Carriers For Drug Delivery Systems Research Articles

Hollow mesoporous silica as a high drug loading carrier for regulation insoluble drug release

The purpose of this study was to develop a high drug loading hollow mesoporous silica nanoparticles (HMS) and apply for regulation insoluble drug release. HMS was synthesized using hard template phenolic resin nanoparticles with the aid of cetyltrimethyl ammonium bromide (CTAB), which was simple and inexpensive. To compare the difference between normal mesoporous silica (NMS) and hollow mesoporous silica in drug loading efficiency, drug release behavior and solid state, NMS was also prepared by soft template method. Transmission electron microscopy (TEM), specific surface area analysis, FT-IR and zeta potential were employed to characterize the morphology structure and physicochemical property of these carriers. The insoluble drugs, carvedilol and fenofibrate(Car and Fen), were chosen as the model drug to be loaded into HMS and NMS. We also chose methylene blue (MB) as a basic dye to estimate the adsorption ability of these carriers from macroscopic and microscopic view, and the drug-loaded carriers were systematically studied by differential scanning calorimetry (DSC), X-ray diffraction (XRD) and UV-vis spectrophotometry. What’ more, the in vivo process of HMS was also study by confocal microscopy and in vivo fluorescence imaging. In order to confirm the gastrointestinal safety of HMS, the pathological examination of stomach and intestine also be evaluated. HMS allowed a higher drug loading than NMS and exhibited a relative sustained release curve, while NMS was immediate-release. And the effect of preventing drugs crystallization was weaker than NMS. As for in vivo process, HMS was cleared relatively rapidly from the mouse gastrointestinal and barely uptake by intestinal epithelial cell in this study due to its large particle size. And the damage of HMS to gastrointestinal could be ignored. This study provided a simple method to obtain high drug loading and regulation insoluble drug release, expanded the application of inorganic carriers in drug delivery system and pharmaceutic adjuvant.

Cubosomes: Innovative Nanostructures for Drug Delivery.

Some amphiphilic lipids can self-assemble to form bicontinuous cubic liquid crystalline materials in aqueous media. These cubic structures have gained considerable attention since they impart unique properties of practical interest. Cubosomes, being dispersions of an inverted type bicontinuous cubic phase, separate two continuous aqueous regions with a lipid bilayer having the propensity to incorporate drugs of varying polar characteristics. These novel versatile materials possess the properties to form a section of the next generation of advanced biocompatible nanoparticles. This review chiefly considers the scope and importance of cubosomes as a proficient drug delivery vehicle. In addition, it also takes into account the various methods of preparation, the drug loading and release behavior as well as different methods of characterization. Their current advances in various arenas ranging from sustained drug release, burn management, melanoma therapy, vaccine delivery, protein delivery, cosmeceutical and theranostic applications are briefly summarized in this overview. The drug release from cubosomal dispersions have shown enhancement in bioavailability by solubilisation of poorly water soluble drugs, decrease in adverse effects, enhancement of intracellular penetration, protection against degradation, possibility of sustained drug release and the biodegradable nature of lipids is an added advantage. Recognizing the desirable properties of cubosomes, it has been proposed as a novel carrier for drug delivery systems. Their unique solubilizing, encapsulating, transporting and protecting capabilities make them an attractive vehicle for numerous in vivo drug delivery routes.

LCA of Starch Aerogels for Biomedical Applications

Aerogels are a special class of nanoporous materials with increasing interest in biomedical and pharmaceutical applications due to their open pore structure and high surface area. Among them, polysaccharide aerogels are biodegradable and biocompatible and, therefore, can be used as carriers for drug delivery systems. In this work, an analysis of their production from the environmental point of view was made, following a Life Cycle Assessment (LCA) approach with the aim of reducing the total emissions. Maize starch aerogels were produced on a pilot scale using a three-step process: first, the gel is prepared using an aqueous solution, then water is replaced by ethanol forming an alcogel and finally, carbon dioxide at supercritical conditions is used as non-solvent to dry the gel and obtain the aerogel. The materials and energy consumptions were determined and the emissions to air, soil and water due the aerogel production were evaluated; all data were normalized to the functional unit (1 g of final aerogel). The environmental analysis was conducted using SimaPro 8.0.4 software and the data for the life cycle inventory were experimentally measured or recovered from the Ecoinvent database.

