Upon activation, T cells of various subsets are the most important mediators in cell-mediated immune responses. Activated T cells play an important role in immune system related diseases such as chronic inflammatory diseases, viral infections, autoimmune disease, transplant rejection, Crohn disease, diabetes, and many more. Therefore, efforts have been made to both visualize and treat activated T cells specifically. This review summarizes imaging approaches and selective therapeutics for activated T cells and gives an outlook on how tracking and treating can be combined into theragnositc agents for activated T cells.
Despite the wide variety of highly potent anti-HIV drugs that have been developed and made available in clinical practice over the years, eradication of HIV infection has not been achieved. Currently, HIV infection and AIDS are thought to be chronically treatable. HIV attacks host immune cells namely macrophages and CD4(+)T-cells and sequesters itself into sanctuary and reservoir sites such as the lymphoid tissues, testes, and brain. Initial drug delivery efforts with prodrugs and drug conjugates focused on improving the physicochemical (i.e. solubility), biopharmaceutic (i.e. absorption, metabolism), and pharmacokinetic (i.e. blood concentrations) properties of the parent drugs. Eradicating HIV, however, will require advanced drug delivery approaches in order to access and maintain effective drug concentrations for prolonged periods of time in sanctuary sites. The current review discusses prodrug/conjugate efforts, clinical successes and describes drug delivery challenges and approaches for eradicating HIV infection.
Facilitation of protein transport across biomimetic polymers and carriers used in drug delivery is a subject of major importance in the field of oral delivery. Quantitative immunofluorescence of epithelial tight junctions can be a valuable tool in the evaluation of paracellular permeation enhancement and macromolecular drug absorption. The tight junctional space is composed of transmembrane protein networks that provide both mechanical support and a transport barrier. Both of these may be affected by drug delivery agents that enhance paracytosis. Imaging is the only tool that can tease apart these processes. A confocal microscopy imaging method was developed to determine the effect of microparticulate poly(methacrylic acid) grafted poly(ethylene glycol) (P(MAA-g-EG)) hydrogel drug carriers on the integrity of claudin-1 and E-cadherin networks in Caco-2 monolayers. Z-stack projection images showed the lateral disruption of tight junctions in the presence of drug carriers. Tight junction image fraction measurements showed more significant differences between membranes exposed to microparticles and a control group. Mechanical disruption was much more pronounced in the presence of P(MAA-g-EG) microparticles as compared to the effect of EDTA.
Tools to selectively and reversibly control gene expression are useful to study and model cellular functions. When optimized, these cellular switches can turn a protein's function "on" and "off" based on cues designated by the researcher. These cues include small molecules, drugs, hormones, and even temperature variations. Here we review three distinct areas in gene expression that are commonly targeted when designing cellular switches. Transcriptional switches target gene expression at the level of mRNA polymerization, with examples including the tetracycline gene induction system as well as nuclear receptors. Translational switches target the process of turning the mRNA signal into protein, with examples including riboswitches and RNA interference. Post-translational switches control how proteins interact with one another to attenuate or relay signals. Examples of post-translational modification include dimerization and intein splicing. In general, the delay times between switch and effect decreases from transcription to translation to post-translation; furthermore, the fastest switches may offer the most elegant opportunities to influence and study cell behavior. We discuss the pros and cons of these strategies, which directly influence their usefulness to study and implement drug targeting at the tissue and cellular level.
Chemotherapy is one of the primary treatment mechanisms for treating cancer. Current chemotherapy is systemically delivered and causes significant side effects; therefore the development of new chemotherapeutic agents or enhancing the effectiveness of current chemotherapeutic could prove vital to patients and cancer care. The purpose of this research was to develop a new conjugate composed of doxorubicin (chemotherapeutic) and inulin (polysaccharide chain) and evaluate its potential as a new therapeutic agent for cancer treatment. The synergistic effect of inulin conjugated to doxorubicin has allowed the same cytotoxic response to be maintained or improved at lower doses as compared to doxorubicin. Supporting results include cytotoxicity profiles, calf thymus DNA binding studies, confocal microscopy, and transport studies.
A pharmacokinetic model is proposed to describe the glucoregulatory process. The model describes the dynamics of glucose, amino acids, and fatty acids, as well as both the hormonal actions and dynamics of insulin, glucagon, epinephrine, and glucagon-like peptide-one. The model was developed assuming that the dynamics of each species occurrs in only one compartment. Several forms of the metabolic absorption and elimination rates, along with possibilities for increasing the complexity of each compartmental model are discussed. Once properly identified and validated, the novel model has the potential to be more descriptive than other models describing glucose dynamics in the body.
