Can Carbon Quantum Dots (CQDs) or Boron Compounds be an Ultimate Solution for COVID-19 Therapy?

Severe acute respiratory syndrome (SARS) is an infectious and highly transmissible disease that is affected by SARS coronavirus (SARS-CoV) and for which there are presently no approved treatments. COVID-19 is a new strain of coronavirus that has not been previously identified in humans. It is also a member of the coronaviruse family and known to cause similar illnesses in humans. The last outbreak has been identified as a Pandemic because of COVID-19 infections in humans. This review has been prepared to give some information to readers or scientists about some new generation of boron-doped or boron attached composite quantum dots during the design phase of the drug or drug delivery systems to be developed to combat COVID-19 and to help in the design of new drugs and systems by opening some new horizons. All scientists and researchers must quickly share their ideas and experiences in the fight against COVID-19 to find a better therapy or strategy for humans, and thus we can be successful. In this sense, this review offers readers some new ideas and rational perspectives. In conclusion, boron-containing composite carbon quantum dots appear to be the most suitable delivery system for treating COVID-19 infections especially when they are delivered through the lung.

Development and validation of highly selective method for the determination of imatinib mesylate and dexketoprofen trometamol combination in three different media

Imatinib mesylate is a small molecule used in cancer therapy as a thyrosine kinase inhibitor. Dexketoprofen trometamol is a non-steroidal anti-inflammatory drug that has seen use in cancer therapy in combination with an anticancer drug to minimize tumor size and to reduce pain in patients. In the present study, imatinib mesylate and dexketoprofen trometamol were selected as potential model drugs to be used in combination. A new, simple and selective Ultra Performance Liquid Chromatography method was developed and validated to determine the drug substances in distilled water, in a pH 7.4 phosphate buffer and in Dulbecco's Modified Eagle Medium. The proposed method was developed using a BEH C-18 column with isocratic elution. A mixture of methanol:acetonitrile (80:20, v/v) and pH 9.5, 0.05 M ammonium acetate were (70:30, v/v) used as a mobile phase. Detection was carried out with a flow rate of 0.3 mL/min, a column temperature of 30°C and an injection volume of 20 µL. The method was validated considering linearity, accuracy, precision, specificity, robustness, detection limit and quantitation limit values, and was found to be linear in a range from 0.05 to 20.0 µg/mL for the three different media

Efficacy of targeted liposomes and nanocochleates containing imatinib plus dexketoprofen against fibrosarcoma.

The main challenges in treating cancer using chemotherapeutics are insufficient dose at the target site and the development of drug resistance, while higher doses can induce side effects by damaging nontarget tissues. Combinatorial drug therapy may overcome these limitations by permitting lower doses and more specific targeting, thereby mitigating drug resistance and nontarget side effects. Recent reports indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer potential and can be used together with conventional chemotherapeutics to improve efficacy and safety. In the present study, imatinib mesylate and dexketoprofen trometamol were selected as model drugs to develop targeted surface-modified liposome and nanocochleate formulations for fibrosarcoma treatment. The physicochemical properties and in vitro efficacy of various formulations were evaluated by measurement of particle size distribution, polydispersity index, zeta potential, encapsulation efficiency, diffusion through Caco-2 cells, and toxicity in culture. Selected formulations were then evaluated in fibrosarcoma-bearing model mice by histopathological observations and tyrosine kinase receptor inhibition assays. The most effective formulation on the fibrosarcoma model was a PEGylated nanocochleate formulation. These findings provide a foundation for developing more effective formulations and chemotherapeutic strategies for the treatment of fibrosarcoma and other types of cancer.

Novel Approach to the Treatment of Diabetes: Embryonic Stem Cell and Insulin-Loaded Liposomes and Nanocochleates.

