PDADMAC/Alginate-Coated Gold Nanorod For Eradication of Staphylococcus Aureus Biofilms.

Introduction: Over 75% of clinical microbiological infections are caused by bacterial biofilms that grow on wounds or implantable medical devices. This work describes the development of a new poly(diallyldimethylammonium chloride) (PDADMAC)/alginate-coated gold nanorod (GNR/Alg/PDADMAC) that effectively disintegrates the biofilms of Staphylococcus aureus (S. aureus), a prominent pathogen responsible for hospital-acquired infections. Methods: GNR was synthesised via seed-mediated growth method, and the resulting nanoparticles were coated first with Alg and then PDADMAC. FTIR, zeta potential, transmission electron microscopy, and UV-Vis spectrophotometry analysis were performed to characterise the nanoparticles. The efficacy and speed of the non-coated GNR and GNR/Alg/PDADMAC in disintegrating S. aureus-preformed biofilms, as well as their in vitro biocompatibility (L929 murine fibroblast) were then studied. Results: The synthesised GNR/Alg/PDADMAC (mean length: 55.71 ± 1.15 nm, mean width: 23.70 ± 1.13 nm, aspect ratio: 2.35) was biocompatible and potent in eradicating preformed biofilms of methicillin-resistant (MRSA) and methicillin-susceptible S. aureus (MSSA) when compared to triclosan, an antiseptic used for disinfecting S. aureus colonisation on abiotic surfaces in the hospital. The minimum biofilm eradication concentrations of GNR/Alg/PDADMAC (MBEC50 for MRSA biofilm = 0.029 nM; MBEC50 for MSSA biofilm = 0.032 nM) were significantly lower than those of triclosan (MBEC50 for MRSA biofilm = 10,784 nM; MBEC50 for MRSA biofilm 5967 nM). Moreover, GNR/Alg/PDADMAC was effective in eradicating 50% of MRSA and MSSA biofilms within 17 min when used at a low concentration (0.15 nM), similar to triclosan at a much higher concentration (50 µM). Disintegration of MRSA and MSSA biofilms was confirmed by field emission scanning electron microscopy and confocal laser scanning microscopy. Conclusion: These findings support the potential application of GNR/Alg/PDADMAC as an alternative agent to conventional antiseptics and antibiotics for the eradication of medically important MRSA and MSSA biofilms.

Bispecific antibodies for targeted delivery of anti-cancer therapeutic agents: A review.

Monospecific antibodies have been utilised increasingly for anti-cancer drug targeting owing to their ability to minimise off-target toxicity by binding specifically to a tumour epitope, hence selectively delivering drugs to the tumour cells. Nevertheless, the monospecific antibodies only engage a single cell surface epitope to deliver their drug payload. Hence, their performance is often unsatisfactory in cancers where multiple epitopes need to be engaged for optimal cellular internalisation. In this context, bispecific antibodies (bsAbs) that simultaneously target two distinct antigens or two distinct epitopes of the same antigen offer a promising alternative in antibody-based drug delivery. This review describes the recent advances in developing bsAb-based drug delivery strategies, encompassing the direct conjugation of drug to bsAbs to form bispecific antibody-drug conjugates (bsADCs) and the surface functionalisation of nanoconstructs with bsAbs to form bsAb-coupled nanoconstructs. The article first details the roles of bsAbs in enhancing the internalisation and intracellular trafficking of bsADCs with subsequent release of chemotherapeutic drugs for an augmented therapeutic efficacy, particularly among heterogeneous tumour cell populations. Then, the article discusses the roles of bsAbs in facilitating the delivery of drug-encapsulating nanoconstructs, including organic/inorganic nanoparticles and large bacteria-derived minicells, that provide a larger drug loading capacity and better stability in blood circulation than bsADCs. The limitations of each type of bsAb-based drug delivery strategy and the future prospects of more versatile strategies (e.g., trispecific antibodies, autonomous drug delivery systems, theranostics) are also elaborated.

ROS-generating alginate-coated gold nanorods as biocompatible nanosonosensitisers for effective sonodynamic therapy of cancer.

