A Glance at Antimicrobial Strategies to Prevent Catheter-Associated Medical Infections.

Urinary and intravascular catheters are two of the most used invasive medical devices; however, microbial colonization of catheter surfaces is responsible for most healthcare-associated infections (HAIs). Several antimicrobial-coated catheters are available, but recurrent antibiotic therapy can decrease their potential activity against resistant bacterial strains. The aim of this Review is to question the actual effectiveness of currently used (coated) catheters and describe the progress and promise of alternative antimicrobial coatings. Different strategies have been reviewed with the common goal of preventing biofilm formation on catheters, including release-based approaches using antibiotics, antiseptics, nitric oxide, 5-fluorouracil, and silver as well as contact-killing approaches employing quaternary ammonium compounds, chitosan, antimicrobial peptides, and enzymes. All of these strategies have given proof of antimicrobial efficacy by modifying the physiology of pathogens or disrupting their structural integrity. The aim for synergistic approaches using multitarget processes and the combination of both antifouling and bactericidal properties holds potential for the near future. Despite intensive research in biofilm preventive strategies, laboratorial studies still present some limitations since experimental conditions usually are not the same and also differ from biological conditions encountered when the catheter is inserted in the human body. Consequently, in most cases, the efficacy data obtained from in vitro studies is not properly reflected in the clinical setting. Thus, further well-designed clinical trials and additional cytotoxicity studies are needed to prove the efficacy and safety of the developed antimicrobial strategies in the prevention of biofilm formation at catheter surfaces.

A scope at antifouling strategies to prevent catheter-associated infections.

The use of invasive medical devices is becoming more common nowadays, with catheters representing one of the most used medical devices. However, there is a risk of infection associated with the use of these devices, since they are made of materials that are prone to bacterial adhesion with biofilm formation, often requiring catheter removal as the only therapeutic option. Catheter-related urinary tract infections (CAUTIs) and central line-associated bloodstream infections (CLABSIs) are among the most common causes of healthcare-associated infections (HAIs) worldwide while endotracheal intubation is responsible for ventilator-associated pneumonia (VAP). Therefore, to avoid the use of biocides due to the potential risk of bacterial resistance development, antifouling strategies aiming at the prevention of bacterial adherence and colonization of catheter surfaces represent important alternative measures. This review is focused on the main strategies that are able to modify the physical or chemical properties of biomaterials, leading to the creation of antiadhesive surfaces. The most promising approaches include coating the surfaces with hydrophilic polymers, such as poly(ethylene glycol) (PEG), poly(acrylamide) and poly(acrylates), betaine-based zwitterionic polymers and amphiphilic polymers or the use of bulk-modified poly(urethanes). Natural polysaccharides and its modifications with heparin, have also been used to improve hemocompatibility. Recently developed bioinspired techniques yielding very promising results in the prevention of bacterial adhesion and colonization of surfaces include slippery liquid-infused porous surfaces (SLIPS) based on the superhydrophilic rim of the pitcher plant and the Sharklet topography inspired by the shark skin, which are potential candidates as surface-modifying approaches for biomedical devices. Concerning the potential application of most of these strategies in catheters, more in vivo studies and clinical trials are needed to assure their efficacy and safety for possible future use.

Anticancer Hybrid Combinations: Mechanisms of Action, Implications and Future Perspectives.

The exponential growth of cancer cases worldwide together with recent advances concerning the pathophysiological mechanisms of the disease at the molecular level led to a paradigm shift in chemotherapy, from monotherapy to targeted drug combination regimens. However, adverse effects and the emergence of multidrug resistance (MDR) limit the effectiveness of these therapies. In this context, hybrid combinations mixing anticancer drugs and bioactive phytochemical components from medicinal plants, or even plant extracts, that can act synergistically on multiple targets and signaling pathways represent a promising approach with the potential to expand the current therapeutic arsenal. This review aims to provide a synopsis on anticancer hybrid combinations based on their multi-target mechanisms and synergistic effects from an extensive literature search focusing mainly on publications from the last ten years. In most of these combinations, the phytochemical component was shown to enhance the anticancer activity of the chemotherapeutic agent and to sensitize chemoresistant tumors in several types of cancer. Hybrid combinations, due to synergistic interactions, are also associated with less severe adverse events since lower doses can be used to achieve the same therapeutic effect. Further preclinical and clinical studies are needed, as well as the development of an adequate regulatory framework, before hybrid combination therapy can be translated into clinical practice.

Development of novel sophorolipids with improved cytotoxic activity toward MDA-MB-231 breast cancer cells.

Sophorolipids (SLs) are glycolipid biosurfactants, produced as a mixture of several compounds by some nonpathogenic yeast. In the current study, separation of individual SLs from mixtures with further evaluation of their surface properties and biologic activity on MDA-MB-321 breast cancer cell line were investigated. SLs were biosynthesized by Starmerella bombicola in a culture media supplemented with borage oil. A reverse-phase flash chromatography method with an automated system coupled with a prepacked cartridge was used to separate and purify the main SLs. Compositional analysis of SLs was performed by high-performance liquid chromatography with electrospray ionization mass spectrometry and tandem mass spectrometry. The following diacetylated lactonic SLs were isolated and purified: C18:0, C18:1, C18:2, and C18:3. The critical micelle concentration (CMC) and surface tension at CMC (γCMC ) of the purified SLs showed an increase with the number of double bonds. High cytotoxic effect against MDA-MB-231 cells was observed with C18:0 and C18:1 lactonic SLs. The cytotoxic effects of C18:3 lactonic SL on cancerous cells were for the first time studied. This cytotoxic effect was considerably higher than the promoted by acidic SLs; however, it induced a lower effect than the previously mentioned SLs, C18:0 and C18:1. To our knowledge, for the first time, C18:1 lactonic SL, in selected concentrations, proved to be able to inhibit MDA-MB-231 cell migration without compromising cell viability and to increase intracellular reactive oxygen species.