Principal components analysis (PCA) and multivariate regression analysis have been employed to study the relationship between a series of calculated physicochemical properties of terpenes (solubility parameter, calculated logKoct, molecular mass, molecular volume, calculated surface tension, scaled H-bonding donor and acceptor values, non-carbonyl carbons per molecule) to the permeation enhancing activity of each terpene for propranolol HCl across newborn pig skin. With PCA, a smaller number of new variables (five principal components) were used as predictors in regression analysis in order to predict the enhancing activity of terpenes on the permeation of the model drug propranolol HCl. A fairly high coefficient of determination (R2 = 0.87) suggested that the resultant regression equation was able to adequately predict trends in the enhancing activity of the terpenes. PCA results suggested the importance of a combination of the physicochemical properties on the enhancing activities of the terpenes. A suitable balance between these terpene properties is required to lead to a considerable enhancement of propranolol HCl penetration.
This review describes the application of customized surface modifications using biomimetic polymers to attempt to reduce unspecific protein adsorption to the materials or promote specific cell adhesion to implants or tissue engineering scaffolds. Various polymers that are suited to suppress almost all unspecific protein interactions and underlying mechanisms of cell adhesion are presented and discussed. Suitable modifications to the inert polymers that can later favor the adhesion of specific cell types are also described. These modifications involve utilizing the binding characteristics of peptide sequences to promote specific cell attachment, and techniques to incorporate these sequences into the polymers are explained. Finally, it is shown that biomimetic surface modification techniques are also of tremendous importance for drug delivery with nanoparticles, and the opportunities and limits associated with these approaches are demonstrated.
The aim of the present study was to compare different regularly used transfection agents, i.e.poly(L-lysine) (PLL), branched poly(ethyleneimine) (BPEI), linear PEI (LPEI), poly(2-(dimethylamino)ethyl methacrylate)(pDMAEMA) and 1,2-dioleyl-3-trimethylammonium-propane (DOTAP), regarding their in vivo transfection behavior after intravenous administration. An attempt was made to study whether the in vitro behavior of these transfectants is relevant for the in vivo situation in terms of their transfection efficiency and serum aggregation properties. In vivo, at an N/P ratio of 5, transfection mediated by the various cationic transfectants mainly occurred in the lungs. The order of decreasing lung transfection was: DOTAP > LPEI > pDMAEMA > BPEI > PLL. Similar rankings were found in in vitro experiments regarding the extent of serum-induced aggregation, suggesting that in vitro studies are certainly relevant for the in vivo situation. As a whole, the in vitro data suggest that the induction of aggregates in the circulation is a major mechanistic factor underlying the phenomenon of dominant lung transfection.
Microporous polycaprolactone (PCL) matrices loaded with hydrophobic steroidal drugs or a hydrophilic drug - pilocarpine hydrochloride - were produced by precipitation casting using solutions of PCL in acetone. The efficiency of steroid incorporation in the final matrix (progesterone (56 %) testosterone (46 %) dexamethasone (80 %)) depended on the nature of the drug initially co-dissolved in the PCL solution. Approximately 90 % w/w of the initial load of progesterone, 85 % testosterone and 50 % dexamethasone was released from the matrices in PBS at 37°C over 8 days. Pilocarpine hydrochloride (PH)-loaded PCL matrices, prepared by dispersion of powder in PCL solution, released 70-90 % of the PH content over 12 days in PBS. Application of the Higuchi model revealed that the kinetics of steroid and PH release were consistent with a Fickian diffusion mechanism with corresponding diffusion coefficients of 5.8 × 10-9 (progesterone), 3.9 × 10 -9 (testosterone), 7.1 × 10-10 (dexamethasone) and 22 × 10-8 cm2/s (pilocarpine hydrochloride). The formulation techniques described are expected to be useful for production of implantable, insertable and topical devices for sustained delivery of a range of bioactive molecules of interest in drug delivery and tissue engineering.
