Metal ion chelation of poly(aspartic acid): From scale inhibition to therapeutic potentials.

Poly(aspartic acid) (PASP) is a biodegradable, biocompatible water-soluble synthetic anionic polypeptide. PASP has shown a strong affinity and thus robust complexation with heavy and alkaline earth metal ions, from which several applications are currently benefiting, and several more could also originate. This paper discusses different areas where the ion chelation ability of PASP has thus far been exploited. Due to its calcium chelation ability, PASP prevents precipitation of calcium salts and hence is widely used as an effective scale inhibitor in industry. Due to potassium chelation, PASP prevents precipitation of potassium tartrate and is employed as an efficient and edible stabilizer for wine preservation. Due to iron chelation, PASP inhibits corrosion of steel surfaces in harsh environments. Due to chelation, PASP can also enhance stability of various colloidal systems that contain metal ions. The chelation ability of PASP alleviated the toxicity of heavy metals in Zebrafish, inhibited the formation of kidney stones and dissolved calcium phosphate which is the main mineral of the calcified vasculature. These findings and beyond, along with the biocompatibility and biodegradability of the polymer could direct future investigations towards chelation therapy by PASP and other novel and undiscovered areas where metal ions play a key role.

Poly(succinimide) nanoparticles as reservoirs for spontaneous and sustained synthesis of poly(aspartic acid) under physiological conditions: potential for vascular calcification therapy and oral drug delivery.

This paper describes the preparation of poly(succinimide) nanoparticles (PSI NPs) and investigates their properties and characteristics. Employing direct and inverse precipitation methods, stable PSI NPs with tunable size and narrow dispersity were prepared without the use of any stabilizer or emulsifier. It was demonstrated that PSI NPs convert to poly(aspartic acid) (PASP) gradually under physiological conditions (37 °C, pH 7.4), while remaining stable under mildly acidic conditions. The dissolution profile was tuned and delayed by chemical modification of PSI. Through grafting a fluorophore to the PSI backbone, it was also demonstrated that such a spontaneous conversion could offer great potential for oral delivery of therapeutic agents to the colon. Sustained PASP synthesis also contributed to a sustained reduction of reactive oxygen species induced by iron. Furthermore, PSI NPs effectively prevented in vitro calcification of smooth muscle cells. This was attributed to the chelation of calcium ions to PASP, thereby inhibiting calcium deposition, because under cell culture conditions PSI NPs serve as reservoirs for the sustained synthesis of PASP. Overall, this study sheds light on the preparation and features of biocompatible and biodegradable PSI-based NPs and paves the way for further research to discover as-yet unfulfilled potential of this polymer in the form of nanoparticles.

A Bioactive Disintegrable Polymer Nanoparticle for Synergistic Vascular Anticalcification.

Although poly(aspartic acid) (PASP), a strong calcium chelating agent, may be potentially effective in inhibition of vascular calcification, its direct administration may lead to side effects. In this study, we employed polysuccinimide, a precursor of PASP, to prepare targeted polysuccinimide-based nanoparticles (PSI NPs) that not only acted as a prodrug but also functioned as a carrier of additional therapeutics to provide powerful synergistic vascular anticalcification effect. This paper shows that chemically modified PSI-NPs can serve as effective nanocarriers for loading of hydrophobic drugs, in addition to anticalcification and antireactive oxygen species (anti-ROS) activities. Curcumin (Cur), with high loading efficiency, was encapsulated into the NPs. The NPs were stable for 16 h in physiological conditions and then slowly dissolved/hydrolyzed to release the therapeutic PASP and the encapsulated drug. The drug release profile was found to be in good agreement with the NP dissolution profile such that complete release occurred after 48 h at physiological conditions. However, under acidic conditions, the NPs were stable, and Cur cumulative release reached only 30% after 1 week. Though highly effective in the prevention of calcium deposition, PSI NPs could not prevent the osteogenic trans-differentiation of vascular smooth muscle cells (VSMCs). The presence of Cur addressed this problem. It not only further reduced ROS level in macrophages but also prevented osteogenic differentiation of VSMCs in vitro. The NPs were examined in vivo in a rat model of vascular calcification induced by kidney failure through an adenine diet. The inclusion of Cur and PSI NPs combined the therapeutic effects of both. Cur-loaded NPs significantly reduced calcium deposition in the aorta without adversely affecting bone integrity or noticeable side effects/toxicity as examined by organ histological and serum biochemistry analyses.

