drug delivery systems, have been developed to address the critical points of complex tumor microenvironment, which are partially or mostly satisfied for tumor treatment. In this paper, we carefully reviewed the novel targeting delivery strategies developed in recent years. The most powerful method is passive targeting delivery based on the enhanced permeability and retention (EPR) effect, and most commercial nanomedicines are based on the EPR effect. However, the high permeability and retention require different particle sizes, thus several kinds of size-changeable nanoparticles are developed, such as size reducible particles and assemble particles, to satisfy the controversial requirement for particle size and enhance both tumor retention and penetration. Surface charge reversible nanoparticles also shows a high efficiency because the anionic charge in blood circulation and normal organs decrease the unintended internalization. The charge can change into positive in tumor microenvironment, facilitating drug uptake by tumor cells. Additionally, tumor microenvironment responsive drug release is important to decrease drug side effect, and many strategies are developed, such as pH sensitive release and enzyme sensitive release. Except the responsive nanoparticles, shaping tumor microenvironment could attenuate the barriers in drug delivery, for example, decreasing tumor collagen intensity and normalizing tumor microvessels to decrease the internal fluid pressure. All these strategies could enhance the accumulation and penetration of nanoparticles into tumor, leading to a homogenous distribution of drugs in tumor. To enhance the internalization by specific cells, active targeting delivery strategies are developed. There were many surface markers, receptors or carriers overexpressed on specific kinds of cells, thus the corresponding ligands were utilized to mediate active tar-geting to certain cells, including tumor cells, cancer stem cells, tumor neovasculatures, tumor associated macrophages and other tumor stroma cells. Targeting more than one cell type may provide an improved antitumor effect. Although these passive and active targeting strategies all have promising outcome in the treatment of tumor, some shortages are still unaddressed, such as the specificity of responsive is not good enough, and the active targeting may be diminished by the protein corona. Thus more research is required to promote the drug delivery study.
ABSTRACT
In recent years, the development of molecular biology and medicine has prompted the research of gene therapy for brain diseases. In this review, we summarized the current gene therapy approaches of major brain diseases. Against the pathogenesis of major brain diseases, including brain tumors, Parkinson's disease, Alzheimer's disease and cerebrovascular disorders, there are several effective gene therapy strategies. It is no doubt that, gene therapy, as a novel treatment, is of great significance for understanding the causes, as well as comprehensive treatment for brain diseases.
Subject(s)
Humans , Alzheimer Disease , Genetics , Therapeutics , Brain Neoplasms , Genetics , Therapeutics , Cerebrovascular Disorders , Genetics , Therapeutics , Genetic Therapy , Methods , Parkinson Disease , Genetics , TherapeuticsABSTRACT
Various geometric shapes and structures self-assembled of amphiphilic lipids when present in an aqueous environment, as active delivery vehicles, are becoming one of focuses of drug delivery system. Lipid-based cubic liquid crystalline nanoparticles (or Cubosomes) consisting of "honeycombed (cavernous)" structure spontaneously formed when a certain concentration of amphiphilic lipids dispersed in aqueous solution has curved bicontinuous lipid bilayer in three dimensions, separating two congruent networks of water channels. Its unique structure consists of internal double water channels and large interfacial areas, which reveal great flexibility in encapsulation efficiency of various polarities and amount of drugs, and has variegated range of drugs encapsulated. As a drug delivery vehicle, high drug payloads, stabilization of peptides or proteins and simple preparation process are also its advantages. The ability of cubic phase to incorporate and control release of drugs of varying size and polar characteristics, and biodegradability of lipids make it an interesting drug delivery system for various routes of administration, including oral, topical (or mucosal) and intravenous administrations, with extensive application in a multitude of dosage forms. Furthermore, a number of different proteins in cubic phase appear to retain their native conformation and bioactivity, and are protected against chemical and physical inactivation. In this paper, investigations of lipid-based cubic liquid crystalline nanoparticles are reviewed and summarized, with a hope to provide a reference for its in-depth study. At the end, the authors made a development prospect of this novel excellent candidate for active ingredients delivery vehicle.
