Identification of Novel and Potent Indole-Based Benzenesulfonamides as Selective Human Carbonic Anhydrase II Inhibitors: Design, Synthesis, In Vitro, and In Silico Studies.

In recent decades, human carbonic anhydrase inhibitors (hCAIs) have emerged as an important therapeutic class with various applications including antiglaucoma, anticonvulsants, and anticancer agents. Herein, a novel series of indole-based benzenesulfonamides were designed, synthesized, and biologically evaluated as potential hCAIs. A regioisomerism of the sulfonamide moiety was carried out to afford a total of fifteen indole-based benzenesulfonamides possessing different amide linkers that enable the ligands to be flexible and develop potential H-bond interaction(s) with the target protein. The activity of the synthesized compounds was evaluated against four hCA isoforms (I, II, IX and, XII). Compounds 2b, 2c, 2d, 2f, 2h and 2o exhibited potent and selective profiles over the hCA II isoform with Ki values of 7.3, 9.0, 7.1, 16.0, 8.6 and 7.5 nM, respectively. Among all, compound 2a demonstrated the most potent inhibition against the hCA II isoform with an inhibitory constant (Ki) of 5.9 nM, with 13-, 34-, and 9-fold selectivity for hCA II over I, IX and XII isoforms, respectively. Structure-activity relationship data attained for various substitutions were rationalized. Furthermore, a molecular docking study gave insights into both inhibitory activity and selectivity of the target compounds. Accordingly, this report presents a successful scaffold hoping approach that reveals compound 2a as a highly potent and selective indole-based hCA II inhibitor worthy of further investigation.

Targeting EGFR/HER2 tyrosine kinases with a new potent series of 6-substituted 4-anilinoquinazoline hybrids: Design, synthesis, kinase assay, cell-based assay, and molecular docking.

Coexpression of EGFR and HER2 has been found in many tumors such as breast, ovarian, colon and prostate cancers, with poor prognosis of the patients. Herein, our team has designed and synthesized new eighteen compounds with 6-substituted 4-anilinoquinazoline core to selectively inhibit EGFR/HER2 tyrosine kinases. Twelve compounds (8a-8d, 9a, 9c, 9d, 10a, 10c, 11b, 14, and 15) showed nanomolar range of IC50 values on EGFR and/or HER2 kinases. Accordingly, a detailed structure activity relationship (SAR) was established. A molecular docking study demonstrated the favorable binding modes of 8d, 9b, 9d and 10d at the ATP active site of both kinases. A kinase selectivity profile performed for compound 8d showed great selectivity for EGFR and HER2. In addition, 8d, 9c, and 9d exerted selective promising cytotoxic activity over BT-474 cell line with IC50 values of 2.70, 1.82 and 1.95 µM, respectively. From these results, we report analogs 8d, 9c, and 9d as promising candidates for the discovery of well-balanced compounds in terms of the kinase inhibitory potency and antiproliferative activity.

Reinforcement of interfacial adhesion of a coated polymer layer on a cobalt-chromium surface for drug-eluting stents.

During the balloon expansion of several commercially available drug-eluting stents, various types of defects in the polymer layer have been observed. The aim of this study is to prevent these defects by increasing the interfacial adhesion between the metal substrate and the drug-in-polymer matrix using poly(caprolactone) (PCL) brushes onto a cobalt-chromium (Co-Cr or CC) alloy surface. The chemical modification of the Co-Cr surface was accomplished by grafting ricinoleic acid (RA) onto the metal substrate followed by surface-initiated ring opening polymerization of ε-caprolactone. The unmodified, RA-grafted (CC-RA), and PCL-grafted Co-Cr substrates (CC-RA-PCL3D and CC-RA-PCL6D) were characterized by various surface analyses. Poly(d,l-lactide) containing sirolimus was spray coated onto the unmodified and modified substrates. The adhesion property of the polymer coating on the PCL-grafted surfaces was improved compared to those of other samples. Among all of the drug-in-polymer coated samples, both CC-RA-PCL3D and CC-RA-PCL6D exhibited a stabilized drug release profile over 49 days. It was also revealed that CC-RA-PCL6D showed the slowest drug release of all the samples. On the basis of these results, the proposed nanocoupling method has shown not only improved adhesion of the drug-in-polymer matrix to the Co-Cr substrate but also controlled drug release.

Biocompatible and functional inorganic magnesium ceramic particles for biomedical applications.