Interactions between ß-cyclodextrin and an amino acid-based anionic gemini surfactant derived from cysteine.

The interaction between ß-cyclodextrin (ß-CD) and an amino acid-based anionic gemini surfactant derived from cysteine (C(8)Cys)(2) was studied by three independent techniques: electrical conductivity, UV-Vis spectral displacement technique using phenolphthalein as probe, and (1)H NMR spectroscopy. The data obtained indicated the formation of a 1:1 inclusion complex between ß-CD and the gemini surfactant studied and allowed for the determination of the binding constant, K(1), by considering this stoichiometry. Electrical conductivity, spectral displacement technique, and NMR chemical shift measurements, obtained for aqueous ß-CD-surfactant systems, yielded consistent K(1) values in the order of 10(2) dm(3) mol(-1), typical of a weakly bound ß-CD-surfactant complex. The influence of the presence of the inclusion complex on the micellization process of the gemini surfactant has also been studied and the apparent critical micelle concentration (cmc(∗)) has been obtained. Increasing ß-CD concentration was found to shift the cmc(∗) to higher values, as complexed surfactant monomers are not available to form micelles and aggregation takes place only when all ß-CD cavities are occupied.

Mixed micelle formation between amino acid-based surfactants and phospholipids.

The mixed micelle formation in aqueous solutions between an anionic gemini surfactant derived from the amino acid cystine (C(8)Cys)(2), and the phospholipids 1,2-diheptanoyl-sn-glycero-3-phosphocholine (DHPC, a micelle-forming phospholipid) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC, a vesicle-forming phospholipid) has been studied by conductivity and the results compared with the ones obtained for the mixed systems with the single-chain surfactant derived from cysteine, C(8)Cys. Phospholipid-surfactant interactions were found to be synergistic in nature and dependent on the type of phospholipid and on surfactant hydrophobicity. Regular solution theory was used to analyse the gemini surfactant-DHPC binary mixtures and the interaction parameter, ß(12), has been evaluated, as well as mixed micelle composition. The results have been interpreted in terms of the interplay between reduction of the electrostatic repulsions among the ionic head groups of the surfactants and steric hindrances arising from incorporation of the zwitterionic phospholipids in the mixed micelles.

Dimeric and monomeric surfactants derived from sulfur-containing amino acids.

Anionic urea-based dimeric (gemini) surfactants derived from the amino acids L-cystine, D-cystine and DL-cystine, as well as monomeric surfactants derived from L-cysteine, L-methionine and L-cysteic acid were synthesized and their solution properties characterized by electrical conductivity, equilibrium surface tension, and steady-state fluorescence spectroscopy techniques. The geminis studied showed the lowest critical micelle concentration (cmc) values, however the monomeric cysteine counterpart exhibited superior efficiency in lowering surface tension, an unusual finding that can be attributed to the free sulfhydryl group. Chirality seems to play a role in the surface active properties of the gemini surfactants, but not on micelle formation. All the surfactants studied showed a higher preference for adsorption at the air/water interface rather than to form micelles, a fact that may be related to the urea moiety. The polarity of the interfacial region, measured with the solvatochromic probe E(T)(30) (Reichardt's betaine dye), was similar to sodium dodecyl sulphate (SDS) micelles.

Gemini surfactant-protein interactions: effect of pH, temperature, and surfactant stereochemistry.

The interactions between bovine serum albumin (BSA) and gemini surfactants derived from cystine have been investigated and were compared with the conventional single-chain surfactant derived from cysteine. The influence of the stereochemistry of the gemini surfactant on its behavior toward BSA was also investigated, as well as the effects of pH and temperature. Electrical conductivity and surface tension measurements were used to obtain important system parameters such as critical aggregation concentration (cac), polymer saturation point (psp), degree of ionization (alpha), and the amount of surfactant binding to protein (M). Stereochemistry was found to influence the surface properties of the surfactants studied and their interaction with BSA but not their micellar properties in solution.

New urea-based surfactants derived from alpha,omega-amino acids.

New anionic urea-based surfactants derived from alpha,omega-amino acids and in particular from beta-alanine were synthesized and their solution properties characterized by electrical conductivity, equilibrium surface tension, and steady-state fluorescence spectroscopy techniques. Double-chain surfactants and the single-chain surfactant containing a sulfate head group exhibited the lowest critical micelle concentration (cmc) values and superior efficiency in lowering surface tension. All surfactants promoted adsorption relative to micellization, and micellar parameters were sensitive to the hydrophobicity of the amino acid residue. The polarity of the interfacial region, measured with the solvatochromic probe E(T)(30) (Reichardt's betaine dye), was similar to sodium dodecyl sulfate (SDS) micelles.