This study aims to investigate and compare the effects of insulin and embryonic stem-cell (ESC) loaded liposomes (LPs) and nanocochleate formulations and their PEGylated forms on the glucose levels. All formulations were characterized considering particle size, zeta potential, polydispersity index and encapsulation efficiencies. In-vitro insulin that releases from the formulations was determined using Franz-type diffusion cells. A cytotoxicity test revealed that none of the formulations was toxic to cells in any concentrations. The effects of the formulations on diabetic cells induced with glucose and streptozotocin (STZ) were then investigated in cell culture studies. Although glucose levels were decreased by the formulations after incubation, the liposomal formulations were found to be better. In experiments that were conducted on mice, it was observed again that blood glucose levels decreased successfully when diabetic pancreatic beta TC cells were incubated with the formulations, and all formulations were found to be effective in decreasing blood glucose levels in diabetic mice. Although ESC-loaded LPs were found to be the most effective formulation, LPs and nanocochleate formulations may also be used for the repair of pancreatic cells. This proposed ESC treatment is considered to be an attractive approach and a potential source for cell replacement therapy in the treatment of diabetes.

Development of Nanocochleates Containing Erlotinib HCl and Dexketoprofen Trometamol and Evaluation of In Vitro Characteristic Properties.

OBJECTIVES: Erlotinib HCI is a tyrosine kinase receptor inhibitor and an anticancer agent that was first approved by the FDA in 2004 for treatment of non-small-cell lung cancer and pancreatic cancer. Dexketoprofen trometamol is a NSAID, but recent studies showed that dexketoprofen trometamol also had an effect in carcinoma due to its inhibitor effects on prostaglandins. The combination of dexketoprofen and anti-cancer agents reduces pain caused by cancer by diminishing the tumors pressure, which causes necrosis; it also lowers the poor prognosis of cancer. Combination therapy will make life easier for patients, considering drug administration and dosing. Nanocochleates are new drug delivery systems that have not been examined as much as liposomes, but they have more advantages than liposomes. MATERIALS AND METHODS: In this study, erlotinib HCl and dexketoprofen trometamol were loaded into nanocochleates with various formulations and particle sizes/distributions, polydispersity indexes, and zeta potential analyses were performed. Transmission electron microscopy imaging was performed with the obtained optimal formulation and drug-release studies using Franz diffusion cells were conducted. RESULTS: As a result, drug carrier systems with a particle size of 196.42-312.33 nm and zeta potential greater than 15 mV were produced. The highest encapsulation efficiency for the main active ingredient, erlotinib HCl, was obtained in the KOH-1B formulation with 86.22±1.45%. CONCLUSION: This study showed that the drugs were successfully loaded into the nanocochleates and the nanocochleates actively released the drugs.

The Effectiveness of Raloxifene-Loaded Liposomes and Cochleates in Breast Cancer Therapy.

Liposome (spherical vesicles) and cochleate (multilayer crystalline, spiral structure) formulations containing raloxifene have been developed having dimethyl-ß-cyclodextrin (DM-ß-CD) or sodium taurocholate (NaTC). Raloxifene was approved initially for the treatment of osteoporosis but it is also effective on breast tissue and endometrial cells. Raloxifene inhibits matrix metalloproteinase-2 (MMP-2) enzyme, which is known to be responsible for tumor invasion and the initiation of angiogenesis during the tumor growth. Therefore, raloxifene was selected as a model drug. A series of raloxifene-loaded liposome and cochleate formulations were prepared. In vitro release studies and in vivo tests were performed. Breast cancer cell lines (MCF-7) were also used to find the most effective formulation. Highest antitumor activity was observed, and MMP-2 enzyme was also found to be inhibited with raloxifene-loaded cochleates containing DM-ß-CD. These developed formulations can be helpful for further treatment alternatives and new strategies for cancer therapy.

Nanoparticle and liposome formulations of doxycycline: transport properties through Caco-2 cell line and effects on matrix metalloproteinase secretion.