Magnesium ceramics hold promise for numerous biological applications. This review covers the synthesis of magnesium ceramic particles with specific morphologies and potential modification techniques. Magnesium ceramic particles possess multiple characteristics directly applicable to human biology; they are anti-inflammatory, antibacterial, antiviral, and offer anti-cancer effects. Based on these advantages, magnesium hydroxide nanoparticles have been extensively utilized across biomedical fields. In a vascular stent, the incorporation of magnesium ceramic nanoparticles enhances re-endothelialization. Additionally, tissue regeneration for bone, cartilage, and kidney can be promoted by magnesium ceramics. This review enables researchers to identify the optimum synthetic conditions to prepare magnesium ceramics with specific morphologies and sizes and select the appropriate modification protocols. It is also intended to elucidate the desirable physicochemical properties and biological benefits of magnesium ceramics.

Magnesium hydroxide-incorporated PLGA composite attenuates inflammation and promotes BMP2-induced bone formation in spinal fusion.

Spinal fusion has become a common surgical technique to join two or more vertebrae to stabilize a damaged spine; however, the rate of pseudarthrosis (failure of fusion) is still high. To minimize pseudarthrosis, bone morphogenetic protein-2 (BMP2) has been approved for use in humans. In this study, we developed a poly(lactide-co-glycolide) (PLGA) composite incorporated with magnesium hydroxide (MH) nanoparticles for the delivery of BMP2. This study aimed to evaluate the effects of released BMP2 from BMP2-immobilized PLGA/MH composite scaffold in an in vitro test and an in vivo mice spinal fusion model. The PLGA/MH composite films were fabricated via solvent casting technique. The surface of the PLGA/MH composite scaffold was modified with polydopamine (PDA) to effectively immobilize BMP2 on the PLGA/MH composite scaffold. Analyzes of the scaffold revealed that using PLGA/MH-PDA improved hydrophilicity, degradation performance, neutralization effects, and increased BMP2 loading efficiency. In addition, releasing BMP2 from the PLGA/MH scaffold significantly promoted the proliferation and osteogenic differentiation of MC3T3-E1 cells. Furthermore, the pH neutralization effect significantly increased in MC3T3-E1 cells cultured on the BMP2-immobilized PLGA/MH scaffold. In our animal study, the PLGA/MH scaffold as a BMP2 carrier attenuates inflammatory responses and promotes BMP2-induced bone formation in posterolateral spinal fusion model. These results collectively demonstrate that the BMP2-immobilized PLGA/MH scaffold offers great potential in effectively inducing bone formation in spinal fusion surgery.

Persulfated flavonoids accelerated re-endothelialization and improved blood compatibility for vascular medical implants.

Drug-eluting stents (DESs) have been used for the treatment of cardiovascular diseases including stenosis. However, in-stent restenosis, thrombosis, and delayed re-endothelialization represent challenges for their clinical applications. Here, we demonstrate a novel work to overcome these limitations through surface modification technology. The cobalt-chromium (Co-Cr) surface was modified with antioxidants such as gallic acid (GA) and rutin (Ru) and the corresponding persulfates derivatives (i.e., GAS, and RuS) through a simple conjugation procedure. Various analyses tools such as ATR-FTIR, XPS, water contact angle, SEM, and AFM characterized the functionalized surface. The surface characterization confirmed that the antioxidant and the additional persulfates were successfully bonded to the Co-Cr surface. The results of in vitro endothelial cells proved that the persulfates derivatives showed the highest tendency to get rapid re-endothelialization especially RuS. In addition, it showed inhibition to smooth muscle cells (SMCs) as compared to control Co-Cr substrate. The persulfates modified substrates reduced the amount of adsorbed fibrinogen and albumin with higher stability to fetal bovine serum. Moreover, platelet study also demonstrated that Ru and RuS presented lower platelet adhesion with round shape morphology, whereas the control Co-Cr adhere and activate many platelets with pseudopodium morphology. Moreover, these modification processes did not cause any inflammatory responses. In conclusion, it is believed that the persulfates flavonoids have a great potential in the field of drug-eluting stents and blood contacting medical implants to improve blood compatibility, suppress SMCs, and get rapid re-endothelialization.

Augmented re-endothelialization and anti-inflammation of coronary drug-eluting stent by abluminal coating with magnesium hydroxide.

Drug-eluting stents (DESs) have been widely used as a treatment approach for coronary artery diseases. Generally, conventional DESs were fully covered with drugs and biodegradable polymers on both abluminal and luminal layers (i.e., conformal coating). However, uncontrolled drug release from the luminal drug-coating layer of the stent is known to inhibit re-endothelialization. Furthermore, the acidification of the surrounding tissue by the decomposed coating polymer causes inflammation, resulting in restenosis and late thrombosis. To overcome these limitations, here we demonstrated a functional DES coated with poly(lactic-co-glycolic acid) (PLGA), sirolimus (SRL), and magnesium hydroxide (Mg(OH)2, MH) precisely only on the abluminal layer. The acidic neutralization effect of MH was elucidated by measuring the pH change of the fabricated film in PBS solution. In an in vitro cell study, the stent coated with MH exhibited higher compatibility with human coronary artery endothelial cells (ECs) and a lower inflammation score as compared to the control stent. Finally, in an in vivo large porcine model, the abluminal coated DES with SRL and MH showed excellent re-endothelialization and anti-inflammatory and anti-thrombotic effects. In conclusion, it is believed that this approach has great potential for the development of functional DES for the treatment of cardiovascular diseases.

