Application or function of citric acid in drug delivery platforms.

Nontoxic materials with natural origin are promising materials in the designing and preparation of the new drug delivery systems (DDSs). Today's, citric acid (CA) has attracted a great deal of attention because of its special features; green nature, biocompatibility, low price, biodegradability, and commercially available property. So, CA has been employed in the preparation of the various platforms to induce a suitable property on their structure. Recently, several research groups investigated the CA-based platforms in different forms like tablets, dendrimers, hyperbranched polymers, (co)polymer, hydrogels, and nanoparticles as efficient DDSs. By considering an increasing amount of published articles in this field, for the first time, in this review, an overview of the published works regarding CA applications in the design of various DDSs is presented with a detailed and insightful discussion.

Synthesis of novel organosilicon compounds possessing highly substituted imidazole core catalyzed by antimony trioxide.

A general synthetic route for the exclusive preparation of tetrasubstituted imidazoles, possessing benzylic methyl groups has been developed using Sb2O3 via solvent-free, one-pot reaction conditions. Detailed results from our investigation on the bromination of the benzylic methyl groups of imidazoles are described. The products generated during this study were utilized as substrates for the synthesis of organosilicon-containing imidazoles. Synthesis of tris(triorganosilyl)methylimidazole derivatives was carried out using organolithium reagents (RSiMe2)3CLi, (R= H, Me, Ph) prepared via metalation of (RSiMe2)3CH with lithiumdiisopropylamide or methyllithium in THF, in excellent yields. (RSiMe2)3CLi, (R= Me, Ph) were treated with formylated imidazole to afford imidazole containing 2,2-bis(organosilyl)ethenyl groups. 2-(4-(2,2-bis(trimethylsilyl)vinyl)phenyl)-1,4,5-triphenyl-1H-imidazole was obtained via Peterson reaction in high yield. However, compound 2-(4-(2,2-bis(dimethyl(phenyl)silyl)vinyl)phenyl)-1,4,5-triphenyl-1H-imidazole was obtained in low yield likely because of the steric hindrance of the (PhSiMe2)3C- group.

Hyaluronic acid functionalized citric acid dendrimer/UiO-66-COOH as a stable and biocompatible platform for daunorubicin delivery.

This work aimed to prepare a new system for daunorubicin (DNR) delivery to improve therapeutic efficiency and decrease unwanted side effects. Typically, at first, a carboxylic acid functional group containing metal-organic framework (UiO-66-COOH) was synthesized in a simple way. Then, a third generation of citric acid dendrimer (CAD G3) was grown on it (UiO-66-COOH-CAD G3). Finally, the system was functionalized with pre-modified hyaluronic acid (UiO-66-COOH-CAD-HA). SEM analysis displayed that the synthesized particles have a spherical shape with an average particle size ranging from 260 to 280 nm. An increase in hydrodynamic diameter from 223 nm for UiO-66-COOH to 481 nm for UiO-66-COOH-CAD-HA is a sign of success in the performed reactions. Also, the average pore size was calculated at about 4.04 nm. The DNR loading efficiency of UiO-66-COOH-CAD-HA was evaluated at ∼74 % (DNR@UiO-66-COOH-CAD-HA). It was observed that the drug release rate at a lower pH is more than higher pH. The maximum hemolysis of <3 % means that the UiO-66-COOH-CAD-HA is hemocompatible. The use of DNR-loaded UiO-66-COOH-CAD-HA led to cell-killing of 77.9 % for MDA-MB 231. These results specified the great potential of UiO-66-COOH-CAD-HA for tumor drug delivery, so it could be proposed as a new carrier for anticancer agents to minimize adverse effects and improve therapeutic efficacy.

Efficient adsorptive removal of used drugs during the COVID-19 pandemic from contaminated water by magnetic graphene oxide/MIL-88 metal-organic framework/alginate hydrogel beads.

Currently, the presence of drugs used in the COVID-19 pandemic in water bodies is worrisome due to their high toxicity, which necessitates their critical removal by developing highly efficient adsorbents. Hence, in this study, alginate hydrogel beads of magnetic graphene oxide@MIL-88 metal-organic framework (GO@Fe3O4@MIL-88@Alg) were prepared for the first time and then utilized as a new absorption system for the removal of COVID-19 drugs such as doxycycline (DOX), hydroxychloroquine (HCQ), naproxen (NAP), and dipyrone (DIP) from aqueous solutions by batch adsorption manner. The effects of different experimental factors, such as adsorbent dosage, contact time, pH, drug concentration, temperature, ionic strength, presence of an external magnetic field (EMF), and magnet distance from the adsorption flask were optimized for the removal of COVID-19 drugs. The adsorption equilibrium isotherm proved that the adsorption process of DOX, HCQ, NAP, and DIP drugs on GO@Fe3O4@MIL-88@Alg hydrogel beads conformed to the Langmuir model and followed the pseudo-second-order adsorption kinetics. The maximum adsorption capacities of DOX, HCQ, NAP, and DIP drugs obtained for GO@Fe3O4@MIL-88@Alg hydrogel beads with the Langmuir model were 131.57, 79.92, 55.55, and 49.26 mg/g at 298 K, respectively. The thermodynamic study suggested a spontaneous endothermic adsorption process. Also, the conclusion from this study confirmed the validity of GO@Fe3O4@MIL-88@Alg hydrogel beads for excellent removal of COVID-19 drugs from water samples. It was also found that the GO@Fe3O4@MIL-88@Alg hydrogel beads could be reused with satisfactory removal efficiency in six cycles. Based on the study, the GO@Fe3O4@MIL-88@Alg hydrogel beads could be considered a sustainable, simple, economical, environmentally friendly absorption system for the removal of pharmaceutical contaminants from water.