Hierarchical self-assembly of heparin-PEG end-capped porous silica as a redox sensitive nanocarrier for doxorubicin delivery

Porous nanosilica (PNS) has been attracting a great attention in fabrication carriers for drug delivery system (DDS). However, unmodified PNS-based carriers exhibited the initial burst release of loaded bioactive molecules, which may limit their potential clinical application. In this study, the surface of PNS was conjugated with adamantylamine (A) via disulfide bonds (PNS-SS-A) which was functionalized with cyclodextrin-heparin-polyethylene glycol (CD-HPEG) for redox triggered doxorubicin (DOX) delivery. The modified PNS was successfully formed with spherical shape and diameter around 50nm determined by transmission electron microscopy (TEM). DOX was efficiently trapped in the PNS-SS-A@CD-HPEG and slowly released in phosphate buffered saline (PBS) without any initial burst effect. Importantly, the release of DOX was triggered due to the cleavage of the disulfide bonds in the presence of dithiothreitol (DTT). In addition, the MTT assay data showed that PNS-SS-A@CD-HPEG was a biocompatible nanocarrier and reduced the toxicity of DOX. These results demonstrated that PNS-SS-A@CD-HPEG has great potential as a novel nanocarrier for anticancer drug in cancer therapy.

Syntheses and characterization of amphiphilic quaternary ammonium chitosan derivatives

Amphiphilic chitosan derivatives possess improved physico-chemical properties and could be used as carriers in drug delivery systems. The aim of this study was to investigate the behaviour of an amphiphilic system involving (5-pentyl) trimethylammonium and dodecyl aldehyde-modified chitosan. Amphiphilic chitosan derivatives were synthesized and characterized by 1HNMR and ATR-FTIR spectroscopy. Self-assembled aggregates formed in aqueous solution have hydrophobic cores that were characterized by fluorescence spectroscopy using pyrene as probe and dynamic light scattering (DLS). The critical aggregation concentration of the aggregates in water varied from 0.004 to 0.037g/L and the average size distribution was in the 230–500nm range. The ζ-potential (+15.5 to +44.8mV) confirmed that the surfaces of the aggregates were positively charged and stable in physiological-like environments. TEM images suggest that the aggregates have a spherical shape, showing good agreement with DLS results. These results suggest that the synthesized copolymers have the capability of being used as carriers for hydrophobic drugs.

Comprehensive study on the structure of the BSA from extended-to aged form in wide (2–12) pH range

In this work we studied the structure of the bovine serum albumin (BSA) and the protein-ligand interactions since researchers prefer to use them as carriers in drug delivery systems. Systematic study (between pH 2–12, in double distilled water and physiological salt solution) was carried out to determine the changes in the secondary and the tertiary structures of the BSA, the apparent molecular weight (Mw), the size (dLS) and the electrokinetic potential (ζ). At pH 7, the BSA has higher stability in the absence (ζ=−69mV, dLS=2.2nm, A2=1.4×10−3mlmol/g2) than in the presence of salt solution (ζ=−2.4mV, dLS=5.3nm, A2=−3.2×10−4mlmol/g2). The Mw strongly depends on the pH and the ionic strength (at pH 3 in the absence of salt, the Mw is 54.6kDa while in the presence of salt is 114kDa) which determines the geometry of the protein. The protein-ligand interactions were characterized by fluorescence (FL) and isothermal microcalorimetry (ITC) methods; these independent techniques provided similar thermodynamic parameters such as the binding constant (K) and the Gibbs free energy (ΔG).