Nanoparticle and liposome formulations containing doxycycline or doxycycline and sodium taurocholate (NaTC) were developed in this study. The anticancer effects of doxycycline and penetration properties from those formulations through Caco-2 cell monolayers were investigated. Matrix metalloproteinases (MMPs) have been reported to play a role in the negative prognosis of many malignant tumors including glioblastoma multiforme (GBM). This study is presented to demonstrate that these developed nanoparticle and liposome formulations of doxycycline are capable of inhibiting MMP-2 release from cultured Caco-2 cells. In this study, Caco-2 cells were used as model cell cultures. A MTT test was performed to determine the effect of doxycycline on the viability of Caco-2 cells. Doxycycline nanoparticles were prepared using emulsion polymerization and doxycycline liposomes were prepared using the dry film hydration method. Transport studies of doxycycline through Caco-2 cells were investigated. MMP-2 was found to be inhibited more with doxycycline if NaTC is present in the formulation. NaTC was also found to be useful to increase penetration due to the inhibition of efflux by interacting with p-glycoproteins, in addition to the penetration enhancing effect as a result of opening tight junctions. These developed formulations were proposed to use for the treatment of tumors and GBM.

Evaluation of chitosan gel containing liposome-loaded epidermal growth factor on burn wound healing.

The objective of this study is to develop a chitosan gel formulation containing liposomes loaded with epidermal growth factor (EGF) and to evaluate their effects on the healing of second-degree burn wounds in rats by immunohistochemical, histochemical and histological methods. EGF-containing multilamellar liposomes which were carried in chitosan gel, EGF gel and EGF-loaded liposome formulations were prepared. The in vivo experiments were performed on female Sprague Dawley rats. Second-degree standard burn wounds were formed on rats and liposomes containing 10 µg/ml EGF in 2% chitosan gel, EGF-chitosan gel and EGF-loaded liposome formulations were applied daily to the burn wounds and biopsies were taken at the 3rd, 7th and 14th day of the treatment. When the results were evaluated immunohistochemically, there were significant increases in cell proliferation observed in the EGF-containing liposome in chitosan gel (ELJ) formulation applied group (P < 0·001). The histochemical results showed that the epithelisation rate in the ELJ group was the highest compared with the other group results (P < 0·001). The histological results indicated and supported these findings and faster epithelisation was observed in the ELJ group compared with the other groups.

New perspective for the treatment of Alzheimer diseases: liposomal rivastigmine formulations.

The aim of this study was to determine the transportations of rivastigmine containing from various liposome formulations through Madin Darby Canine Kidney (MDCK) cells monolayer and to compare the in vitro test results with in vivo. There is no other liposome formulation of rivastigmine and the transportations of rivastigmine through MDCK cell monolayers or related study available in the literature. Cytotoxicity (MTT) test was used to determine cell viabilities. The effect of sodium-taurocholate or dimethyl-beta-cyclodextrine as penetration enhancer was also investigated. Characterization and stability studies for liposome formulations were performed. Permeation experiments of rivastigmine were performed through MDCK cells and dialysis membrane. The kinetic of release from liposomes was also investigated. The highest apparent permeability coefficient (log. values) was obtained with sodium-taurocholate liposomes for -1.15 ± 0.16 for MDCK cell. Rivastigmine liposomes and solutions were also administered to mice orally and intraperitonally. Acetylcholinesterase (AChE) activity was determined by Ellman method. AChE% inhibition values were calculated for both blood and brain after administration of rivastigmine solution and liposomes. The highest AChE inhibition was observed for rivastigmine-sodium-taurocholate liposomes. Histological observations of the mice' brains were performed under transmission electron microscope (TEM). The histological results were also indicated and supported all these findings.

Use of microparticulate systems to accelerate skin wound healing.