Although numerous drugs are used to treat HIV infection with increasing efficacy, the patient's brain is often infected by the virus and acts as a sanctuary where drugs cannot penetrate due to their low passage through the blood brain barrier. Therefore, the design of new medicine able to reach the brain is extemely challenging. An approach based on prodrug synthesis and encapsulation into PEGylated nanocarriers was proposed and applied to didanosine, a nucleosidic analogue used to treat HIV-1 associated dementia. In this study, appropriate formulations of PEGylated liposomes were designed to incorporate two glycerolipidic prodrugs of didanosine. Preparation methods based on Bangham's or emulsion/evaporation techniques formulations exhibited particle size under 300 nm with high incorporation of prodrugs as shown by light scattering, optical microscopy experiments and differential scanning calorimetry. Finally the uptake of fluorescently labeled PEGylated formulations by rat brain immortalized endothelial cells modeling the BBB was evidence by confocal laser scanning microscopy. All the results suggest that the encapsulation of didanosine prodrugs into PEGylated liposomes is a promising approach in the goal increasing didanosine concentration in the brain and treating HIV-1-associated dementia.
Propolis is a natural resinous substance, with a high polyphenol content, produced by honeybees and characterized by antimicrobial, anti-inflammatory and antioxidant properties, which make it useful for different therapeutic applications, especially in the stomatological field in the treatment of mild buccal diseases. The aim of this study was to prepare some polymeric film formulations for local delivery of propolis into the oral cavity. For this purpose, a commercial propolis fluid extract and three extracts (dry, ethanolic, glyceric) obtained from raw propolis were previously characterized with regard to their polyphenolic fraction composition and their antimicrobial properties against Candida albicans, Escherichia coli and Staphylococcus aureus strains. Commercial fluid extract, judged the most suitable in terms of polyphenol content and antimicrobial activity, was then incorporated into alginate, alginate-chitosan and agar films, prepared using a casting-solvent evaporation technique, which were finally evaluated in terms of thickness, total polyphenol content, in vitro polyphenol release profiles, swelling behaviour and antimicrobial properties. Our results demonstrate that polymeric films can be proposed as new propolis vehicles in the treatment of dental and buccal diseases.
The purpose of this study was to evaluate the effect of cyclosporine (CyA)-cyclodextrin (CD) complex incorporated within PLGA inicrospheres on microsphere characteristics, with particular emphasis on drug release kinetics. For this purpose, microspheres encapsulated with CyA and those loaded by CyA-CD complex were prepared by solvent evaporation and multiple emulsification solvent evaporation methods, respectively. Morphology, size, encapsulation efficiency and drug release pattern from microspheres were evaluated. Also, physicochemical properties of drug inside microspheres were characterized by differential scanning calorimetry (DSC) and infrared spectroscopy (IR) studies. Scanning electron microscopy (SEM) studies showed that microspheres encapsulated with CyA had islands on the microsphere surface but the islands were not seen on the surface of microspheres loaded by complex. Size range varied from 1 to 25 mu m for CyA encapsulated microspheres and 1 to 50 mu m for complex loaded microspheres. The release of CyA was biphasic with an initial more rapid release phase followed by a slower phase but drug release was twice as fast for complex loaded microspheres. IR studies did not indicate any chemical interaction between the components of microspheres and DSC thermograms revealed that CyA was present either in its amorphous state in microspheres or the presence of CyA as an inclusion complex within microspheres loaded by complex. In conclusion, using CyA as an inclusion complex with CD within microspheres can affect microsphere characteristics and drug release and it is possible to modify microsphere properties like drug release by incorporating CDs as complexing agents.
Cyclodextrins are cyclic oligosaccharides that are able to form water-soluble complexes with many lipophilic drugs. Thus, through cyclodextrin complexation it is possible to formulate lipophilic water-insoluble drugs as aqueous eye drop solutions. The ocular barrier to topical drug delivery into the eye consists of the aqueous tear film and lipophilic epithelium, and most drugs permeate this barrier via passive diffusion. Cyclodextrins enhance permeation of lipophilic drugs through the aqueous tear film to the epithelial surface increasing drug availability immediately to the membrane surface. However, since hydrophilic cyclodextrins and cyclodextrin complexes do not readily permeate lipophilic membranes, excess amounts of cyclodextrin will hamper drug penetration into the eye. Cyclodextrins frequently reduce drug delivery of hydrophilic drugs.