pH-sensitive biosystem based on laponite RD/chitosan/polyvinyl alcohol hydrogels for controlled delivery of curcumin to breast cancer cells.

In this study, a pH-responsive hydrogels based on laponite rapid dispersion (Lap®)/chitosan (CS)/polyvinyl alcohol (PVA) designed and was used for controlled delivery of the anticancer drug curcumin (CUR). First, it was accomplished by dissolving CUR in Lap® dispersion under the influence of the pH of the environment. Then, in the presence of Lap®CUR cross-linking was incorporated between CS and PVA polymers. The structural features of Lap®CUR/CS@PVA hydrogels are characterized using FT-IR, XRD, SEM/EDS, TEM, TGA, Zeta potential, and XPS. The in vitro drug release profiles confirmed a pH-responsive controlled release of CUR in acidic pH for all hydrogels. During 12 h, the cumulative release of CUR from Lap®CUR/0.1CS@PVA hydrogel was 27.9% and 12.3%, at pH 5.5 and 7.4, respectively. While during three days the release rate reached 48.5% and 18.5%. The CUR release kinetic from hydrogels also suggests that the kinetic data well fitted to the Korsmeyer-Peppas, diffusion-controlled and Fickian diffusion. Furthermore, in vitro cytotoxicity and DAPI staining study clearly illustrated that Lap®CUR/0.1CS@PVA hydrogel had lower cytotoxicity than CUR against MDA-MB 231 cancer cells, which confirmed the controlled release of drug through hydrogels. Meanwhile, in vitro hemolysis, antioxidant and antibacterial tests revealed that the prepared hydrogels have good blood compatibility, excellent antioxidant properties, and antibacterial activity. Based on the obtained results, the designed hydrogels could be potentially applied as pH-controlled drug delivery systems for cancer therapy.

Fabrication of biocompatible magnetic maltose/MIL-88 metal-organic frameworks decorated with folic acid-chitosan for targeted and pH-responsive controlled release of doxorubicin.

Recently, metal-organic frameworks (MOFs) have attracted tremendous attention as promising porous drug delivery systems for cancer treatment. In this work, for the first time, a novel magnetic maltose disaccharide molecule modified with MIL-88 metal-organic framework (Fe3O4@C@MIL-88) was prepared, and then this targeted system was used for the delivery of the doxorubicin (DOX) drug. Eventually, Fe3O4@C@MIL-88-DOX were successfully decorated with folic acid conjugated chitosan (Fe3O4@C@MIL-88-DOX-FC) as a new targeted and controlled release drug system for treatment of MCF-7 breast cancer. The encapsulation efficiency of the DOX in the Fe3O4@C@MIL-88 was obtained at ∼83.6%. The in vitro drug release profiles showed a pH-responsive controlled release of DOX in acidic pH confirming the performance of the systems in the cancerous environment. The DOX release mechanism from systems at pH 5 also showed that the kinetic data well fitted to the Korsmeyer-Peppas and Fickian diffusion. Furthermore, in vitro cytotoxicity and DAPI staining study clearly illustrated that the synthesized Fe3O4@C@MIL-88 system had low cytotoxicity and good biocompatibility against MCF-7 cancer cells and MCF-10A normal cells. Whereas, Fe3O4@C@MIL-88-DOX and Fe3O4@C@MIL-88-DOX-FC exhibited good antitumor activity as a result of targeted delivery of DOX, which indicated the MCF-7 cell death with apoptotic effects. Based on these findings, the resulting carriers could be used as promising targeted drug delivery systems for cancer therapy.

Development of the new pH-driven carrier from alginate/carboxymethyl starch bio-coated co-drugs@COF-OH for controlled and concomitant colon cancer treatment.

To develop a new more efficient colon cancer treatment bio-vehicle, in frontier research, for the first time, an attempt has been made to design a unique colon-targeted bio-carrier containing polysaccharides along with nanoporous materials. So, at first, an imine-based covalent organic framework (COF-OH) with respectively an average pore diameter and surface area at 8.5058 nm and 208.29 m2·g-1 was fabricated. In the next step, about 41.68 % and 95.8 % of 5-fluorouracil (5-Fu) and curcumin (CUR) respectively were loaded on COF-OH, and 5-Fu + CUR@COF-OH was achieved. Due to the higher rate of drug releases in simulated stomach media, 5-Fu + CUR@COF-OH was coated with a mixture of alginate (Alg) and carboxymethyl starch (CMS) via the ionic crosslinking (Alg/CMS@(5-Fu + CUR@COF-OH)). Findings displayed that the use of polysaccharide coat reduce the drug releases in simulated gastric and improved it in simulated intestinal and colonic fluids. The beads swelled about 93.33 % under simulated gastrointestinal conditions, but this value was found higher in the simulated colonic environment and reached 326.67 %. The hemolysis rate lower than 5 %, as well as the cell viability higher than 80 %, were the main showing signs of system biocompatibility. Altogether, the results of the preliminary investigations can highlight the potential of the Alg/CMS@(5-Fu + CUR@COF-OH) for colon-specific drug delivery.