Rapid and proper healing is important in the treatment of skin wounds. The dressing achieves the functions of the natural skin by protecting the wound area from the bulk loss of tissue and creating an effective barrier to outside contaminants without increasing the bacterial load on the wound surface. There are many wound dressings available on the market which can be used in the healing process. Different dressings have been used according to the condition of the wound and the phases of wound healing. Biodegradable polymers are being widely used in drug delivery and also in wound healing. These polymers that are applicable as a wound dressing protect the wound site against unwanted external effects, inhibit wound contraction, and, if possible, stimulate the healing process. Micro- and nanoparticulates are currently being evaluated as a potential drug delivery in clinical applications. Growth factors also play a vital role in wound healing. Polymers used in wound healing act as sustained release vehicles for growth factors. Controlled release of growth factors from microspheres has provided a higher degree of healing in the wound areas. This review is intended to provide information regarding the various formulations and microparticulate systems used in wound healing.

Investigation of epidermal growth factor containing liposome formulation effects on burn wound healing.

It was aimed to develop liposome formulations containing epidermal growth factor (EGF) and to investigate the healing effects of these formulations on second-degree burn wounds in rats. Multilamellar type liposomes containing EGF were prepared by film formation method. In vitro releases of EGF from liposome formulations were determined using spectrofluorometer. Second-degree standard burn wounds were formed on rats and liposome formulations containing 10 microg/mL EGF (ELP group), EGF solution (ES group), liposome without containing EGF (LP group), and Silverdine ointment (SIL group) were applied daily. Untreated control groups [unburned (S) and untreated (Y) rats] were also evaluated. Biopsies were taken at the 3rd, 7th, and 14th day of the treatment from the wounds and histological observations were performed under transmission electron microscope. Bromodeoxyuridine (BrdU) staining technique was used for immunohistochemical analysis. After trichrome stainings, the thicknesses of the epidermis and the areas of the fibroblast nucleus were measured using a light microscope and Vision Screening Analysis Program. It was observed that the healing in the ELP group was the fastest among all groups (p < 0.05) at the 14th day of therapy. The healing effect in order from highest to lowest efficacy was found to be ELP>SIL>ES groups, respectively, at the 14th day. All results indicated that the EGF-liposome formulation is effective and can be used for the treatment of burn wounds.

Oral administration of liposomal insulin.

There have been several attempts published in the literature related with orally effective insulin formulations, which are increasing in popularity. Some of the results indicate that it is possible to reduce blood glucose level by orally administered liposomal insulin formulations, but there is general need to understand the mechanism and effective components of the liposome formulations. In our study, liposomal insulin formulations were prepared using insulin (Humulin R) or protamine- containing insulin (Humulin N) with cholesterol, dipalmitoyl phosphatidylcholine (egg) (DPPC)-cholesterol mixture, and mucoadhesive agent (methyl cellulose, MC)-added DPPC-cholesterol mixture. A tablet formulation of insulin was also prepared. Formulations of liposomal insulin were introduced to mice and rats orally and reduced blood glucose levels were observed. The composition of phospholipid (DPPC, cholesterol and MC mixture) was found to be quite effective in reducing blood glucose levels. The pH of the solution and the presence of the protamine sulfate were found to be important. The application site was also found to be important because liposomal insulin formulations administered through the mouth or esophagus resulted in reduced blood glucose levels. Reduced blood glucose levels were also observed when tablet formulations of insulin were administered to rats orally.

An investigation on burn wound healing in rats with chitosan gel formulation containing epidermal growth factor.

Various studies have shown that chitosan is effective in promoting wound healing. In this study, we aimed to develop an effective chitosan gel formulation containing epidermal growth factor (EGF), and to determine the effect on healing of second-degree burn wounds in rats. Ten micrograms per millilitre EGF in 2% chitosan gel was prepared. In an in vitro study to investigate release of EGF from the formulations, the release rate was 97.3% after 24 h. In in vivo studies, animals were divided into six groups as follows: silver sulfadiazine [Silverdin cream (SIL)], chitosan gel with and without EGF (EJ, J), EGF solution (ES) and untreated control groups [unburned (S) and untreated (Y) rats] applied groups, respectively. A uniform deep second-degree burn of the backskin was performed with water heated to 94+/-1 degrees C during a 15-s exposure. The EGF formulations were repeatedly applied on the burned areas with a dose of 0.160 microg/cm2 for 14 days (one application per day). Healing of the wounds was evaluated immunohistochemically, histochemically and histologically on the tissue samples. When the results were evaluated immunohistochemically, there were significant increases in cell proliferation observed in the EGF containing gel applied group (p<0.001). The histochemical results showed that the epithelization rate in the EJ group was the highest compared to the ES group results (p<0.001). The histological results indicated and supported these findings. It can be concluded that a better and faster epithelization was observed in the EJ group compared to the other groups.