Nanosuspension has been widely used to improve the bioavailability of poorly soluble drugs. ZL-004, a promising small molecular compound with the function of raising counts of white blood cells, was developed to nanosuspensions to solve the low solubility and bioavailability by the precipitation method. The effects of the important factors (THF/Water ratio, Tween-80, PEG 400) on the particle size were investigated by a central composite design. After freeze drying, with 6% sucrose as protective agent, a 399 ± 20 nm nanosuspension (NS-A) and a 208 ± 14 nm nanosuspension (NS-B) were obtained with good appearances, rapid redispersity, and stable particle sizes. The morphology and crystal forms were evaluated by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). In vitro release test proved that the solubility and dissolution rate were improved by reducing the particle size. In vivo pharmacokinetic study and tissue distribution study in rats showed that particle size affected the pharmacokinetic behavior significantly by different accumulation in reticuloendothelial system (RES). NS-A with a larger particle size was captured and accumulated more in RES, achieving higher t1/2 and MRT; NS-B with a smaller particle size was captured and accumulated less in RES, achieving higher AUC and Cmax.
The incidence and prevalence of spinal cord injury (SCI) as a high disabling injury have enc ouraged the researchers to find some therapeutic strategies. The spinal cord is highly sensitive to oxidative stress and maintaining homeostasis is essential for redox status in neurons. Therefore, in this study. On the other hand, the application of drugs can induce some unwanted effects on the viability of neurons. Therefore, in this study, 1,2-benzisoxazole-3-methanesulfonamide (zonisamide) as a second-generation antiepileptic drug was formulated by micelles and characterized by TEM and DLS techniques. Afterwards the protective effects of 1,2-benzisoxazole-3-methanesulfonamide-loaded micelles against stimulated oxidative stress and cytotoxicity were assessed by MTT, ROS, staining and enzyme activity assays. It was shown that the fabricated 1,2-benzisoxazole-3-methanesulfonamide-loaded micelles with a size of about 60-90 nm have a good colloidal stability and show a sustained drug release at physiological pH. Furthermore, it was determined that the neuroprotective effects of 1,2-benzisoxazole-3-methanesulfonamide-loaded micelles against cytotoxicity, ROS production, morphological changes, caspase-3 activation triggered by H2O2 was more pronounced than non-formulated drug. In conclusion, this study may provide useful information regarding the advancement of therapeutic approach for treatment of SCI.
Benzodiazepines form a class of drugs that are used to treat wide variety of conditions such as anxiety, seizures, and insomnia. In general, benzodiazepines are lipophilic and poorly soluble in water at physiologic pH, and when solubilized undergo hydrolytic degradation. Thus, marketed products containing solubilized benzodiazepines most often consist of organic solvents or aqueous solutions containing relatively high concentrations of organic cosolvents and surfactants. There is however one exception. Midazolam injection is essentially pure aqueous solution of midazolam, unbuffered at pH of about 3 and shelf-life of over 2 years at room temperature. While most benzodiazepines form an unstable protonated ring-open form at acidic pH, the ring-open form of midazolam is both relatively stable and water-soluble. Still, for more concentrated midazolam solutions, such as nasal spray, organic solvents have been used. Benzodiazepines can be solubilized through formation of water-soluble cyclodextrin complexes but in spite of numerous successful clinical studies in humans, as well as in vivo studies in animals, no benzodiazepine/cyclodextrin formulations have reached the market. Here the chemistry of 1,4-benzodiazepines, their unusual degradation pathways and solubility in water is reviewed.
Emphysema is a type of chronic obstructive pulmonary disease (COPD) usually leading to difficulty breathing. It is highly in need of effective interventions to prevent airspace damage and stretch. Herein, we studied the protective effect of 1,8-cineole (CIN) on porcine pancreatic elastase (PPE)-induced emphysema in mice via quantitative pulmonary administration. To overcome the volatility, instability and poor water solubility of CIN that limits its pharmacological activities in vivo, a hyaluronic acid (HA)-coated liposome was prepared to encapsulate CIN (Lipo/[email protected]), which facilitated the delivery of CIN to lung tissue and improved its therapeutic effect for emphysema. A MicrosprayerⓇ aerosolizer was used to deliver free CIN and its liposomal preparations every other day for four weeks and evaluate the therapeutic effects on emphysema in mice. The results clearly showed that CIN significantly reduced the level of inflammation and oxidative stress, resulting in less lung cell apoptosis. Compared with the free CIN and Lipo/CIN, Lipo/[email protected] exhibited superior protective effects on mice to prevent the PPE-induced emphysema. Furthermore, the therapeutic mechanisms were verified to be mainly mediated by Nrf2/NQO1 and NF-κB/IκBα pathways. In conclusion, quantitative pulmonary administration of CIN could alleviate the progression of emphysema and the therapeutic effects were further improved by the HA-coated liposome carrier.