Sonodynamic therapy (SDT) emerges as a promising non-invasive alternative for eradicating malignant tumours. However, its therapeutic efficacy remains limited due to the lack of sonosensitisers with high potency and biosafety. Previously, gold nanorods (AuNRs) have been extensively studied for their applications in photodynamic or photothermal cancer therapy, but their sonosensitising properties are largely unexplored. Here, we reported the applicability of alginate-coated AuNRs (AuNRsALG) with improved biocompatibility profiles as promising nanosonosensitisers for SDT for the first time. AuNRsALG were found stable under ultrasound irradiation (1.0 W/cm2, 5 min) and maintained structural integrity for 3 cycles of irradiation. The exposure of the AuNRsALG to ultrasound irradiation (1.0 W/cm2, 5 min) was shown to enhance the cavitation effect significantly and generate a 3 to 8-fold higher amount of singlet oxygen (1O2) than other reported commercial titanium dioxide nanosonosensitisers. AuNRsALG exerted dose-dependent sonotoxicity on human MDA-MB-231 breast cancer cells in vitro, with âˆ¼ 81% cancer cell killing efficacy at a sub-nanomolar level (IC50 was 0.68 nM) predominantly through apoptosis. The protein expression analysis showed significant DNA damage and downregulation of anti-apoptotic Bcl-2, suggesting AuNRsALG induced cell death through the mitochondrial pathway. The addition of mannitol, a reactive oxygen species (ROS) scavenger, inhibited cancer-killing effect of AuNRsALG-mediated SDT, further verifying that the sonotoxicity of AuNRsALG is driven by the production of ROS. Overall, these results highlight the potential application of AuNRsALG as an effective nanosonosensitising agent in clinical settings.

Recent development of biodegradable synthetic rubbers and bio-based rubbers using sustainable materials from biological sources.

Rubber is an amorphous hyperelastic polymer which is widely used in this modern era. Natural rubber is considered the ultimate rubber in terms of mechanical performance, but over the years, some limitations and challenges in natural rubber cultivation that could result in serious shortages in the supply chain had been identified. Since then, the search for alternatives including new natural and synthetic rubbers has been rather intense. The initiative to explore new sources of natural rubber which started during the 1940s has been reignited recently due to the increasing demand for natural rubber. The commercialization of natural rubber from the Parthenium argentatum and Taraxacum kok-saghyz species, with the cooperation from rubber product manufacturing companies, has somewhat improved the sustainability of the natural rubber supply chain. Meanwhile, the high demand for synthetic rubber drastically increases the rate of depletion of fossil fuels and amplifies the adverse environmental effect of overexploitation of fossil fuels. Moreover, rubber and plastic products disposal have been a major issue for many decades, causing environmental pollution and the expansion of landfills. Sustainable synthetic rubber products could be realized through the incorporation of materials from biological sources. They are renewable, low cost, and most importantly, biodegradable in nature. In this review, brief introduction to natural and synthetic rubbers, challenges in the rubber industry, alternatives to conventional natural rubber, and recent advances in biodegradable and/or bio-based synthetic rubbers are discussed. The effect of incorporating various types of biologically sourced materials in the synthetic rubbers are also elaborated in detail.

Chitosan-Coated-PLGA Nanoparticles Enhance the Antitumor and Antimigration Activity of Stattic - A STAT3 Dimerization Blocker.

PURPOSE: The use of nanocarriers to improve the delivery and efficacy of antimetastatic agents is less explored when compared to cytotoxic agents. This study reports the entrapment of an antimetastatic Signal Transducer and Activator of Transcription 3 (STAT3) dimerization blocker, Stattic (S) into a chitosan-coated-poly(lactic-co-glycolic acid) (C-PLGA) nanocarrier and the improvement on the drug's physicochemical, in vitro and in vivo antimetastatic properties post entrapment. METHODS: In vitro, physicochemical properties of the Stattic-entrapped C-PLGA nanoparticles (S@C-PLGA) and Stattic-entrapped PLGA nanoparticles (S@PLGA, control) in terms of size, zeta potential, polydispersity index, drug loading, entrapment efficiency, Stattic release in different medium and cytotoxicity were firstly evaluated. The in vitro antimigration properties of the nanoparticles on breast cancer cell lines were then studied by Scratch assay and Transwell assay. Study on the in vivo antitumor efficacy and antimetastatic properties of S@C-PLGA compared to Stattic were then performed on 4T1 tumor bearing mice. RESULTS: The S@C-PLGA nanoparticles (141.8 ± 2.3 nm) was hemocompatible and exhibited low Stattic release (12%) in plasma. S@C-PLGA also exhibited enhanced in vitro anti-cell migration potency (by >10-fold in MDA-MB-231 and 5-fold in 4T1 cells) and in vivo tumor growth suppression (by 33.6%) in 4T1 murine metastatic mammary tumor bearing mice when compared to that of the Stattic-treated group. Interestingly, the number of lung and liver metastatic foci was found to reduce by 50% and 56.6%, respectively, and the average size of the lung metastatic foci was reduced by 75.4% in 4T1 tumor-bearing mice treated with S@C-PLGA compared to Stattic-treated group (p < 0.001). CONCLUSION: These findings suggest the usage of C-PLGA nanocarrier to improve the delivery and efficacy of antimetastatic agents, such as Stattic, in cancer therapy.