Prediction of permeability coefficients of compounds through caco-2 cell monolayer using artificial neural network analysis.

Artificial neural network (ANN) analysis was used to predict the permeability of selected compounds through Caco-2 cell monolayers. Previously reported models, which were shown to be useful in the prediction of permeability values, use many structural parameters. More complex equations have also been proposed using both linear and non-linear relationships, including ANN analysis and various structural parameters. But proposed models still need to be developed using different neuron patterns for more precise predictions and a better understanding of which factors affect the permeation. To develop a simple and useful model or method for easy prediction is also a general need. Permeability coefficients (log kp) were obtained from various literature sources. Some structural parameters were calculated using computer programs. Multiple linear regression analysis (MLRA) was used to predict Caco-2 cell permeability for the set of 50 compounds (r2=0.403). A successful ANN model was developed, and the ANN produced log kp values that correlated well with the experimental ones (r2=0.952). The permeability of a compound, famotidine, which has not previously been studied, through the Caco-2 cell monolayer was investigated, and its permeability coefficient determined. It was then possible to compare the experimental data with that predicted using the trained ANN with previously determined Caco-2 cell permeability values and structural parameters of compounds. The model was also tested using literature values. The developed and described ANN model in this publication does not require any experimental parameters; it could potentially provide useful and precise prediction of permeability for new drugs or other penetrants.

Caco-2 cell culture as a model for famotidine absorption.

The aim of the study was to determine penetration properties of Famotidine fro the formulations through colon adenocarcinoma (Caco)-2 cell monolayers and to compare in vitro with in vivo test results. It also aimed to determine the effect of particle size on the penetration properties of Famotidine when microsphere formulations were used. Famotidine was chosen as a model drug and Caco-2 cell culture model was used. Biodegradable Famotidine microspheres of poly(lactide-co-glycolide)(PLGA) polymer (50:50) were prepared by using multiple emulsion technique. Microspheres were coded according to their particle size and polymer[LHIV:60 microm Famotidine-PLGA(high viscosity), SHIV:6 microm Famotidine PLGA(high viscosity), LLIV:60 microm Famotidine-PLGA (low viscosity), SLIV:6 microm Famotidine-PLGA (low viscosity)]. Famotidine solution(5 mg/ml) and microsphere formulations were administered orally to mice and blood drug levels were determined and compared with the Caco-2 cell experiments. Permeability values of Famotidine through Caco-2 cells from various formulations were determined (log k(solution) = 7,274 +/- 0,010,log kSHIV = -3,884 +/- 0,033,log kLHIV = -2,300 +/- 0,009,log kSLIV = -4,076 +/- 0,208,log kLLIV = 3,525 +/- 0,045). Our results showed that H2 receptor antagonists alter the barrier properties of the Caco-2 cell monolayer by causing an increment in the tightness of the tight junctions. Therefore, amount of the H2 receptor antagonist-like drug at the site of action was found to be important as well as polymer type and particle size of microspheres for drug permeation. Permeation of the drug was lower when higher amounts of Famotidine were present at the diffusion site. A controlled release dosage form of H2 receptor antagonist-like drugs may be beneficial for long-term treatments.

Rectal and vaginal administration of insulin-chitosan formulations: an experimental study in rabbits.