Subject(s)
Drug Carriers , Chemistry , Drug Delivery Systems , Methods , Lipids , Chemistry , Liquid Crystals , Chemistry , NanoparticlesABSTRACT
<p><b>AIM</b>A method of coculture of brain capillary endothelial cells (BCECs) and astrocytes of rats was used to evaluate nanoparticle's blood-brain barrier (BBB) transcytosis and toxicity at the endothelial tight junction.</p><p><b>METHODS</b>A lipophilic fluorescent probe, 6-coumarin, was incorporated in poly (ethyleneglycol)-poly (lactide) nanoparticle using double emulsion/solvent evaporation method. BCECs and astrocytes were firstly isolated from brain of newborn rats and characterized by their morphology and immunocytochemistry staining, separately. Subsequently, a coculture model with BCECs on the top of micro-porous membrane of cell culture insert and astrocytes on the bottom side was established. The permeability of 14C-labeled sucrose and nanoparticle were determined, separately.</p><p><b>RESULTS</b>The mean weight-based diameter of 6-coumarin loaded nanoparticles was (102.4 +/- 6.8) nm, with zeta potential of (-16.81 +/- 1.05) mV. BCECs were positive for factor VIII staining and glial fibrillary acidic protein was expressed in astrocytes. The transendothelial electrical resistance reached up to (313 +/- 23) omega x cm2. The tight junction between BCECs in the coculture model could be visualized by both scanning electron microscopy and transmission electron microscopy. The unchanged paracellular transport of sucrose proved that nanoparticle with concentration lower than 200 microg x mL(-1) did not impact the integrity of BBB endothelial tight junctions. The permeability of 10 microg x mL(-1) 6-coumarin labeled nanoparticle was 0.29 x 10(-3) cm x min(-1).</p><p><b>CONCLUSION</b>This in vitro experimental model of rat BBB was close to resemble the in vivo situation for examination of the permeability of nanoparticle and toxicity evaluation.</p>
Subject(s)
Animals , Rats , Animals, Newborn , Astrocytes , Metabolism , Biological Transport , Blood-Brain Barrier , Brain , Cell Biology , Capillaries , Cell Biology , Cell Membrane Permeability , Coculture Techniques , Coumarins , Pharmacokinetics , Toxicity , Endothelial Cells , Metabolism , Factor VIII , Metabolism , Glial Fibrillary Acidic Protein , Metabolism , Nanoparticles , Polyesters , Polyethylene Glycols , Rats, Sprague-Dawley , Sucrose , PharmacokineticsABSTRACT
<p><b>AIM</b>To investigate the effect of nimodipine (NM) on cerebral blood flow (CBF) in dogs following intranasal administration.</p><p><b>METHODS</b>NM solution was administered intranasally, intravenously (i.v.), and orally to dogs and the change of CBF was determined by using electromagnetic blood flowmeter. MFLab experimental program was applied to monitor the experimental process and analyze data.</p><p><b>RESULTS</b>CBF markedly increased after iv and intranasal application, while large variance was observed after oral dosing. CBF in dogs after three administrations increased by 26.4%, 28.0% and 8.5%, respectively, compared with that of baseline. Following intranasal administration, the onset of action was slightly slower than that after iv injection [(5 +/- 4) min vs (2.2 +/- 1.2) min], however the duration of improvement was the longest [ (25 +/- 17) min].</p><p><b>CONCLUSION</b>Intranasal delivery for NM can be a promising alternative to parenteral or oral administration.</p>
Subject(s)
Animals , Dogs , Female , Male , Administration, Intranasal , Administration, Oral , Blood Flow Velocity , Cerebrovascular Circulation , Injections, Intravenous , Nimodipine , Pharmacology , Vasodilator Agents , PharmacologyABSTRACT
<p><b>AIM</b>To investigate the extent of systemic absorption and uptake of meptazinol (MEP) hydrochloride in cerebrospinal fluid (CSF) after intranasal administration on rats and compare with oral administration.</p><p><b>METHODS</b>CSF samples were collected by a serial sampling method. The concentration of MEP in the biological samples was measured by HPLC with fluorescence detector.</p><p><b>RESULTS</b>Rapid and significant levels of MEP in plasma and CSF can be achieved after nasal administration whereas the oral administration resulted in considerably lower drug concentrations. AUC in plasma and CSF from the nasal route are 7.375 and 15.6 folds compared with those of the oral route, respectively.</p><p><b>CONCLUSION</b>Intranasal MEP is able to show quick absorption and improve the bioavailability, which could be a promising alternative to oral administration.</p>
Subject(s)
Animals , Male , Rats , Administration, Intranasal , Administration, Oral , Analgesics, Opioid , Blood , Cerebrospinal Fluid , Pharmacokinetics , Area Under Curve , Biological Availability , Chromatography, High Pressure Liquid , Methods , Meptazinol , Blood , Cerebrospinal Fluid , Pharmacokinetics , Rats, Sprague-DawleyABSTRACT
<p><b>AIM</b>To evaluate the pharmacokinetic profiles of the pharmacologically active primary amine metabolite of sibutramine, N-di-desmethyl sibutramine (BTS 54505) in Chinese origin.</p><p><b>METHODS</b>According to a randomized cross-over design, a single oral dose of 20 mg of sibutramine hydrochloride capsule was given to 20 healthy Chinese young volunteers. After dosing, serial blood samples were collected for a period of 72 h. BTS 54505 concentration in plasma was analyzed by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry.</p><p><b>RESULTS</b>Various pharmacokinetic parameters including AUC0-t, AUC0-infinity, Cmax, Tmax, T1/2, Kelm and MRT were determined for both test and reference capsules and found to be in good agreement with literature values.</p><p><b>CONCLUSION</b>The test and reference sibutramine capsules were bioequivalent.</p>