Renal Nano-drug delivery for acute kidney Injury: Current status and future perspectives.

Acute kidney injury (AKI) causes considerable morbidity and mortality, particularly in the case of post-cardiac infarction or kidney transplantation; however, the site-specific accumulation of small molecule reno-protective agents for AKI has often proved ineffective due to dynamic fluid and solute excretion and non-selectivity, which impedes therapeutic efficacy. This article reviews the current status and future trajectories of renal nanomedicine research for AKI management from pharmacological and clinical perspectives, with a particular focus on appraising nanosized drug carrier (NDC) use for the delivery of reno-protective agents of different pharmacological classes and the effectiveness of NDCs in improving renal tissue targeting selectivity and efficacy of said agents. This review reveals the critical shift in the role of the small molecule reno-protective agents in AKI pharmacotherapy - from prophylaxis to treatment - when using NDCs for delivery to the kidney. We also highlight the need to identify the accumulation sites of NDCs carrying reno-protective agents in renal tissues during in vivo assessments and detail the less-explored pharmacological classes of reno-protective agents whose efficacies may be improved via NDC-based delivery. We conclude the paper by outlining the challenges and future perspectives of NDC-based reno-protective agent delivery for better clinical management of AKI.

Development of nanostructured lipid carrier (NLC) assisted with polysorbate nonionic surfactants as a carrier for l-ascorbic acid and Gold Tri.E 30.

Lipid nanocarrier displays the advantages over conventional drug carriers as they are formulated with biodegradable and non-irritant lipids. However, the main drawbacks are the agglomeration of lipid particles, instability over storage, low drug loading, and the burst release of active ingredients. In this study, we investigated the effects of various polysorbate nonionic surfactants namely Tween 20, 40, 60, or 80 on the nanostructured lipid carrier (NLC). NLC incorporated with polysorbate nonionic surfactant was prepared by using high-pressure homogenization technique. The average size was reduced to 139.9 ± 15.8 nm in the presence of Tween 80 and remained stable in nano-size even incubated for 28 days. Encapsulation of l-ascorbic acid or Gold Tri.E 30 showed a high encapsulation efficiency of more than 75%, where the highest was Gold Tri.E in the presence of Tween 60 at 99.7%. In vitro release study showed that the release of both l-ascorbic acid and Gold Tri.E was significantly reduced in NLC with Tween as compared to bare active ingredients and NLC without Tween. In conclusion, the incorporation of Tween successfully produced a lipid nanocarrier that has the potential to be developed as a carrier of various active ingredients such as nutrients, extracts, and drugs.

Rheological behavior of biodegradable N-succinyl chitosan-g-poly (acrylic acid) hydrogels and their applications as drug carrier and in vitro theophylline release.

