Carriers For Drug Delivery Systems Research Articles

CYCLODEXTRIN IN DRUG DELIVERY APPLICATION: A REVIEW

The cyclodextrins have a wide range of applications in various areas of drug delivery and pharmaceutical industry due to their complexation ability and other versatile characteristics. The most popular pharmaceutical application of cyclodextrin is to increase the solubility, stability, safety and bioavailability of drug molecules. The idea of this review article is to solve and study any of the findings and application of cyclodextrin (CD) and their derivatives in different areas of drug delivery. This review article introduce the molecular structure, properties like complexation, solubility etc. of cyclodextrins and targeted on its use for parenteral, oral, ophthalmic and nasal drug delivery. Other routes including dermal, rectal, sublingual and pulmonary delivery are again briefly addressed. The aim of this contribution is to focus on the potential application of chemically altared cyclodextrins as high-performance drug carriers in drug delivery systems with emphasis on the other recent developments. Thus cyclodextrins, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different other novel drugs through different delivery routes.
 Keywords: Cyclodextrin, complexing agents, bioavailability, industrial application

Design and evaluation of anti-fibrosis drug engineered resealed erythrocytes for targeted delivery.

Resealed erythrocytes (RSE) are potential, site-specific carrier system for drug delivery with prolonged drug release activity. In this study, erythrocytes obtained from Wistar albino rats were loaded with ambroxol hydrochloride (AH) with the focus to convenience the lung targeting possibility of the carrier erythrocytes. AH loading in erythrocytes using preswell dilution technique with glutaraldehyde (GA) as a cross-linking agent was evaluated and validated. Drug-loaded erythrocyte was characterized in terms of in vitro drug release followed by osmotic fragility study which showed amplified drug entrapment efficiency (DEE) and hemoglobin content values as well. In vivo lung fibrosis study, rats were sensitized to egg albumin by intraperitoneal (i.p.) injection and then inhalation in a whole body inhalation chamber. A sign of inflammation, airway sub-mucosal fibrosis, hypertrophy, and hyperplasia was observed. A series of in vivo studies were carried out to describe the effect of AH-loaded RSE including measurement of cytokines in Bronchoalveolar Lavage (BAL) fluid and histopathology study. AH showed a stepwise reduced level of cytokines in BAL at a different time interval after being injected of AH-loaded RSE. Furthermore, in vivo lung distribution experiments were performed for optimized formulation, and degree of distribution of the drugs inside the targeted organ was found to be satisfactory.

Effects of preparation methods on the characteristics of niosomes

Niosomes are colloidal vesicles that capable of encapsulating drugs as a carrier for drug delivery system. They are formed by self-assembly of a non-ionic surfactant with cholesterol and co-surfactant. In this work, cinnarizine-containing niosomes comprised of sorbitan monostearate (Span® 60), cholesterol and co-surfactant (Cremophor® ELP, Cremophor® RH40 or Solutol® HS15) were prepared using conventional thin film hydration and microfluidic methods. Effects on characteristics of niosomes with the presence of poorly water-soluble drug, cinnarizine in the niosomal formulations prepared using different methods and incorporation of different co-surfactants were studied and compared for their particle size, polydispersity index (PDI) and encapsulation efficiency. Dynamic light scattering was employed for particle size measurements and drug loading studies were analysed using high performance liquid chromatography (HPLC). The morphology of niosomes was characterized using optical light microscopy.

Evaluation of hydroxyapatite nanoparticles - induced in vivo toxicity in Drosophila melanogaster

Hydroxyapatite (HAp), a compound similar in composition to human hard tissues such as bone and teeth, has widespread applications in bulk as well as nanoparticle form in numerous fields due to excellent biocompatibility and stability. The increased use of this nanoparticle thus warrants the study of its toxic potential in in vivo models. In this study, the toxicity induced by HAp NPs administered via the oral route using Drosophila as an in vivo model was investigated. Biochemical assays such as lipid peroxidation and nitro blue tetrazolium assay did not reveal toxicity at lowest (10 μg/ml) as well as highest (1000 μg/ml) doses. The HAp nanoparticle-treated flies and larvae did not exhibit signs of behavioral change as evidenced from the negative geotaxis assay and larvae crawling assay, respectively. Survival assay to assess the chronic toxicity of HAp nanoparticles also did not reveal any signs of toxicity at both lowest and highest doses. This demonstrates that hydroxyapatite nanoparticles do not elicit significant in vivo toxicity. Considering the paucity of studies available to support the non-toxic effect of HAp nanoparticles, further investigations are warranted in Drosophila and other in vivo models. Moreover, such HAp nanoparticles can also serve as reliable carrier for drug delivery system.