Sustained drug release using cobalt oxide nanowires for the preparation of polymer-free drug-eluting stents.

Polymer-based drug-eluting stents (DESs) represented attractive application for the treatment of cardiovascular diseases; however, polymer coating has caused serious adverse responses to tissues such as chronic inflammation due to acidic by-products. Therefore, polymer-free DESs have recently emerged as promising candidates for the treatment; however, burst release of drug(s) from the surface limited its applications. In this study, we focused on delivery of therapeutic drug from polymer-free (or -less) DESs through surface modification using cobalt oxide nanowires (Co3O4 NWs) to improve and control the drug release. The results demonstrated that Co3O4 NWs could be simply fabricated on cobalt-chromium substrate by ammonia-evaporation-induced method. The Co3O4 NWs were uniformly arrayed with diameters of 50-100 nm and lengths of 10 µm. It was found that Co3O4 NWs were comparatively stable without any delamination or change of the morphology under in vitro long-term stability using circulating system. Sirolimus was used as a model drug for studying in vitro release behavior under physiological conditions. The sirolimus release behavior from flat cobalt-chromium showed an initial burst (over 90%) after one day. On the other hand, Co3O4 NWs presented a sustained sirolimus release rate for up to seven days. Similarly, the polymer-less specimens on Co3O4 NWs substrates sustained sirolimus release for a longer-period of time when compared to flat Co-Cr substrates. In summary, the current approach of using Co3O4 NWs-based substrates might have a great potential to sustain drug release for drug-eluting implants and medical devices including stents.

Recent advances to accelerate re-endothelialization for vascular stents.

Cardiovascular diseases are considered as one of the serious diseases that leads to the death of millions of people all over the world. Stent implantation has been approved as an easy and promising way to treat cardiovascular diseases. However, in-stent restenosis and thrombosis remain serious problems after stent implantation. It was demonstrated in a large body of previously published literature that endothelium impairment represents a major factor for restenosis. This discovery became the driving force for many studies trying to achieve an optimized methodology for accelerated re-endothelialization to prevent restenosis. Thus, in this review, we summarize the different methodologies opted to achieve re-endothelialization, such as, but not limited to, manipulation of surface chemistry and surface topography.

The effect of solvents and hydrophilic additive on stable coating and controllable sirolimus release system for drug-eluting stent.

Various drug-eluting stents (DESs) have been developed to prevent restenosis after stent implantation. However, DES still needs to improve the drug-in-polymer coating stability and control of drug release for effective clinical treatment. In this study, the cobalt-chromium (CoCr) alloy surface was coated with biodegradable poly(D,L-lactide) (PDLLA) and sirolimus (SRL) mixed with hydrophilic Pluronic F127 additive by using ultrasonic spray coating system in order to achieve a stable coating surface and control SRL release. The degradation of PDLLA/SRL coating was studied under physiological solution. It was found that adding F127 reduced the degradation of PDLLA and improved the coating stability during 60days. The effects of organic solvent such as chloroform and tetrahydrofuran (THF) on the coating uniformity were also examined. It was revealed that THF produced a very smooth and uniform coating compared to chloroform. The patterns of in vitro drug release according to the type of organic solvent and hydrophilic additive proposed the possibility of controllable drug release design in DES. It was found that using F127 the drug release was sustained regardless of the organic solvent used. In addition, THF was able to get faster and controlled release profile when compared to chloroform. The structure of SRL molecules in different organic solvents was investigated using ultra-small angle neutron scattering. Furthermore, the structure of SRL is concentration-dependent in chloroform with tight nature under high concentration, but concentration-independent in THF. These results strongly demonstrated that coating stability and drug release patterns can be changed by physicochemical properties of various parameters such as organic solvents, additive, and coating strategy.

A Promising Approach for Improving the Coating Stability and In Vivo Performance of Biodegradable Polymer-Coated Sirolimus-Eluting Stent.