Novel pH sensitive N-succinyl chitosan-g-poly (acrylic acid) hydrogels were synthesized through free radical mechanism. Rheometer was used to observe the mechanical strength of the hydrogels. In vitro degradation was conducted in SIF (pH 7.4). The effect of concentration of monomers, initiator, and crosslinking agent and pH and ionic strength of NaCl, CaCl2, and AlCl3 on swelling of the hydrogels was observed. The results showed that equilibrium swelling ratio was highly influenced by concentration of monomers, initiator, and crosslinking agent concentration, and pH and salt solutions of NaCl, CaCl2, and AlCl3. The swelling kinetics revealed that swelling followed non-Fickian anomalous transport. Furthermore, theophylline loading (DL %) and encapsulation efficiency (EE %) of the hydrogels was in the range of 15.5 ±â€¯0.15-22.8 ±â€¯0.06% and 62 ±â€¯0.15-91 ±â€¯0.26%, respectively. The release of theophylline in physiological mediums was strongly influenced by the pH. The theophylline release was in the range of 51 ±â€¯0.20-92 ±â€¯0.12% in SIF and 7.4 ±â€¯0.02-14.9 ±â€¯0.03% in SGF (pH 1.2), respectively. The release data fitted well to Korsmeyer-Peppas model. The chemical activity of the theophylline suggested that drug maintained its chemical activity after release in vitro. The results suggest that synthesized hydrogels are excellent drug carriers.

Correction: pH responsive N-succinyl chitosan/Poly (acrylamide-co-acrylic acid) hydrogels and in vitro release of 5-fluorouracil.

[This corrects the article DOI: 10.1371/journal.pone.0179250.].

pH responsive N-succinyl chitosan/Poly (acrylamide-co-acrylic acid) hydrogels and in vitro release of 5-fluorouracil.

There has been significant progress in the last few decades in addressing the biomedical applications of polymer hydrogels. Particularly, stimuli responsive hydrogels have been inspected as elegant drug delivery systems capable to deliver at the appropriate site of action within the specific time. The present work describes the synthesis of pH responsive semi-interpenetrating network (semi-IPN) hydrogels of N-succinyl-chitosan (NSC) via Schiff base mechanism using glutaraldehyde as a crosslinking agent and Poly (acrylamide-co-acrylic acid)(Poly (AAm-co-AA)) was embedded within the N-succinyl chitosan network. The physico-chemical interactions were characterized by Fourier transform infrared (FTIR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), and field emission scanning electron microscope (FESEM). The synthesized hydrogels constitute porous structure. The swelling ability was analyzed in physiological mediums of pH 7.4 and pH 1.2 at 37°C. Swelling properties of formulations with various amounts of NSC/ Poly (AAm-co-AA) and crosslinking agent at pH 7.4 and pH 1.2 were investigated. Hydrogels showed higher swelling ratios at pH 7.4 while lower at pH 1.2. Swelling kinetics and diffusion parameters were also determined. Drug loading, encapsulation efficiency, and in vitro release of 5-fluorouracil (5-FU) from the synthesized hydrogels were observed. In vitro release profile revealed the significant influence of pH, amount of NSC, Poly (AAm-co-AA), and crosslinking agent on the release of 5-FU. Accordingly, rapid and large release of drug was observed at pH 7.4 than at pH 1.2. The maximum encapsulation efficiency and release of 5-FU from SP2 were found to be 72.45% and 85.99%, respectively. Kinetics of drug release suggested controlled release mechanism of 5-FU is according to trend of non-Fickian. From the above results, it can be concluded that the synthesized hydrogels have capability to adapt their potential exploitation as targeted oral drug delivery carriers.

Distribution and health risk assessment of trace metals in freshwater tilapia from three different aquaculture sites in Jelebu Region (Malaysia).

The trace metal concentrations in edible muscle of red tilapia (Oreochromis spp.) sampled from a former tin mining pool, concrete tank and earthen pond in Jelebu were analysed with microwave assisted digestion-inductively coupled plasma-mass spectrometry. Results were compared with established legal limits and the daily ingestion exposures simulated using the Monte Carlo algorithm for potential health risks. Among the metals investigated, arsenic was found to be the key contaminant, which may have arisen from the use of formulated feeding pellets. Although the risks of toxicity associated with consumption of red tilapia from the sites investigated were found to be within the tolerable range, the preliminary probabilistic estimation of As cancer risk shows that the 95th percentile risk level surpassed the benchmark level of 10(-5). In general, the probabilistic health risks associated with ingestion of red tilapia can be ranked as follows: former tin mining pool > concrete tank > earthen pond.

Effect of PEGylated lipid and Lecinol S-10 on physico-chemical properties and encapsulation efficiency of palmitoleate-palmitoleic acid vesicles.