Monocyte as an Emerging Tool for Targeted Drug Delivery: A Review.

Monocytes are leading component of the mononuclear phagocytic system that play a key role in phagocytosis and removal of several kinds of microbes from the body. Monocytes are bone marrow precursor cells that stay in the blood for a few days and migrate towards tissues where they differentiate into macrophages. Monocytes can be used as a carrier for delivery of active agents into tissues, where other carriers have no significant access. Targeting monocytes is possible both through passive and active targeting, the former one is simply achieved by enhanced permeation and retention effect while the later one by attachment of ligands on the surface of the lipid-based particulate system. Monocytes have many receptors e.g., mannose, scavenger, integrins, cluster of differentiation 14 (CD14) and cluster of differentiation 36 (CD36). The ligands used against these receptors are peptides, lectins, antibodies, glycolipids, and glycoproteins. This review encloses extensive introduction of monocytes as a suitable carrier system for drug delivery, the design of lipid-based carrier system, possible ways for delivery of therapeutics to monocytes, and the role of monocytes in the treatment of life compromising diseases such as cancer, inflammation, stroke, etc.

Planar lipid bilayers formed from thermodynamically-optimized liposomes as new featured carriers for drug delivery systems through human skin

The fundamental objective pursued in this work is to investigate how liposomes formed with a thermodynamically optimized molar composition formed by the main components of the stratum corneum matrix behave on the human skin surface when used as drug delivery systems. To this purpose we engineered liposomes using phosphatidylcholines, ceramides and cholesterol. The specific molar ratio of the three components was established after studying the mixing properties of the lipid monolayers of the lipid components formed at the air–water interface. Liposomes loaded and unloaded with ibuprofen and hyaluronic acid were characterized by quasi-elastic light scattering and fluorescence polarization. Optimized liposomes, with and without drugs, were applied onto human skin and the structures formed evaluated using atomic force microscopy. Since penetration enhancers improve the permeation of the drugs encapsulated, we also examined the effects of Tween® 80 on the physical properties of the liposomes and on their extensibility over skin.In the present work we were able to observe the deposition and extension of liposomes in suspension onto human skin demonstrating the potential of liposomes without a secondary vehicle for releasing drugs in transdermal applications.

Osteogenic Enhancement Between Icariin and Bone Morphogenetic Protein 2: A Potential Osteogenic Compound for Bone Tissue Engineering.

Icariin, a typical flavonol glycoside, is the main active component of Herba Epimedii, which was used to cure bone-related diseases in China for centuries. It has been reported that Icariin can be delivered locally by biomaterials and it has an osteogenic potential for bone tissue engineering. Biomimetic calcium phosphate (BioCaP) bone substitute is a novel drug delivery carrier system. Our study aimed to evaluate the osteogenic potential when Icariin was internally incorporated into the BioCaP granules. The BioCaP combined with Icariin and bone morphogenetic protein 2 (BMP-2) was investigated in vitro using an MC3T3-E1 cell line. We also investigated its efficacy to repair 8 mm diameter critical size bone defects in the skull of SD male rats. BioCaP was fabricated according to a well-established biomimetic mineralization process. In vitro, the effects of BioCaP alone or BioCaP with Icariin and/or BMP-2 on cell proliferation and osteogenic differentiation of MC3T3-E1 cells were systematically evaluated. In vivo, BioCaP alone or BioCaP with Icariin and/or BMP-2 were used to study the bone formation in a critical-sized bone defect created in a rat skull. Samples were retrieved for Micro-CT and histological analysis 12 weeks after surgery. The results indicated that BioCaP with or without the incorporation of Icariin had a positive effect on the osteogenic differentiation of MC3T3-E1. BioCaP with Icariin had better osteogenic efficiency, but had no influence on cell proliferation. BioCap + Icariin + BMP-2 showed better osteogenic potential compared with BioCaP with BMP-2 alone. The protein and mRNA expression of alkaline phosphatase and osteocalcin and mineralization were higher as well. In vivo, BioCaP incorporate internally with both Icariin and BMP-2 induced significantly more newly formed bone than the control group and BioCaP with either Icariin or BMP-2 did. Micro-CT analysis revealed that no significant differences were found between the bone mineral density induced by BioCaP with icariin and that induced by BioCaP with BMP-2. Therefore, co-administration of Icariin and BMP-2 was helpful for bone tissue engineering.