Fabrication of a new photoluminescent and pH-responsive nanocomposite based on a hyperbranched polymer prepared from amino acid for targeted drug delivery applications.

In this study, the Fe3O4 nanoparticles were encapsulated in the hyperbranched poly L-lysine citramid (HBPLC). The Fe3O4-HBPLC nanocomposite modified with L-arginine and quantum dots (QDs) to obtain Fe3O4-HBPLC-Arg/QDs as a new photoluminescent and magnetic nanocarrier for the pH-responsive release and targeted delivery of Doxorubicin (DOX). The prepared magnetic nanocarrier was fully characterized using different techniques. Its various potential as a magnetic nanocarrier was evaluated. The in-vitro drug release studies exhibited that the prepared nanocomposite has pH-responsive behavior. The antioxidant study revealed good antioxidant properties of the nanocarrier. Also, the nanocomposite revealed excellent photoluminescence with a quantum yield of 48.5 %. Cellular uptake studies showed that Fe3O4-HBPLC-Arg/QD has high cell uptake in MCF-7 cells and can be used for bioimaging applications. In-vitro cytotoxicity, colloidal stability, and enzymatic degradability studies revealed that the prepared nanocarrier is non-toxic (with cell viability of 94%), stabile and biodegradable (about 37%). The nanocarrier was hemocompatible with 8% hemolysis. Also, according to the apoptosis and MTT assays, the Fe3O4-HBPLC-Arg/QD-DOX induced greater toxicity and cellular apoptosis against breast cancer cells about 47.0 %.

pH-sensitive biocompatible chitosan/sepiolite-based cross-linked citric acid magnetic nanocarrier for efficient sunitinib release.

In this study, the magnetite nanoparticles were immobilized on the sepiolite needles via co-precipitation of iron ions. Then, the resulted magnetic sepiolite (mSep) nanoparticles were coated with chitosan biopolymer (Chito) in the presence of citric acid (CA) to prepare mSep@Chito core-shell drug nanocarriers (NCs). TEM images showed magnetic Fe3O4 nanoparticles with small sizes (less than 25 nm) on the sepiolite needles. Sunitinib anticancer drug loading efficiencies were ⁓45 and 83.7 % for the NCs with low and high content of Chito, respectively. The in-vitro drug release results exhibited that the mSep@Chito NCs have a sustained release behavior with high pH-dependent properties. Cytotoxic results (MTT assay) showed that the sunitinib-loaded mSep@Chito2 NC had a significant cytotoxic effect on the MCF-7 cell lines. Also, the in-vitro compatibility of erythrocytes, physiological stability, biodegradability, and antibacterial and antioxidant activities of NCs was evaluated. The results showed that the synthesized NCs had excellent hemocompatibility, good antioxidant properties, and were sufficiently stable and biocompatible. Based on the antibacterial data, the minimal inhibitory concentration (MIC) values for mSep@Chito1, mSep@Chito2, and mSep@Chito3 were obtained as 125, 62.5, and 31.2 µg/mL towards S. aureus, respectively. All in all, the prepared NCs could be potentially used as a pH-triggered system for biomedical applications.

Carboxymethyl cellulose@multi wall carbon nanotubes functionalized with Ugi reaction as a new curcumin carrier.

In recent years, the fabrication of new drug delivery systems (DDSs) based on functionalization by multi-component reactions (MCRs) has received special attention. In this regard, to obtain a new oral administration system for colon-specific cancer treatment, the CMC@MWCNTs@FCA carrier was designed and prepared from the functionalization of the CMC@MWCNTs as a biocompatible raw material with carboxamide group by the Ugi reaction. FT-IR analysis confirmed the successful synthesis of the product through the change in the functional groups of reagents. Additionally, the crystalline structure and porosity of the samples were studied by XRD and BET techniques. After a detailed characterization, the curcumin (CUR) was loaded on CMC@MWCNTs and CMC@MWCNTs@FCA, respectively, about 29 % and 38 %. In vitro drug release behavior studies for CUR-loaded CMC@MWCNTs@FCA showed the controlled release for it, so 11.6 % and 76.5 % of CUR, respectively were released at pH 1.2 and pH 7.4. Toxicological analysis displayed the IC50 of CMC@MWCNTs@FCA@CUR is 752 µg/mL. In conclusion, the obtained findings display that the fabricated system can be proposed as a biocompatible carrier for specific colon cancer treatment.