Responsive nanogels for application as smart carriers in endocytic pH-triggered drug delivery systems

Various specially designed poly(N-isopropylacrylamide-co-acrylic acid) (NIPA-co-AAc) nanogels (NGs) with different NIPA/AAc molar composition were synthesized by precipitation/dispersion polymerization and evaluated as carriers for drug delivery systems (DDSs) of doxorubicin hydrochloride (DOXO·HCl) for cancer therapies. The NGs presented excellent dispersability in physiological environments (pH 7.4 and 5 at 37°C), as shown by dynamic light scattering (DLS). Moreover, the NGs exhibited high drug loading capacity and efficiency due to the ionic interaction of the cationic drug with the anionic NGs. NG-DOXO·HCl formulation presented excellent dispersability in water and minimal leakage of the cargo at plasma simulated medium (pH 7.4 and 0.14M NaCl) at 37°C and a triggered release at lysosomal simulated medium (pH 5 and 0.14M NaCl). This release behavior together with their size and the low cytotoxicity determined by the MTT assay converts these NGs in great candidates for their application as carriers in cancer therapies based on the enhanced permeability and retention effect (EPR) with drug pH-triggered release after endocytosis in tumor cells.

Polymers' ultrafine particles for drug delivery systems precipitated by supercritical carbon dioxide + organic solvent mixtures

The applicability of supercritical antisolvent precipitation (SAS) is restricted to hydrophobic substances because of the very limited solubility of water in CO2 at ordinary SAS operating conditions (40–60°C, 10–25MPa). To overcome this limitation, a technique has been developed, named expanded liquid antisolvent (ELAS), in which mixtures of supercritical carbon dioxide (scCO2) and organic solvents, at expanded liquid conditions, are used as the antisolvent: water solubility is widely enhanced.In this work, sodium alginate and polyvinyl alcohol (PVA), two water-soluble polymers, used as carrier for drug delivery systems, were successfully micronized by ELAS. Different antisolvent mixtures were used: scCO2+ethanol, scCO2+acetone and scCO2+isopropyl alcohol. Operating at 15MPa and 40°C, varying the organic co-antisolvent, the co-antisolvent mole fraction and the concentration of the polymer in the aqueous solution, nanoparticles (with a mean diameter of about 200nm), microparticles with smooth surface (with a mean diameter in the range of 0.9–12.5μm for sodium alginate and 2–9μm for PVA) and nanostructured microparticles (with a mean diameter of about 11μm) were produced. XRD analyses on the processed powders revealed that no modifications in the polymer structure were induced by ELAS processing. Solvent residue analyses revealed that the co-antisolvent residue ranged between 50 and 300ppm depending on the organic solvent used.

Synthesis and properties of CO2-responsive copolymer by the combination of reversible addition-fragmentation chain transfer polymerization and click chemistry

Amphiphilic block copolymer of poly(ethylene glycol) and polymer containing N′-Propargyl-N,N-dimethylacetamidines (PEG-b-PADS) was easily synthesized via the combination of reversible addition-fragmentation chain transfer polymerization (RAFT) and click chemistry. The structure of the copolymer was characterized by nuclear magnetic resonance (1H NMR) and attenuated total internal reflectance fourier transform infrared spectroscopy (ATR FT-IR). As an amphiphilic copolymer, PEG-b-PADS can self-assemble to micelles with PEG shell and PADS core in aqueous medium, and its self-assembly behavior and CO2-responsive properties were investigated by transmission electron microscopy (TEM) and dynamic light scatting (DLS). The size and morphologies of the micelles can be controlled by bubbling CO2 or Ar into the solution. Alternating treatment with CO2 and Ar could realize a reversible contraction–expansion transformation of the micelles. As a carrier for drug delivery systems, the micelles showed good controlled release behavior for drug molecules. Investigation shows that the release rate and level of doxorubicin (DOX) could be controlled through bubbling with CO2 and Ar alternatively.

Synthesis and characterisation of poly(acryalamide) grafted carboxymethyl xanthan gum copolymer

In the present work, an unreported graft copolymer of carboxymethyl xanthan gum and acrylamide has been synthesised by free radical polymerisation in a nitrogen atmosphere using ammonium persulphate as an initiator. The optimum reaction conditions adopted for affording maximum percentage of grafting including its grafting efficiency were obtained by varying the concentration of carboxymethyl xanthan gum from 4 to 24gdm−3; ammonium persulphate from 5×10−4 to 30×10−4moldm−3; acrylamide from 0.4 to 1.2moldm−3; reaction temperature from 55 to 75°C and reaction time from 30 to 90min. The synthesised graft copolymer has been characterised by 1H NMR, FTIR spectroscopy, X-ray diffraction measurement, thermal analysis, viscosity measurement and scanning electron microscopy. However, grafting of acrylamide onto carboxymethyl xanthan gum backbone enhanced its thermal stability. This graft copolymer might be well exploited globally as a potential carrier for drug delivery system.