Protein Nanoparticle Fabrication for Optimized Reticuloendothelial System Evasion and Tumor Accumulation.

Nanoparticles (NPs) of protein-based materials have become one of the most promising candidates for drug carriers in drug-delivery systems because of their in vivo nontoxicity, biodegradability, compatibility with hydrophilic drugs, and adaptability to the human body. Many studies have investigated the fabrication of protein NPs from human serum albumin (HSA) as a new drug carrier. It is important for these NPs to remain in the blood until they reach their therapeutic target to achieve the desired effect; the quicker the clearance of drugs from the body, the shorter is the residence time of drugs in the body, which eventually reduces drug efficacy. Macrophage uptake is a major mechanism for clearance of NPs from the body, so, reducing the degree of macrophage uptake is a major challenge in drug-delivery systems. Original studies of HSA NP uptake by macrophages showed that denatured HSA and HSA NPs synthesized with 80% (v/v) ethanol showed a high degree of macrophage uptake. We found that HSA NPs synthesized with lower ethanol content at pH 7 showed lower macrophage uptake in in vitro macrophage cellular uptake experiments. The effects of the preparation parameters of ethanol concentration, pH, and glutaraldehyde on the macrophage uptake of NPs were thoroughly studied. This newly developed protein NP with lower macrophage uptake has potential application as a drug carrier for many delivery systems.

Microalgae: Therapeutic Applications of Phytoplankton, with an Emphasis on Diatoms and Coccolithophores (Adv. Therap. 2/2019)

In article number adtp.201800099, Mihai Lomora, Abhay Pandit and co-workers summarize a range of therapeutic applications involving various phytoplankton. Intricate structures are harvested from microalgae for surface functionalization as carrier systems for drug delivery, in diagnostics, or cell anchoring. Phytoplankton represent a rich source of metabolites allowing the discovery of bioactive compounds, or as a source of oxygen for autotrophic tissue engineering.

Antimicrobial activity evaluation for gentamicin loaded PLA microspheres

Abstract Poly(lactic) acid (PLA) is well known as a drug carrier in drug delivery system. Double emulsion and solvent evaporation technique was used to encapsulate gentamicin within PLA microspheres. The ability of PLA microspheres to encapsulate gentamicin was investigated at three different wt%; 0.125%, 0.25% and 0.375%. The highest encapsulation efficiency (42.3%) and drug loading (26.5x10-3%) was observed at 0.375 wt% gentamicin loaded. For antimicrobial assay, the diameter for zone of inhibition was measured and compared for each wt% of gentamicin used. This evaluation was done to determine the effectiveness of gentamicin delivery from the PLA microspheres to inhibit the growth of Staphylococcus aureus. The higher wt% of gentamicin loaded into the PLA microspheres, the larger the diameter for zone of inhibition was obtained with the highest diameter at 0.375 wt% (2.3 cm). The study showed that the PLA is having potential to serve as a slow and sustained release drug delivery vehicle since the inhibition zone only can be measured after day 3 of incubation.

New Biocompatible Mesoporous Silica/Polysaccharide Hybrid Materials as Possible Drug Delivery Systems.