A clinical study was performed to determine the in vivo mass loss of both lozenges in 16 healthy volunteers. In vitro, mass loss over time was measured for both formulations and correlated to the release of CPC and benzocaine. In vivo, the oral mass loss profiles of both lozenges were similar, with a mean difference between the two curves, up to the first point greater than 85% of 3.2%, and a f2 similarity factor of 69%. In vitro, the mass loss of both lozenges was similar and a strong correlation between mass loss and release of CPC and benzocaine was observed, indicating that the active ingredients were homogeneously dispersed within the lozenges. Based on the results, it was possible to establish a link between the in vitro and in vivo drug release and mass losses using an in vitro–in vivo correlation (IVIVC). In vivo release profiles of benzocaine and CPC were calculated and found to be similar for the sugar-free and sugared lozenges; more than 85% of the active ingredients were released in 186 and 209 s, respectively. These results suggest that in vitro mass loss and corresponding drug release is an adequate surrogate for bioequivalence studies, waiving their need for lozenges with excipient changes, and that the clinical risk–benefit profile of sugar-free CPC/benzocaine (1.4 mg/10 mg) lozenges is unlikely to differ from sugared lozenges.
Nanocrystal technology is a common strategy to enhance the oral bioavailability of poorly-soluble drugs, and how to enlarge the enhancing ability on oral absorption via nanocrystals has become a pharmaceutical research field. In this study, we selected andrographolide (ADR), a typical poorly-soluble drug, as the model drug, and employed sodium dodecyl sulfate and D-ɑ-Tocopherol polyethylene glycol 1000 succinate copolymer (SDS-TPGS) to construct novel SDS-TPGS modified andrographolide nanocrystals (S-TANs). We found that the particle sizes of SDS/TPGS physical mixture modified nanocrystals (STANs) were about 553.4 ± 4.1 nm, while that of SDS-TPGS modified nanocrystals (S-TANs) were 604.6 ± 5.7 nm. During the production process of nanocrystals, the crystallinity of ADR was slightly decreased. Nanocrystals enhanced the saturation solubility of ADR, and improved oral absorption, Cmax and AUC0-∞ of S-TANs was about 2.10 and 1.24 fold increased, STAN about 2.63, 2.97 fold. In a Real-time distribution study, we found the distribution time of andrographolide, SDS and TPGS in SDS/TPGS physical mixture modified nanocrystals system varies widely, while the distribution times of these materials were similar in SDS-TPGS copolymer modified nanocrystals system. These results indicated that modified with functional stabilizer was an efficient strategy to enlarge the enhancing ability on oral absorption of nanocrystals, and synthesized copolymer containing different functional stabilizers showed higher ability on enhancing oral bioavailability than physical mixtures.
In this study, a new formulation of miRNA-loaded cationic liposomes (CLs) was prepared for bone marrow cells. CLs and miRNA-loaded cationic liposomes (CL/miR-101) were prepared and their characteristics were assessed using Dynamic light scattering (DLS) technique. MTT assay was used for bone marrow cell lines (KG-1 and HBMF-SPH cell lines) to evaluate cytotoxicity of CLs and CL/miR-101. The results have shown that the size and charge of the prepared CLs with new formulation were 84.5 nm and 20.1 mV and for CL/miR-101 were 126.6 nm and 4.31 mV. MTT assay results have demonstrated that different concentrations of CLs had no obvious cytotoxicity in both KG-1 and HBMF-SPH cells. The cytotoxicity of CL/miR-101 was approximately 12% more than the bare miRNA-101 in KG-1 cells and comparatively less significant amount of cytotoxicity was seen in HBMF-SPH cells. In this study, a new formulation of cationic liposome was successfully designed to deliver miRNA into bone marrow cells effectively. The suitable size and charge of CLs made them capable to form efficient CL/miR-101 complex, which was stable and penetrated significantly into the cells. CL/miR-101 complex proved to be cytotoxic for cancer cells and hence can be considered as a novel gene therapy system.
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).
This article has been retracted at the request of the editor as one of the named authors (Liang Zhang) has plagiarized part of a paper that had already appeared in Nanomaterials 2018, 8(2), 126 (https://doi.org/10.3390/nano8020126). One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and has not appeared in a publication elsewhere. Re-use of any data should be appropriately cited. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.
The editor would like to add that there are indications that this manuscript was submitted by Liang Zhang without the knowledge of the other named authors, Yue Zhang, Yan Du, Jing Wang, Lijun Chi. If the submission happened without their knowledge, then they are not at fault for this retraction.