Human Serum Albumin as Carrier in Drug Delivery Systems

Recently, human serum albumin (HSA) has emerged as a versatile carrier for therapeutic agents against diabetes, cancer, and infectious diseases. Market-approved products include fatty acid derivatives of human insulin for diabetes and the paclitaxel-HSA nanoparticle for various cancers such as metastatic breast cancer and advanced pancreatic cancer. In this review, we focus on the next-generation approach including HSA-binding bioactive gas such as nitric oxide (NO) for treating ischemic/reperfusion injury, cancer, and bacterial infection. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by unwanted side effects. Therefore, novel NO donors with better pharmacological and pharmacokinetic properties are highly desirable. The S-nitrosothiol fraction in plasma is largely composed of endogenous S-nitrosated HSA (SNO-HSA), which is why we are investigating whether this albumin form can be therapeutically useful. Recently, we have developed SNO-HSA analogues such as SNO-HSA with many conjugated SNO groups (poly-SNO-HSA) prepared using chemical modification. Unexpectedly, we found striking inverse effects between poly-SNO-HSA and SNO-HSA. Despite the fact that SNO-HSA inhibits apoptosis, poly-SNO-HSA possesses very strong pro-apoptotic effects against tumor cells. Furthermore, poly-SNO-HSA can reduce or even completely eliminate the multidrug resistance often developed by cancer cells. In this review, we put forward the possibility that poly-SNO-HSA can be used as a safe, effective multifunctional antitumor agent.

Development and Evaluation of Surface Modified Poly (lactic acid) Microsphere via Irradiation Techniques for Drug Delivery System

Poly (lactic acid) (PLA) has been used in medical field because it is biocompatible, biodegradable and has good mechanical properties. However, its surface characteristic which is hydrophobic and chemically inert is not suitable as a carrier in drug delivery system. Purpose of this study is to modify and improve PLA microspheres surface by grafting hydrophilic monomers onto its surface via irradiation techniques. Two sets of PLA microspheres with and without hydrophilic monomers were irradiated using high energy irradiations which are electron beam and Gamma (γ) rays respectively. Although dose used in irradiating samples were same for both electron beam and γ-rays, but the dose rate were different where electron beam has the higher dose rate. Free radicals will be formed when a matter is irradiated with ionising radiation and these radicals will interact with monomers and initiate grafting. Three hydrophilic monomers were used in this study i.e. Acrylic Acid (AA), Acrylamide and Maleic Anhydride (MAH). Surface modified PLA microspheres were characterised using Fourier Transform Infrared (FTIR) and Scanning Electron Microscopy (SEM). PLA microspheres surface were successfully modified and grafted with selected monomers and confirmed by FTIR results. The degrees of grafting were found to be dependent on irradiation dose and dose rate of irradiation as well as monomer used in the grafting. SEM shows surface of PLA microsphere after surface modification is rougher compared to before surface modification.

Advances in Drug Delivery Strategies for Cancer Therapeutics

In spite of intensive research is being reported on cancer and its therapy, still it is identified as a leading killer worldwide. It is reported that around 7 million deaths occur every year and WHO (2007) estimated that around 16 million new cancer cases will be detected every year by 2020. The major cancer mortality by all types of cancer is stomach, lung, colon, liver and breast cancers. The carcinogens such as tobacco, smoke, infectious or chemical agents and radiation leads to genetic abnormalities and causes cancer. Different treatment approaches available currently and under evolution are based on surgical removal of malignant cells, radiation therapy, chemotherapy, target and immunotherapy [1]. The treatment approach is decided based on location, stage and grade of the tumor including general state of the patient, but chemotherapy has been observed as one of the best way to treat cancer. The success of treatment depends on types of drug delivery carrier system selected and their target approach.

Preparation of Self-Activated Fluorescence Mesoporous Silica Hollow Nanoellipsoids for Theranostics.