A high number of studies support the use of mesoporous silica nanoparticles (MSN) as carriers for drug delivery systems due to its high biocompatibility both in vitro and in vivo, its large surface area, controlled pore size and, more than this, its good excretion capacity from the body. In this work we attempt to establish the optimal encapsulation parameters of benzalkonium chloride (BZC) into MSN and further study its drug release. The influence of different parameters towards the drug loading in MSN such as pH, contact time and temperature were considered. The adsorption mechanism of the drug has been determined by using the equilibrium data. The modification process was proved using several methods such as Fourier transform-infrared (FT-IR), ultraviolet-visible (UV-VIS), X-ray photoelectron spectroscopy (XPS) and thermogravimetric analysis (TGA). Since MSN shows a lower drug release amount due to the agglomeration tendency, in order to increase MSN dispersion and drug release amount from MSN, two common biocompatible and biodegradable polymers were used as polymer matrix in which the MSN-BZC can be dispersed. The drug release profile of the MSN-BZC and of the synthesized hybrid materials were studied both in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Polymer-MSN-BZC hybrid materials exhibit a higher drug release percent than the pure MSN-BZC when a higher dispersion is achieved. The dispersion of MSN into the hybrid materials was pointed out in scanning electron microscope (SEM) images. The release mechanism was determined using four mathematic models including first-order, Higuchi, Korsmeyer–Peppas and Weibull.

Advances in the application of poly(ethylenimine) conjugated bio- reducible dendrimers for gene delivery systems

The bio-reducible dendrimers containing poly(ethylenimine) and disulfides are interested in gene delivery systems as carrier for gene therapy. The synthesisand characterization of poly(ethylenimine) conjugated polymers has been reviewed for the development of gene delivery systems. The linear PEIs and branched PEIs of bio-reducible dendrimers have briefly introduced in this paper. The preparation and application of poly(ethylenimine)s conjugated bio-reducible dendrimers are also discussed for the discovery of gene delivery systems. The bio-reducible poly(ethylenimine)s dendrimers have a great potential as gene carriers in drug delivery systems. It has reported that the bio-reducible PEIs branched dendrimers have a great potential as a gene delivery system consisting of PEI (1.8kDa) with disulfide bonds.

Quantitative Structure-Property Relationship for pH-Triggered Drug Release Performance of Acid-Responsive Four/Six-Arms Star Polymeric Micelles.

The pH-responsive copolymer micelles are widely used as carriers in drug delivery system, but there are few micro-level mechanistically explorations on the pH-triggered drug release. Here we elucidate the relationship between drug release behavior of four/six-arms star copolymer micelles and the copolymer structures. The net cumulative drug release percentage (En) was taken as the dependent variables, block unit autocorrelation descriptors as independent variables. The quantitative structure-property relationship models of drug release from block copolymers were developed at pH7.4 and 5.0 of two periods (stage I: 0~12h, stage II: 12~96h). The models built are of good fitting ability, internal predictive ability, stability and statistically significance. Drug diffusion is mainly influenced by the intra-block force, and micellar erosion by inter-block force. At pH5.0, lowest unoccupied molecular orbital energy of copolymer unit is the main factor influencing the En. Stage I of drug release is affected by hydrophobic property and stage II by regional polar of copolymer molecules. The models present good performance, factors affecting drug release behavior at different pH conditions can offer guidance for the design of copolymer structures to control the drug release behavior of micelles in a targeted and quantitatively way.

Multimetal organic frameworks as drug carriers: aceclofenac as a drug candidate.

BackgroundMultimetal organic frameworks (M-MOFs) were synthesized by including a second metal ion with the main base metal in the synthesis process to enhance their applications for drug delivery. Aceclofenac (ACF), a nonsteroidal anti-inflammatory analgesic drug of low aqueous solubility, was selected as a candidate for the drug delivery systemPurposeThis study aimed to evaluate the loading capacity (LC) and entrapment efficiency (EE) percentages of multi-Material of Institute Lavoisier (MIL)-100(Fe) (M-MIL-100(Fe)) for ACF.Materials and methodsHydrothermal synthesis procedure was used to prepare multi-MIL-100(Fe) samples (Zn I-MIL-100(Fe), Zn II-MIL-100(Fe), Ca I-MIL-100(Fe), Ca II-MIL-100-(Fe), Mg I-MIL-100(Fe), Mg II-MIL-100(Fe), Mn I-MIL-100(Fe), and Mn II-MIL-100(Fe)). The characterization of M-MIL-100(Fe) samples was evaluated by X-ray powder diffraction (XRD), Fourier transform infrared spectra, scanning electron microscope (SEM), TGA, and N2 adsorption isotherms. The LC of M-MIL-100(Fe) and EE of ACF were determined. Nuclear magnetic resonance (NMR) and zeta-potential analyses were employed to confirm qualitatively the drug loading within M-MIL-100(Fe).ResultsThe ACF LC of MIL-100(Fe) was 27%, whereas the LC of M-MIL-100(Fe) was significantly increased and ranged from 37% in Ca I-MIL-100(Fe) to about 57% and 59% in Mn II-MIL-100(Fe) and Zn II-MIL-100(Fe), respectively. The ACF@M-MOFs release profiles showed slow release rates in phosphate buffer solutions at pH 6.8 and 7.4 as compared to the ACF@MIL-100(Fe).ConclusionTherefore, M-MOFs showed a significant potential as a carrier for drug delivery systems.