Enhanced in vitro and in vivo anticancer activity through the development of Sunitinib-Loaded nanoniosomes with controlled release and improved uptake.

This study aims to develop sunitinib niosomal formulations and assess their in-vitro anti-cancer efficiency against lung cancer cell line, A549. Sunitinib, a highly effective anticancer drug, was loaded in the niosome with high encapsulation efficiency. Collagen was coated on the surface of the niosome for enhanced cellular uptake and prolonged circulation time. Different formulations were produced, while response surface methodology was utilized to optimize the formulations. The stability of the formulations was evaluated over a 2-month period, revealing the importance of collagen coating. MTT assay demonstrated dose-dependent cytotoxicity for all formulations against lung cancer cells. Scratch assay test suggested antiproliferative efficacy of the formulations. The flow cytometry data confirmed the improved cytotoxicity with enhanced apoptosis rate when different formulations used. The 2D fluorescent images proved the presence of drug-containing niosomes in the tumor cells. The activation of the apoptotic pathway leading to protein synthesis was confirmed using an ELISA assay, which specifically evaluated the presence of cas3 and cas7. The results of this study indicated the antiproliferative efficacy of optimized niosomal formulations and their mechanism of action. Therefore, niosomes could be utilized as a suitable carrier for delivering sunitinib into lung cancer cells, paving the way for future clinical studies.

PEG-grafted liposomes for enhanced antibacterial and antibiotic activities: An in vivo study.

Staphylococcus aureus (S. aureus) biofilm-associated infections are a primary concern for public health worldwide. Current therapeutics cannot penetrate the biofilms efficiently, resulting in low drug concentrations at the infected sites and increasing the frequency of drug usage. To solve this issue, nanotechnology platforms seem to be a promising approach. In this study, the potential therapeutic effects of (PEG)ylated liposome (PEG-Lip) for the delivery of nafcillin (NF) antibiotic were assessed. The results demonstrated that NF-loaded liposome (Lip-NF) and NF-loaded PEG-Lip (PEG-Lip-NF) released 76.4 and 62% of the loaded NF, respectively, in a controlled manner after 50 h. Also, it was found that PEG-Lip-NF, compared to Lip-NF and NF, was more effective against a methicillin-susceptible S. aureus (MSSA; minimum inhibitory concentration (MIC): 1.0 ± 0.03, 0.5 ± 0.02, and 0.25 ± 0.01 µg/mL; and minimum biofilm inhibitory concentration (MBIC50): 4.0 ± 0.18, 1.0 ± 0.04, and 0.5 ± 0.02 µg/mL for NF, Lip-NF, and PEG-Lip-NF, respectively). PEG-Lip-NF, compared to NF and Lip-NF, could also more efficiently decrease the side effects of NF through improving human MG-63 osteoblast cell viability (cell viability at 100 µM of NF: 76, 68, and 38% for PEG-Lip-NF, Lip-NF, and NF, respectively). PEG-Lip-NF, compared to control, NF, and Lip-NF groups, was more efficacious by 45, 25, and 10%, respectively, to decrease the virulence of MSSA bacteremia through inhibiting the weight loss of the infected mice. Also, PEG-Lip-NF and Lip-NF, compared to control and NF groups, caused a considerable decrease in the mortality rate in a murine model of bacteremia (number of dead mice: 0, 0, 2, and 8 out of 15 for PEG-Lip-NF, Lip-NF, NF, and control groups, respectively). Overall, the results of this study demonstrated that the loading of NF into PEG-Lip is a promising strategy to decrease the side effects of NF with improved antibacterial effects for the treatment of MSSA biofilm-associated infections.