The newly developed multifunctional (self-activated fluorescent, mesoporous, and biocompatible) hollow mesoporous silica nanoellipsoids (f-hMS) are potentially useful as a delivery system of drugs for therapeutics and imaging purposes. For the synthesis of f-hMS, self-activated fluorescence hydroxyapatite (fHA) was used as a core template. A mesoporous silica shell was obtained by silica formation and subsequent removal of the fHA core, which resulted in a hollow-cored f-hMS. Although the silica shell provided a highly mesoporous structure, enabling an effective loading of drug molecules, the fluorescent property of fHA was also well-preserved in the f-hMS. Cytochrome c and doxorubicin, used as a model protein and anticancer drug, respectively, were shown to be effectively loaded onto f-hMS and were then released in a sustainable and controllable manner. The f-hMS was effectively taken up by the cells and exhibited fluorescent labeling while preserving excellent cell viability. Overall, the f-hMS nanoreservoir may be useful as a multifunctional carrier system for drug delivery and cell imaging.

Preformulation Studies of Bee Venom for the Preparation of Bee Venom-Loaded PLGA Particles.

It is known that allergic people was potentially vulnerable to bee venom (BV), which can induce an anaphylactic shock, eventually leading to death. Up until recently, this kind of allergy was treated only by venom immunotherapy (VIT) and its efficacy has been recognized worldwide. This treatment is practiced by subcutaneous injections that gradually increase the doses of the allergen. This is inconvenient for patients due to frequent injections. Poly (D,L-lactide-co-glycolide) (PLGA) has been broadly studied as a carrier for drug delivery systems (DDS) of proteins and peptides. PLGA particles usually induce a sustained release. In this study, the physicochemical properties of BV were examined prior to the preparation of BV-loaded PLGA nanoparticles NPs). The content of melittin, the main component of BV, was 53.3%. When protected from the light BV was stable at 4 °C in distilled water, during 8 weeks. BV-loaded PLGA particles were prepared using dichloromethane as the most suitable organic solvent and two min of ultrasonic emulsification time. This study has characterized the physicochemical properties of BV for the preparation BV-loaded PLGA NPs in order to design and optimize a suitable sustained release system in the future.

Thermoresponsive Nanoparticles of Self-Assembled Block Copolymers as Potential Carriers for Drug Delivery and Diagnostics.

Thermally responsive hydrogel nanoparticles composed of self-assembled polystyrene-b-poly(N-isopropylacrylamide)-b-polystyrene block copolymers and fluorescent probe 1-anilinonaphthalene-8-sulfonic acid have been prepared by aerosol flow reactor method. We aimed exploring the relationship of intraparticle morphologies, that were, PS spheres and gyroids embedded in PNIPAm matrix, as well PS-PNIPAm lamellar structure, to probe release in aqueous solution below and above the cloud point temperature (CPT) of PNIPAm. The release was detected by fluorescence emission given by the probe binding to bovine serum albumin. Also, the colloidal behavior of hydrogel nanoparticles at varying temperatures were examined by scattering method. The probe release was faster below than above the CPT from all the morphologies of which gyroidal morphology showed the highest release. Colloidal behavior varied from single to moderately aggregated particles in order spheres-gyroids-lamellar. Hydrogel nanoparticles with tunable intra particle self-assembled morphologies can be utilized designing carrier systems for drug delivery and diagnostics.

Noncationic Rigid and Anisotropic Coiled-Coil Proteins Exhibit Cell-Penetration Activity.

Numerous cationic peptides that penetrate cells have been studied intensively as drug delivery system carriers for cellular delivery. However, cationic molecules tend to be cytotoxic and cause inflammation, and their stability in the blood is usually low. We have previously demonstrated that a rigid and fibrous cationic coiled-coil protein exhibited cell-penetrating ability superior to that of previously reported cell-penetrating peptides. Making use of structural properties, here we describe the cell-penetrating activity of a rigid and fibrous coiled-coil protein with a noncationic surface. A fibrous coiled-coil protein of pI 6.5 penetrated 100% of the cells tested in vitro at a concentration of 500 nM, which is comparable to that of previously reported cell-penetrating peptides. We also investigated the effect of cell-strain dependency and short-term cytotoxicity.