Evaluation of a New Hydroxyapatite Nanoparticle as a Drug Delivery System to Oral Squamous Cell Carcinoma Cells.

Due to its abilities of substance adsorption and intracellular transportation, hydroxyapatite is a potential carrier in drug delivery systems (DDS). This in vitro study investigated whether newly-developed, highly-dispersive calcined hydroxyapatite nanoparticles with an average grain diameter of 20 nm (nano-SHAP) were suitable as a DDS for the drugs zoledronic acid (ZA), cisplatin, and carboplatin. The effects of drug-bearing nano-SHAP on cell proliferation were assessed using three human oral squamous cell carcinoma cell lines (HSC-4, KOSC, and SAS) and one human breast cancer cell line (MCF-7). Nano-SHAP alone did not affect proliferation of any cell line until a concentration of 1 μg/ml was reached. Although the effective concentration of ZA in ZA-bearing nano-SHAP differed, it inhibited cell proliferation better than ZA alone. Cisplatin and carboplatin-bearing nano-SHAP had the same effect as these drugs alone. The nano-SHAP system is of potential use as a drug delivery system.

Smart pH-Sensitive Nanogels for Controlled Release in an Acidic Environment.

The encapsulation of therapeutic compounds into nanosized delivery vectors has become an important strategy to improve efficiency and reduce side effects in drug delivery applications. Here, we report the synthesis of pH-sensitive nanogels, which are based on the monomer N-[(2,2-dimethyl-1,3-dioxolane)methyl]acrylamide (DMDOMA) bearing an acid cleavable acetal group. Degradation studies revealed that these nanogels hydrolyze under acidic conditions and degrade completely, depending on the cross-linker, but are stable in physiological environment. The best performing system was further studied regarding its release kinetics using the anticancer drug doxorubicin. In vitro studies revealed a good compatibility of the unloaded nanogel and the capability of the doxorubicin loaded nanogel to mediate cytotoxic effects in a concentration and time-dependent manner with an even higher efficiency than the free drug. Based on the investigated features, the presented nanogels represent a promising and conveniently prepared alternative to existing carrier systems for drug delivery.

Controlling the degradation of an oxidized dextran-based hydrogel independent of the mechanical properties

The objective of this study is to control and elucidate the mechanism of molecular degradation in a polysaccharide hydrogel. Glycidyl methacrylate (GMA) immobilized dextran (Dex-GMA) was oxidized by periodate to introduce aldehyde groups (oxidized Dex-GMA). The hydrogel was formed by the addition of dithiothreitol to the oxidized Dex-GMA solution through thiol Michael addition with the preservation of the aldehyde group for degradation points. It was experimentally determined that the degradation of this hydrogel can be controlled by the addition of amino groups and the speed of degradation can be controlled independently of mechanical properties because crosslinking and degradation points are different. In addition, the molecular mechanism of the crosslinking between the thiol and aldehyde groups was found to control the degradation of dextran derivatives. It is expected that these results will be beneficial in the design of polymer materials in which the speed of degradation can be precisely controlled. In addition, the cytotoxicity of oxidized Dex-GMA was approximately 3000 times lower than that of glutaraldehyde. The low cytotoxicity of the aldehyde in oxidized Dex-GMA was the likely reason for the harmless functionalized polysaccharide material. Possible future clinical applications include cell scaffolds in regenerative medicine and carriers for drug delivery systems.

