Nanosystems Applied to HIV Infection: Prevention and Treatments.

Sexually-transmitted infections (STIs) are a global health concern worldwide as they cause acute diseases, infertility, and significant mortality. Among the bacterial, viral, and parasitic pathogens that can be sexually transmitted, human immunodeficiency virus (HIV) has caused one of the most important pandemic diseases, which is acquired immune deficiency syndrome (AIDS). 32.7 million people have died from AIDS-related illnesses since the start of the epidemic. Moreover, in 2019, 38 million people were living with HIV worldwide. The need to deal with this viral infection becomes more obvious, because it represents not only a problem for public health, but also a substantial economic problem. In this context, it is necessary to focus efforts on developing methods for prevention, detection and treatment of HIV infections that significantly reduce the number of newly infected people and provide a better quality of life for patients. For several decades, biomedical research has been developed allowing quick solutions through the contribution of effective tools. One of them is the use of polymers as vehicles, drug carrier agents, or as macromolecular prodrugs. Moreover, nanosystems (NSs) play an especially important role in the diagnosis, prevention, and therapy against HIV infection. The purpose of this work is to review recent research into diverse NSs as potential candidates for prevention and treatment of HIV infection. Firstly, this review highlights the advantages of using nanosized structures for these medical applications. Furthermore, we provide an overview of different types of NSs used for preventing or combating HIV infection. Then, we briefly evaluate the most recent developments associated with prevention and treatment alternatives. Additionally, the implications of using different NSs are also addressed.

Dual-responsive nanogels based on oligo(ethylene glycol) methacrylates and acidic co-monomers.

Ethylene glycol-based nanogels (NGs) have demonstrated their potential for the development of next-generation formulations for biomedical applications due to their interesting properties. In this work, monodispersed NGs based on oligo(ethylene glycol) methacrylates (OEG) were synthesized through free radical precipitation/dispersion polymerization assisted by ultrasonication. Di(ethylene glycol)methyl ether methacrylate (DEGMA) and oligo(ethylene glycol) methacrylate (OEGMA; Mn 475 g mol-1) were used as the main monomers, acrylic acid (AA) or itaconic acid (IA) as co-monomers (OEG-co-AA and OEG-co-IA, respectively) and tetraethylene glycol dimethacrylate (TEGDMA) as crosslinker. The physicochemical properties of OEG-co-AA and OEG-co-IA NGs were studied including hydrodynamic diameter, poly-dispersity index, zeta potential and pH/temperature responsiveness. Samples with 4 mol% of both AA and IA showed nanometric sizes. Regarding their thermo-responsiveness, unexpected differences between NGs with AA or with IA were observed. Besides, NGs did not impair the cell viability of a breast tumour cell line even when high concentrations were added to the culture medium. The properties of the synthetized NGs showed that either NGs with 4% AA or with 4% IA are outstanding candidates for biomedical applications.

Spatially Resolved Monitoring of Drying of Hierarchical Porous Organic Networks.

Evaporation kinetics of water confined in hierarchal polymeric porous media is studied by low field nuclear magnetic resonance (NMR). Systems synthesized with various degrees of cross-linker density render networks with similar pore sizes but different response when soaked with water. Polymeric networks with low percentage of cross-linker can undergo swelling, which affects the porosity as well as the drying kinetics. The drying process is monitored macroscopically by single-sided NMR, with spatial resolution of 100 µm, while microscopic information is obtained by measurements of spin-spin relaxation times (T2). Transition from a funicular to a pendular regime, where hydraulic connectivity is lost and the capillary flow cannot compensate for the surface evaporation, can be observed from inspection of the water content in different sample layers. Relaxation measurements indicate that even when the larger pore structures are depleted of water, capillary flow occurs through smaller voids.

Enhanced Surface Interaction of Water Confined in Hierarchical Porous Polymers Induced by Hydrogen Bonding.