The use of solid lipid nanoparticles for sustained drug release.

Novel solid lipid drug delivery systems such as solid lipid nanoparticles (SLN) have attracted wide and increasing attention in recent years. It has been sought as an interesting alternative drug delivery carrier system for bioactives for a variety of delivery routes. They show major advantages such as sustained release, improved bioavailability, improved drug incorporation and very wide application. This paper presents a discussion on the production protocols of SLN, lyophilization of SLN and delivery of SLN across the blood-brain barrier. Special attention was also paid to entrapment and release of drugs from SLN and strategies to enhance drug entrapment in SLN for sustained release. Analytical methods for the characterization of SLN were also discussed. Various routes of administration of SLN were presented as well as a consideration of the ethical issues and future prospects in the production and use of SLN for sustained release of bioactives.

Functionalized silica nanoparticles as a carrier for Betamethasone Sodium Phosphate: Drug release study and statistical optimization of drug loading by response surface method.

Mesoporous silica nanoparticles with a hexagonal structure (SBA-15) were synthesized and modified with (3-aminopropyl) triethoxysilane (APTES), and their performance as a carrier for drug delivery system was studied. Chemical structure and morphology of the synthesized and modified SBA-15 were characterized by SEM, BET, TEM, FT-IR and CHN technique. Betamethasone Sodium Phosphate (BSP) as a water soluble drug was loaded on the mesoporous silica particle for the first time. The response surface method was employed to obtain the optimum conditions for the drug/silica nanoparticle preparation, by using Design-Expert software. The effect of time, pH of preparative media, and drug/silica ratio on the drug loading efficiency was investigated by the software. The maximum loading (33.69%) was achieved under optimized condition (pH: 1.8, time: 3.54 (h) and drug/silica ratio: 1.7). The in vitro release behavior of drug loaded particles under various pH values was evaluated. Finally, the release kinetic of the drug was investigated using the Higuchi and Korsmeyer-Peppas models. Cell culture and cytotoxicity assays revealed the synthesized product doesn't have any cytotoxicity against human bladder cell line 5637. Accordingly, the produced drug-loaded nanostructures can be applied via different routes, such as implantation and topical or oral administration.

Development of Rous sarcoma Virus-like Particles Displaying hCC49 scFv for Specific Targeted Drug Delivery to Human Colon Carcinoma Cells

Virus-like particles (VLPs) have been used as drug carriers for drug delivery systems. In this study, hCC49 single chain fragment variable (scFv)-displaying Rous sarcoma virus-like particles (RSV VLPs) were produced in silkworm larvae to be a specific carrier of an anti-cancer drug. RSV VLPs displaying hCC49 scFv were created by the fusion of the transmembrane and cytoplasmic domains of hemagglutinin from influenza A (H1N1) virus and produced in silkworm larvae. The display of hCC49 scFv on the surface of RSV VLPs was confirmed by enzyme-linked immunosorbent assay using tumor-associated glycoprotein-72 (TAG-72), fluorescent microscopy, and immunoelectron microscopy. Fluorescein isothiocyanate (FITC) or doxorubicin (DOX) was incorporated into hCC49 scFv-displaying RSV VLPs by electroporation and specific targeting of these VLPs was investigated by fluorescent microscopy and cytotoxicity assay using LS174T cells. FITC was delivered to LS174T human colon adenocarcinoma cells by hCC49 scFv-displaying RSV VLPs, but not by RSV VLPs. This indicated that hCC49 scFv allowed FITC-loaded RSV VLPs to be delivered to LS174T cells. DOX, which is an anti-cancer drug with intrinsic red fluorescence, was also loaded into hCC49 scFv-displaying RSV VLPs by electroporation; the DOX-loaded hCC49 scFv-displaying RSV VLPs killed LS174T cells via the specific delivery of DOX that was mediated by hCC49 scFv. HEK293 cells were alive even though in the presence of DOX-loaded hCC49 scFv-displaying RSV VLPs. These results showed that hCC49 scFv-displaying RSV VLPs from silkworm larvae offered specific drug delivery to colon carcinoma cells in vitro. This scFv-displaying enveloped VLP system could be applied to drug and gene delivery to other target cells.