Heteroatom modified MCM-41-silica carriers for Lomefloxacin delivery systems

Abstract The paper presents novel Lomefloxacin delivery systems based on heteroatom modified MCM-41-type silica materials. The modification of MCM-41 mesoporous silica with Mg, Fe, Ce or Zn was performed by ion-exchange approach and the resulted materials exhibited an ordered pore framework, high specific surface area (in the range of 510–813 m2/g), total pore volume (from 0.47 to 0.96 cm3/g), and uniform distribution of heteroatoms, which allow their use as carriers in drug delivery systems. The heteroatom modification of MCM-41 silica led either to the formation of amorphous metal oxide on the inner pore surface in the case of Mg and Zn, or materials with a crystalline oxide phase (CeO2 or Fe2O3) on the silica surface. The drug release profiles from heteroatom modified MCM-41 carriers were determined in simulated body fluid pH 7.4 and all Lomefloxacin-loaded samples exhibited a slower release kinetics than the antibiotic dissolution, the lowest delivery rate being obtained for Mg-modified MCM-41 material. All the prepared antibiotic delivery systems presented good bactericide activity against E. coli strain.

A Soft Magnetic Core can Enhance Navigation Performance of Magnetic Nanoparticles in Targeted Drug Delivery

Magnetic nanoparticles (MNPs) are a promising candidate for use as carriers in drug delivery systems. A navigation system with real-time actuation and monitoring of MNPs is inevitably required for more precise targeting and diagnosis. In this paper, we propose a novel electromagnetic navigation system with a coil combined with a soft magnetic core. This system can be used for magnetic particle imaging (MPI) and electromagnetic actuator functions with a higher steering force and enhanced monitoring resolution. A soft magnetic core with coils can increase the magnetic gradient field. However, this also generates harmonic noise, which makes it difficult to acquire MNP monitoring signals with MPI. Therefore, the use of amplitude modulation magnetic particle imaging (AM MPI) is suggested. AM MPI uses a low-amplitude excitation field combined with a low-frequency drive field. Using this system, the measured signal becomes less sensitive to the soft magnetic core. Based on the new MPI scheme and the combination of the coil with the magnetic cores, the proposed navigation system can implement one-dimensional (1-D) MNP navigation and 2-D MPI. The proposed navigation system can shorten the 1-D guidance time by about 25% for MNPs in the size range of 45–60 nm and give an improved 2-D imaging resolution of 43%, compared with an air-coil structure.

Inclusion of Curcumin in β-cyclodextrins as Potential Drug Delivery System: Preparation, Characterization and Its Preliminary Cytotoxicity Approaches

The development and application of organic based drug carrier in drug delivery system (DDSs) with greater efficacy and fewer side effects remains a significant challenge in modern scientific and medical research. The aim of current study was to evaluate the ability of β-cyclodextrin (β-CD) as drug delivery carrier to encapsulate Curcumin (CUR), a promising chemotherapeutic that exhibits low aqueous solubility and poor bioavailability forming inclusion complex by kneading method to enhance its delivery to cancer cells. Different methods and analysis such as Fourier Transform Infrared (FTIR) spectrometer, 1 H Nuclear Magnetic Resonance ( 1 H NMR), X-Ray Diffraction (XRD), Scanning Electron Microscope (SEM) and Thermo-gravimetric Analysis (TGA) were employed to approve the successful formation of the inclusion complex where the aromatic ring of CUR has been encapsulated by the hydrophobic cavity of β-CD. UV absorption indicated that β-CD complex with CUR with an apparent formation constant of 1.09 × 10 -8 mol -1 dm -3 . Based on the data obtained by methylthiazole tetrazolium (MTT), β-CD showed that not only did it enhanced Curcumin delivery, but it also improved and promoted the anti-proliferative effect of CUR during the complexation rather than CUR alone on the MCF-7 human breast cancer cells at 24 h incubation period with IC 50 lower than that of Curcumin alone. The toxicities of the β-CD-CUR towards MCF-7 cells were also compared to the free tamoxifen, Curcumin and β-CD. This study provides a preliminary toxicity evaluation based on β-CD-CUR inclusion complex as potential delivery system towards the selected cancer cells.