Atherothrombosis-on-Chip: A Site-Specific Microfluidic Model for Thrombus Formation and Drug Discovery.

Atherothrombosis, an atherosclerotic plaque disruption condition with superimposed thrombosis, is the underlying cause of cardiovascular episodes. Herein, a unique design is presented to develop a microfluidic site-specific atherothrombosis-on-chip model, providing a universal platform for studying the crosstalk between blood cells and plaque components. The device consists of two interconnected microchannels, namely main and supporting channels: the former mimics the vessel geometry with different stenosis, and the latter introduces plaque components to the circulation simultaneously. The unique design allows the site-specific introduction of plaque components in stenosed channels ranging from 0% to above 50%, resulting in thrombosis, which has not been achieved previously. The device successfully explains the correlation between vessel geometry and thrombus formation phenomenon as well as the influence of shear rate on platelet aggregation, confirming the reliability and the effectiveness of the design. The device exhibits significant sensitivity to aspirin. In therapeutic doses (50 × 10-6 and 100 × 10-6 m), aspirin delays and prevents platelet adhesion, thereby reducing the thrombus area in a dose-dependent manner. Finally, the device is effectively employed in testing the targeted binding of the RGD (arginyl-glycyl-aspartic acid) labeled polymeric nanoparticles on the thrombus, extending the use of the device to examine targeted drug carriers.

Ciprofloxacin-Loaded Titanium Nanotubes Coated with Chitosan: A Promising Formulation with Sustained Release and Enhanced Antibacterial Properties.

Due to their high entrapment efficiency, anodized titanium nanotubes (TiO2-NTs) are considered effective reservoirs for loading/releasing strong antibiotics whose systemic administration is associated with diverse and severe side-effects. In this study, TiO2-NTs were synthesized by anodic oxidation of titanium foils, and the effects of electrolyte percentage and viscosity on their dimensions were evaluated. It was found that as the water content increased from 15 to 30%, the wall thickness, length, and inner diameter of the NTs increase from 5.9 to 15.8 nm, 1.56 to 3.21 µm, and 59 to 84 nm, respectively. Ciprofloxacin, a highly potent antibiotic, was loaded into TiO2-NTs with a high encapsulation efficiency of 93%, followed by coating with different chitosan layers to achieve a sustained release profile. The prepared formulations were characterized by various techniques, such as scanning electron microscopy, differential scanning calorimetry, and contact measurement. In vitro release studies showed that the higher the chitosan layer count, the more sustained the release. Evaluation of antimicrobial activity of the formulation against two endodontic species from Peptostreptococcus and Fusobacterium revealed minimum inhibitory concentrations (MICs) of 1 µg/mL for the former and the latter. To summarize, this study demonstrated that TiO2-NTs are promising reservoirs for drug loading, and that the chitosan coating provides not only a sustained release profile, but also a synergistic antibacterial effect.

On-demand deterministic release of particles and cells using stretchable microfluidics.

Microfluidic technologies have been widely used for single-cell studies as they provide facile, cost-effective, and high-throughput evaluations of single cells with great accuracy. Capturing single cells has been investigated extensively using various microfluidic techniques. Furthermore, cell retrieval is crucial for the subsequent study of cells in applications such as drug screening. However, there are no robust methods for the facile release of the captured cells. Therefore, we developed a stretchable microfluidic cell trapper for easy on-demand release of cells in a deterministic manner. The stretchable microdevice consists of several U-shaped microstructures to capture single cells. The gap at the bottom edge of the microstructure broadens when the device is stretched along its width. By tuning the horizontal elongation of the device, ample space is provided to release particle/cell sizes of interest. The performance of the stretchable microdevice was evaluated using particles and cells. A deterministic release of particles was demonstrated using a mixture of 15 µm and 20 µm particles. The retrieval of the 15 µm particles and the 20 µm particles was achieved with elongation lengths of 1 mm and 5 mm, respectively. Two different cell lines, T47D breast cancer cells and J774A.1 macrophages, were employed to characterise the cell release capability of the device. The proposed stretchable micro cell trapper provided a deterministic recovery of the captured cells by adjusting the elongation length of the device. We believe that this stretchable microfluidic platform can provide an alternative method to facilely release trapped cells for subsequent evaluation.