Hierarchical porous polymer systems are increasingly applied to catalysis, bioengineering, or separation technology because of the versatility provided by the connection of mesopores with percolating macroporous structures. Nuclear magnetic resonance (NMR) is a suitable technique for the study of such systems as it can detect signals stemming from the confined liquid and translate this information into pore size, molecular mobility, and liquid-surface interactions. We focus on the properties of water confined in macroporous polymers of ethylene glycol dimethacrylate and 2-hydroxyethyl methacrylate [poly(EGDMA-co-HEMA)] with different amounts of cross-linkers, in which a substantial variation of hydroxyl groups is achieved. As soft polymer scaffolds may swell upon saturation with determined liquids, the use of NMR is particularly important as it measures the system in its operational state. This study combines different NMR techniques to obtain information on surface interactions of water with hydrophilic polymer chains. A transition from a surface-induced relaxation in which relaxivity depends on the pore size to a regime where the organic pore surface strongly restricts water diffusion is observed. Surface affinities are defined through the molecular residence times near the network surface.

Transferrin Decorated Thermoresponsive Nanogels as Magnetic Trap Devices for Circulating Tumor Cells.

A rational design of magnetic capturing nanodevices, based on a specific interaction with circulating tumor cells (CTCs), can advance the capturing efficiency and initiate the development of modern smart nanoformulations for rapid isolation and detection of these CTCs from the bloodstream. Therefore, the development and evaluation of magnetic nanogels (MNGs) based on magnetic nanoparticles and linear thermoresponsive polyglycerol for the capturing of CTCs with overexpressed transferrin (Tf(+) ) receptors has been presented in this study. The MNGs are synthesized using a strain-promoted "click" approach which has allowed the in situ surface decoration with Tf-polyethylene glycol (PEG) ligands of three different PEG chain lengths as targeting ligands. An optimal value of around 30% of cells captures is achieved with a linker of eight ethylene glycol units. This study shows the potential of MNGs for the capture of CTCs and the necessity of precise control over the linkage of the targeting moiety to the capturing device.

Evaporation kinetics in swollen porous polymeric networks.

NMR is a fast, nondestructive, and noninvasive technique that can provide information about the pore structure of macroporous polymer beads and the dynamics of liquids confined in them. In this work, we describe the study of the pore structure of the macroporous polymer of ethylene glycol dimethacrylate and 2-hydroxyethyl methacrylate [poly(EGDMA-co-HEMA)] in the dry but also in the swollen state by measuring relaxation times of liquids contained in the polymer network. The results show that the pore architecture differs from the dry to the soaked state. The behavior of polar liquids during evaporation and deswelling dynamics is monitored and described. An internal migration of water from the swollen polymer mesh into expanding pores takes place. With this procedure it is possible to obtain information about the microscopic morphology behavior of the matrix during evaporation and deswelling. This information is of great interest with the aspect of possible and future applications for these types of materials.

Work function maps and surface topography characterization of nitroaromatic-ended dendron films on graphite.

Surface topography and work function maps were simultaneously obtained for carbon surfaces modified by a dendritic molecule: 3,5-Bis (3,5-dinitrobenzoylamino) benzoic acid. The dendrons were spontaneously assembled onto highly ordered pyrolytic graphite samples, exhibiting an increase in the surface potential. This fact is consistent with the incorporation of an electron-acceptor functional group that remains electroactive on the surface.

Mesoporous Silica and Oligo (Ethylene Glycol) Methacrylates-Based Dual-Responsive Hybrid Nanogels.

Polymeric-inorganic hybrid nanomaterials have emerged as novel multifunctional platforms because they combine the intrinsic characteristics of both materials with unexpected properties that arise from synergistic effects. In this work, hybrid nanogels based on mesoporous silica nanoparticles, oligo (ethylene glycol) methacrylates, and acidic moieties were developed employing ultrasound-assisted free radical precipitation/dispersion polymerization. Chemical structure was characterized by infrared spectroscopy and nuclear magnetic resonance. Hydrodynamic diameters at different temperatures were determined by dynamic light scattering, and cloud point temperatures were determined by turbidimetry. Cell viability in fibroblast (NIH 3T3) and human prostate cancer (LNCaP) cell lines were studied by a standard colorimetric assay. The synthetic approach allows covalent bonding between the organic and inorganic components. The composition of the polymeric structure of hybrid nanogels was optimized to incorporate high percentages of acidic co-monomer, maintaining homogeneous nanosized distribution, achieving appropriate volume phase transition temperature values for biomedical applications, and remarkable pH response. The cytotoxicity assays show that cell viability was above 80% even at the highest nanogel concentration. Finally, we demonstrated the successful cell inhibition when they were treated with camptothecin-loaded hybrid nanogels.