A vesicle is a microscopic particle composed of a lipid bilayer membrane that separates the inner aqueous compartment from the outer aqueous environment. Palmitoleate-palmitoleic acid vesicles were prepared and their physico-chemical properties were investigated. Moreover, mixed vesicles composed of palmitoleic acid and PEGylated lipid and/or a mixture of phospholipids were also prepared. The stabilizing effects of these double-chain lipids on the formation of palmitoleate-palmitoleic acid vesicles were studied. Stability of the vesicle suspension was examined using particle size and zeta potential at 30 °C. The magnitude of the zeta potential was relatively lower in the vesicle suspension with the presence of phospholipid. Although some of the mixed vesicles that were formed were not very stable, they displayed potential for encapsulating the active ingredient calcein and the encapsulation efficiencies of calcein were encouraging. The palmitoleate-palmitoleic acid-DPPE-PEG2000 vesicle showed the most promising stability and encapsulation efficiency.

Dicyclo-hexyl-ammonium bis-(chloro-difluoro-acetato-κO)cyclo-pentyl-diphenyl-stannate(IV).

The five-coordinate Sn atom in the title mixed organyl stannate compound, (C(12)H(24)N)[Sn(C(5)H(9))(C(6)H(5))(2)(C(2)ClF(2)O(2))], is in a trans-C(3)SnO(2) trigonal-bipyramidal coordination environment. The NH(2) groups of the cations act as hydrogen-bond donors to two symmetry-related anions, resulting in the formation of linear chains. One of the phenyl rings is disordered over two sites with equal occupancies.

Bis[1,3-bis-(diphenyl-phosphino)propane-κP:P']silver(I) bis-(chloro-difluoro-acetato-κO)triphenyl-stannate(IV).

In the title salt, [Ag(C(27)H(26)P(2))(2)][Sn(C(6)H(5))(3)(C(2)ClF(2)O(2))], the Ag(I) atom exists in a tetra-hedral coordination geometry formed by four P atoms [Ag-P = 2.460 (1)-2.501 (1) Å], whereas the Sn(IV) atom exists in a trans-trigonal-bipyramidal coordination geometry formed by two O [Sn-O = 2.208 (3) and 2.233 (3) Å] and three C atoms [Sn-C = 2.115 (4)-2.128 (4) Å;(Σ C-Sn-C)= 360.0 (6)°].

Dicyclo-hexyl-ammonium bis-(chloro-difluoro-acetato-κO)cyclo-hexyl-diphenyl-stannate(IV).

In the title mixed-organyl stannate, (C(12)H(24)N)[Sn(C(6)H(5))(2)(C(6)H(11))(CClF(2)O(2))(2)], there are two cations and two anions in the asymmetric unit. Each five-coordinate Sn atom shows trans-C(3)SnO(2) trigonal bipyramidal coordination. The four Sn-O distances are approximately equal in the two independent anions. Each ammonium cation serves as a hydrogen-bond donor to two stannates, the hydrogen-bonding inter-actions giving rise to linear hydrogen-bonded chains.

[µ-1,4-Bis(diphenyl-phosphino-yl)butane-κO:O']bis-[cyclo-pentyl-diphen-yl(trifluoro-acetato-κO)tin(IV)].

The mol-ecule of the dinuclear title compound, [Sn(2)(C(5)H(9))(2)(C(6)H(5))(4)(C(2)F(3)O(2))(2)(C(28)H(28)O(2)P(2))], lies on a center of inversion at the mid-point of the central C-C bond of the bridging phosphine oxide ligand. The Sn atom is five-coordinate in a trans-C(3)SnO(2) trigonal-bipyramidal geometry.

Bis[1,2-bis-(diphenyl-phosphino)ethane-κP:P']silver(I) bis-(chloro-difluoro-acetato-κO)(4-chloro-phen-yl)diphenyl-stannate(IV).

In the title salt, [Ag(C(26)H(24)P(2))(2)][Sn(C(2)ClF(2)O(2))(2)(C(6)H(5))(2)(C(6)H(4)Cl)], the Ag(I) atom has a tetra-hedral and the Sn(IV) atom a trans-trigonal-bipyramidal coordination geometry. In the anion, the chloro substituent is disordered over two rings (occupancy ratio 0.81:0.19); the two chloro-difluoro-methyl groups are also disordered over two sites for their halogen atoms (occupancy ratios 0.72:0.28 and 0.70:0.30).