A PEGylated Nanostructured Lipid Carrier for Enhanced Oral Delivery of Antibiotics.

Antimicrobial resistance is a major concern for public health throughout the world that severely restricts available treatments. In this context, methicillin-resistant Staphylococcus aureus (MRSA) is responsible for a high percentage of S. aureus infections and mortality. To overcome this challenge, nanoparticles are appropriate tools as drug carriers to improve the therapeutic efficacy and decrease the toxicity of drugs. In this study, a polyethylene glycol (PEG)ylated nanostructured lipid carrier (PEG-NLC) was synthesized to improve the oral delivery of trimethoprim/sulfamethoxazole (TMP/SMZ) for the treatment of MRSA skin infection in vitro and in vivo. The nanoformulation (PEG-TMP/SMZ-NLC) was synthesized with size and drug encapsulation efficiencies of 187 ± 9 nm and 93.3%, respectively, which could release the drugs in a controlled manner at intestinal pH. PEG-TMP/SMZ-NLC was found efficient in decreasing the drugs' toxicity by 2.4-fold in vitro. In addition, the intestinal permeability of TMP/SMZ was enhanced by 54%, and the antibacterial effects of the drugs were enhanced by 8-fold in vitro. The results of the stability study demonstrated that PEG-TMP/SMZ-NLC was stable for three months. In addition, the results demonstrated that PEG-TMP/SMZ-NLC after oral administration could decrease the drugs' side-effects such as renal and hepatic toxicity by ~5-fold in MRSA skin infection in Balb/c mice, while it could improve the antibacterial effects of TMP/SMZ by 3 orders of magnitude. Overall, the results of this study suggest that the application of PEGylated NLC nanoparticles is a promising approach to improving the oral delivery of TMP/SMZ for the treatment of MRSA skin infection.

Collagen and the effect of poly-l-lactic acid based materials on its synthesis.

Collagen is an important protein in various biological functions such as providing elasticity and waterproofing to the skin, structural stability to the cells in connective tissues (e.g. tendons, and bone) and stabilisation of atherosclerotic plaques. Collagen as a peptide with a peculiar triple helical structure is majorly composed of glycine and proline amino acids and is synthesised by fibroblasts via intracellular and extracellular mechanisms. Collagen plays an important role in wound healing, bone repair and plaque build-up during atherosclerosis. Various factors such as interleukins, insulin-like growth factor-I, nicotine, and glucose have been shown to influence collagen synthesis. This paper provides an overview of collagen structure, synthesis mechanisms, and the parameters that stimulate those mechanisms. Poly-l-lactic acid as a well-known biocompatible and biodegradable polymer has proved to stimulate collagen synthesis in various physical forms. As such, in this review special emphasis is laid on the effects of poly-l-lactic acid as well as its mechanism of action on collagen synthesis.

Poly(aspartic acid) in Biomedical Applications: From Polymerization, Modification, Properties, Degradation, and Biocompatibility to Applications.

Poly(aspartic acid) (PASP) is an anionic polypeptide that is a highly versatile, biocompatible, and biodegradable polymer that fulfils key requirements for use in a wide variety of biomedical applications. The derivatives of PASP can be readily tailored via the amine-reactive precursor, poly(succinimide) (PSI), which opens up a large window of opportunity for the design and development of novel biomaterials. PASP also has a strong affinity with calcium ions, resulting in complexation, which has been exploited for bone targeting and biomineralization. In addition, recent studies have further verified the biocompatibility and biodegradability of PASP-based polymers, which is attributed to their protein-like structure. In light of growing interest in PASP and its derivatives, this paper presents a comprehensive review on their synthesis, characterization, modification, biodegradation, biocompatibility, and applications in biomedical areas.

Hydrogels Based on Poly(aspartic acid): Synthesis and Applications.