Chemical Overview of Gel Dosimetry Systems: A Comprehensive Review.

Advances in radiotherapy technology during the last 25 years have significantly improved both dose conformation to tumors and the preservation of healthy tissues, achieving almost real-time feedback by means of high-precision treatments and theranostics. Owing to this, developing high-performance systems capable of coping with the challenging requirements of modern ionizing radiation is a key issue to overcome the limitations of traditional dosimeters. In this regard, a deep understanding of the physicochemical basis of gel dosimetry, as one of the most promising tools for the evaluation of 3D high-spatial-resolution dose distributions, represents the starting point for developing new and innovative systems. This review aims to contribute thorough descriptions of the chemical processes and interactions that condition gel dosimetry outputs, often phenomenologically addressed, and particularly formulations reported since 2017.

pH-induced changes in the fabrication of multilayers of poly(acrylic acid) and chitosan: fabrication, properties, and tests as a drug storage and delivery system.

Multilayers of poly(acrylic acid), PAA, and chitosan, CHI, have been built by the layer-by-layer (LbL) method from aqueous solutions at different pH values and analyzed by the dissipative quartz crystal microbalance (D-QCM) and ellipsometry. The results showed that under all of the assembly conditions considered the growth of the films is nonlinear. The thickness of the PAA layers increases as the pH of the assembling solutions decreases, whereas the adsorption of CHI is almost unaffected by the pH conditions. The comparison of the thickness obtained by D-QCM and by ellipsometry has allowed us to calculate the water content of the films, showing that the multilayers are highly hydrated, with an average water content higher than 20%. The analysis of D-QCM data has provided high-frequency values of the complex shear modulus that are in the megapascal range and shows a transition from mainly viscous to mainly elastic behavior for the added PAA layers, depending on the pH. The monomer surface density in each layer (obtained from the combination of ellipsometry and differential refractive index measurements) indicated that the monomer density depends on the assembly conditions. It was found that the adsorption kinetics is a bimodal process, with characteristic times that depend on the number and nature of the layers. Finally, the possibility of using of these multilayers as a drug storage and delivery system has been evaluated.

Revealing the NIR-triggered chemotherapy therapeutic window of magnetic and thermoresponsive nanogels.

The combination of magnetic nanoparticles and thermoresponsive nanogels represents an appealing strategy for the development of theranostic probes. These hybrid nanocarriers present several advantages such as outstanding properties for guided therapy, magnetic resonance imaging, and triggered release of encapsulated cargoes. Most magnetic thermoresponsive nanogels are built with strategies that comprise a physical interaction of particles with the polymeric network or the covalent attachment of a single particle to the linear polymer. Herein, we report a facile synthetic approach for the synthesis of magnetic and thermoresponsive nanogels that allows the controlled incorporation of multiple superparamagnetic inorganic cores as covalent cross-linkers. An ultrasonication-assisted precipitation-polymerization afforded nanogels with sizes in the nanometric range and similar magnetization and light transduction properties compared to the discrete magnetic nanoparticles. The theranostic capability of these nanocarriers was further investigated both in vitro and in vivo. In vivo experiments demonstrated the capacity of these materials as nanocarriers for near-infrared (NIR) triggered chemotherapy and highlighted the relevance of the correct concentration/dose in this antitumoral modality to achieve a superior therapeutic efficacy.

Physico-chemistry of a successful micro-reactor: Random coils of chitosan backbones used to synthesize size-controlled silver nanoparticles.