Insulin is a polypeptide drug and it is degraded by gastrointestinal enzymes, therefore, it cannot be used via oral route readily. There are only parenteral forms available in the market. The aim of this study was to investigate the effect of rectal and vaginal administration of various insulin gel formulations on the blood glucose level as alternative routes in rabbits. Chitosan gel (CH-gel) was used as a carrier; the penetration enhancing effect of sodium taurocholate and dimethyl-beta-cyclodextrin (DM-betaCD) was also investigated. CH-gel provided longer insulin release. The maximum decreasing effect on blood glucose level was observed with insulin-CH-gel containing 5% DM-betaCD. In conclusion, our results indicate that insulin may penetrate well through the rectal and vaginal mucosae from the CH-gel. DM-betaCD was also found to be a useful agent to enhance the penetration of insulin through rectal and vaginal membranes.

The effect of various liposome formulations on insulin penetration across Caco-2 cell monolayer.

The aim of the study was to determine the penetration properties of various insulin containing liposome formulations through Caco-2 cell monolayer and to compare the in vitro test results with in vivo tests. The effect of sodium taurocholate as a penetration enhancer when it was added to the liposome formulation was also investigated. In vitro permeation experiments were performed in diffusion cells with the Caco-2 cell monolayer used as the membrane. Permeability values of various insulin containing liposome formulations through Caco-2 cells were determined (log k(insulin-solution) = -2.217 +/- 0.0723 cm.h(-1), log k(insulin-liposome) = -2.141 +/- 0.0625 cm.h(-1), log k(insulin-sodium tauroholate liposome)= -1.952 +/- 0.0623 cm.h(-1)). In vivo tests were performed in mice. Formulations were administered orally and blood glucose levels were determined and penetrations were compared with the Caco-2 cell experiment results. In conclusion, the permeability of insulin was increased across Caco-2 cell monolayer when the liposome sodium taurocholate (NaTC) formulation was used. The oral administration of insulin and NaTC incorporated liposomes significantly decreased blood glucose levels. Furthermore, it was shown that a high in vitro/in vivo correlation was observed using the Caco-2 cell monolayer model.

Nonisothermal stability tests of famotidine and nizatidine.

Nonisothermal stability tests have been proposed as an attractive and alternative method to the conventional isothermal stability tests. The stability and the degradation properties of famotidine and nizatidine were investigated using both isothermal and nonisothermal stability test techniques. Linear and logarithmic temperature programs were used and the degradation rate constant and activation energies were calculated using a computer program, which was written in BASIC. Also the advantages and disadvantages of these temperature programs are compared. The method to estimate parameters is based on nonlinear curve fitting the nonisothermal concentration-time-temperature curve equation. The nonisothermal stability test results were compared with the results of isothermal stability tests and similar results were obtained.

The use of liposomal enrofloxacin for intracellular infections in Kangal dogs and visualization of phagocytosis of liposomes.

It is difficult to treat intracellular infections because of the intrinsic resistance of the microorganism to most antibiotics. Moreover, these microorganisms can survive in phagocytic cells (macrophages and neutrophils). In this study, our aims were to encapsulate an antibiotic in liposomes, which will be phagocytized as well as the microorganisms in the phagocytic cell (because liposomes were prepared using lipids which have an antigenic activity and they can be phagocytized, thus, the active substance can be transferred into the cell), and to visualise with microscopy the phagocytic activity of macrophages and neutrophils to liposomes. MLV (multilamellar vesicles) fluorescein-labeled liposomes were prepared and incubated with isolated Kangal shepherd dog macrophages and neutrophils. The phagocytosis of liposomes by monocytes was visualized step by step under the microscope. Liposomes were also observed phagocytized after incubation with neutrophils. Enrofloxacin was chosen as a model drug. Neutrophils and macrophages were isolated from Kangal shepherd dogs and infected with Staphylococcus aureus, and their phagocytic activities (PA) and microbicidal activities (MA) were determined. PA and MA values were redetermined and compared when enrofloxacin formulations were used. Liposomal enrofloxacin was found to be more effective.