This review presents an overview on the recent progress in the synthesis, crosslinking, interpenetrating networks, and applications of poly(aspartic acid) (PASP)-based hydrogels. PASP is a synthetic acidic polypeptide that has drawn a great deal of attention in diverse applications due particularly to its biocompatibility and biodegradability. Facile modification of its precursor, poly(succinimide) (PSI), by primary amines has opened a wide window for the design of state-of-the-art hydrogels. Apart from pH-sensitivity, PASP hydrogels can be modified with suitable species in order to respond to the other desired stimuli such as temperature and reducing/oxidizing media as well. Strategies for fabrication of nanostructured PASP-based hydrogels in the form of particle and fiber are also discussed. Different cross-linking agents for PSI/PASP such as diamines, dopamine, cysteamine, and aminosilanes are also introduced. Finally, applications of PASP-based hydrogels in diverse areas particularly in biomedical are reviewed.

High sensitivity ammonia detection using metal nanoparticles decorated on graphene macroporous frameworks/polyaniline hybrid.

In this paper, we presented the fabrication and properties of new ammonia (NH3) sensors with sensitive layer of nickel nanoparticles decorated on three-dimensional nitrogen-doped graphene-based frameworks/polyaniline (NiNPs@3D-(N)GFs/PANI) hybrid. The hybrid are synthesized through in-situ oxidative polymerization on flexible thin substrate. Synergetic behavior between both components manifested outstanding sensitivity (750.2 at 1000 ppm NH3) and quick response (95 s) and recovery (25 s) times and a lower limit of detection (~ 45 ppb) at room temperature. The sensitivity of NiNPs@3D-(N)GFs/PANI hybrid sensor was shown to be about 14 times more than its of pure PANI sensor at 1000 ppm of NH3. The excellent sensitivity of the as-prepared hybrid is mainly originated from the substantial rise of hole-like carriers by NiNPs@3D-(N)GFs as well as improved inter-molecule interactions via π- π electron networks. The obtained results revealed significant advantages for the synthesized hybrid sensor, making it a suitable choice for real-world applications of NH3 detection.

Universal Coatings Based on Zwitterionic-Dopamine Copolymer Microgels.

Multifunctional coatings that adhere to chemically distinct substrates are vital in many industries, including automotive, aerospace, shipbuilding, construction, petrochemical, biomedical, and pharmaceutical. We design well-defined, nearly monodisperse microgels that integrate hydrophobic dopamine methacrylamide monomers and hydrophilic zwitterionic monomers. The dopamine functionalities operate as both intraparticle cross-linkers and interfacial binders, respectively providing mechanical strength of the coatings and their strong adhesion to different substrates. In tandem, the zwitterionic moieties enable surface hydration to empower antifouling and antifogging properties. Drop-casting of microgel suspensions in ambient as well as humid environments facilitates rapid film formation and tunable roughness through regulation of cross-linking density and deposition conditions.

Soap-free emulsion polymerization of poly (methyl methacrylate-co-butyl acrylate): effects of anionic comonomers and methanol on the different characteristics of the latexes.

Soap-free emulsion polymerization (SFEP) of methyl methacrylate, butyl acrylate was conducted in water/methanol media with sodium salts of four different acidic comonomers, namely styrene sulfonic acid (NaSS), 2-acrylamide-2-methyl-1-propane sulfonic acid (NaAmps), acrylic acid (NaAA), and itaconic acid (Na2ita). It was found that the introduction of methanol as co-solvent (35 wt%) to the medium greatly decreases the amount of water-soluble polyelectrolyte in the cases NaAA and Na2ita while it does not make difference for NaSS and NaAmps. Having employed the concept of conductance dependency to the ion mobility, the onset concentration in which soluble chains were formed was detected. The addition of sulfonic-based comonomers (NaSS and NaAmps), first decreased particle size and then led to predomination of solution polymerization over SFEP. On the contrary, the incorporation of carboxylic-based comonomers (NaAA and Na2ita) led to increase in particle size. Moreover, the particle size results were in good qualitative agreement with the classical Smith-Ewart theory.