Several developments are in progress for improving the performance of drug-eluting stents (DESs) including use of biodegradable polymers, polymer-free DES, fully bioabsorbable stents, and so on. The commercially available DESs still suffer from polymer defects that could affect the performance of a DES through a series of adverse events such as coating delamination and/or peeling-off that lead to non-uniform local drug distribution, restenosis, and thrombosis. The goal of this work was to enhance the stability of drug-in-polymer matrix coating on a stent metal surface through surface modification. The cobalt­chromium (Co­Cr) surface was chemically modified using poly(dopamine) (PDA) nano-coating and poly(L-lactide) (PLLA) nano-brush in order to be applied to a biodegradable polymer-coated DES. The biodegradable polymer loaded with sirolimus was coated using an ultrasonic spray coating instrument. The coating morphology on all samples showed a very smooth and uniform coating. The stability of the coating was evaluated for 2 months under the circulation system in which the drug-in-polymer coating on the PLLA brush-modified stent presented the most stable coating behavior as compared to other samples. The in vitro sirolimus release study from both unmodified and modified stents was studied in phosphate-buffered saline (PBS), and the modified stents showed slower sirolimus release profile as compared to unmodified stents. In vivo study was performed in a porcine coronary artery injury model for 28 days. The percentage of in-stent restenosis area (ISR) for PLLA brush-modified sirolimus-eluting stent (SES) decreased significantly as compared to unmodified SES and bare metal stent (BMS). This study demonstrated that the modification of stent surface using PLLA brushes affects in vitro and in vivo performance effectively to be applied for biodegradable polymercoated DES.

Effects of interfacial layer wettability and thickness on the coating morphology and sirolimus release for drug-eluting stent.

Drug-eluting stents (DESs) have been used to treat coronary artery diseases by placing in the arteries. However, current DESs still suffer from polymer coating defects such as delamination and peeling-off that follows stent deployment. Such coating defects could increase the roughness of DES and might act as a source of late or very late thrombosis and might increase the incident of restenosis. In this regard, we modified the cobalt-chromium (Co-Cr) alloy surface with hydrophilic poly(2-hydroxyethyl methacrylate) (PHEMA) or hydrophobic poly(2-hydroxyethyl methacrylate)-grafted-poly(caprolactone) (PHEMA-g-PCL) brushes. The resulting surfaces were biocompatible and biodegradable, which could act as anchoring layer for the drug-in-polymer matrix coating. The two modifications were characterized by ATR-FTIR, XPS, water contact angle measurements, SEM and AFM. On the control and modified Co-Cr samples, a sirolimus (SRL)-containing poly(D,L-lactide) (PDLLA) were ultrasonically spray-coated, and the drug release was examined for 8weeks under physiological conditions. The results demonstrated that PHEMA as a primer coating improved the coating stability and degradation morphology, and drug release profile for short-term as compared to control Co-Cr, but fails after 7weeks in physiological buffer. On the other hand, the hydrophobic PHEMA-g-PCL brushes not only enhanced the stability and degradation morphology of the PDLLA coating layer, but also sustained SRL release for long-term. At 8-week of release test, the surface morphologies and release profiles of coated PDLLA layers verified the beneficial effect of hydrophobic PCL brushes as well as their thickness on coating stability. Our study concludes that 200nm thickness of PHEMA-g-PCL as interfacial layer affects the stability and degradation morphology of the biodegradable coating intensively to be applied for various biodegradable-based DESs.

Biodegradable polymer brush as nanocoupled interface for improving the durability of polymer coating on metal surface.

Metal-based drug-eluting stents (DESs) have severe drawbacks such as peeling-off and cracking of the coated polymer. To prevent the fracture of polymer-coated layer and improve the durability of DES, poly(l-lactide) (PLLA) brushes were synthesized onto cobalt-chromium (Co-Cr or CC) surface through atom transfer radical polymerization (ATRP) of 2-hydroxyethylmethacrylate (HEMA) followed by surface-initiated ring opening polymerization (SI-ROP) of l-lactide. The polymer brushes were then characterized by attenuated total reflection-Fourier transform infrared (ATR-FTIR), water contact angle, ellipsometry, X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and scanning electron microscopy (SEM). All of the unmodified and modified Co-Cr surfaces were coated with a matrix of poly(d,l-lactide) (PDLLA) and sirolimus (SRL). The in vitro drug release profile was measured for 70 days. The PLLA-modified Co-Cr showed a biphasic release pattern in the initial burst followed by a slow release. On the other hand, the unmodified Co-Cr showed fast drug release and detachment of the coated polymer layer due to the instability of the polymer layer on Co-Cr surface. In comparison, the PLLA-modified Co-Cr preserved a uniform coating without detachment even after 6 weeks of degradation test. The platelet morphology and low density of platelet adhered on the modified layer and the SRL-in-PDLLA coated Co-Cr surfaces demonstrated that these samples would be blood compatible. Therefore, the introduction of PLLA brush onto Co-Cr surface is proved to dramatically improve the durability of the coating layer, and it is a promising strategy to prevent the coating defects found in DESs.