The synthetic system to produce silver nanoparticles (AgNP) based on the thermally activated reduction of aqueous silver ions by chitosan (CS) polysaccharide is investigated to unravel the physicochemical processes controlling AgNP nucleation and growth. An anomalous preeminence of AgNP nucleation over growth is found for conditions under which the opposite trend is obeyed for AgNP synthesized from soluble precursors in homogeneous media. The behavior is modeled assuming the formation of a tridimensional supramolecular structure from silver ions / CS´s amino groups coordination complexes, driving the crosslinking within polymer folding and aggregation in shaping random coils. These structures become reactive precursor structures, that behave as microreactors during thermal treatment, and AgNP size are modulated by controlling the amino groups to silver ion ratio. Stabilized AgNP of high quality are easily produced from an environment-friendly synthetic system, which requires low cost reagents and demands simple and safe laboratory procedures.

Poly(N-vinylcaprolactam) Nanogels with Antiviral Behavior against HIV-1 Infection.

Stimuli-responsive nanogels offer promising perspectives for the development of next generation formulations for biomedical applications. In this work, poly(N-vinylcaprolactam) nanogels were synthesized varying the concentration of monomer and crosslinking agent. Thus, the inhibitory effect of poly(N-vinylcaprolactam) nanogels against HIV-1 infection is presented for the first time. In particular, we have demonstrated that one of the synthesized poly(N-vinylcaprolactam) nanogels with initial concentration of 80 mg of vinylcaprolactam and 4% of crosslinking agent shows antiviral behavior against HIV-1 infection since this nanogel inhibits the viral replication in TZM.bl target cells.

Optimizing Circulating Tumor Cells' Capture Efficiency of Magnetic Nanogels by Transferrin Decoration.

Magnetic nanogels (MNGs) are designed to have all the required features for their use as highly efficient trapping materials in the challenging task of selectively capturing circulating tumor cells (CTCs) from the bloodstream. Advantageously, the discrimination of CTCs from hematological cells, which is a key factor in the capturing process, can be optimized by finely tuning the polymers used to link the targeting moiety to the MNG. We describe herein the relationship between the capturing efficiency of CTCs with overexpressed transferrin receptors and the different strategies on the polymer used as linker to decorate these MNGs with transferrin (Tf). Heterobifunctional polyethylene glycol (PEG) linkers with different molecular weights were coupled to Tf in different ratios. Optimal values over 80% CTC capture efficiency were obtained when 3 PEG linkers with a length of 8 ethylene glycol (EG) units were used, which reveals the important role of the linker in the design of a CTC-sorting system.

Bioadhesive and biocompatible films as wound dressing materials based on a novel dendronized chitosan loaded with ciprofloxacin.

The bioadhesive polymeric films as topical drug delivery systems are interesting alternatives to improve the pharmacotherapy and patient compliances. New derivate biomaterials based on weisocyanate- dendronized PVP- crosslinked chitosan and loaded with ciprofloxacin (CIP), as model drug, were used to prepare bioadhesive films. Relevant in vitro/in vivo attributes to define main physicochemical and biopharmaceutical characteristics for topical wound-healing applications were evaluated. A high proportion of CIP, uniformly dispersed along throughout the film, was loaded. An extended release of CIP and different behaviors of release profiles, depending on the presence of dendron, were observed. The films loaded with CIP were effective in inhibiting the growth of both Gram positive and Gram negative bacteria. In addition, biocompatibility and bioadhesion into conjuntival-sacs of the rabbits suggests that these films have good properties to be applied over skin wounds for topical applications, allowing a reduction of the frequency of administration and improving the residence time of the films.

A novel gel based on an ionic complex from a dendronized polymer and ciprofloxacin: Evaluation of its use for controlled topical drug release.

The development and characterization of a novel, gel-type material based on a dendronized polymer (DP) loaded with ciprofloxacin (CIP), and the evaluation of its possible use for controlled drug release, are presented in this work. DP showed biocompatible and non-toxic behaviors in cultured cells, both of which are considered optimal properties for the design of a final material for biomedical applications. These results were encouraging for the use of the polymer loaded with CIP (as a drug model), under gel form, in the development of a new controlled-release system to be evaluated for topical administration. First, DP-CIP ionic complexes were obtained by an acid-base reaction using the high density of carboxylic acid groups of the DP and the amine groups of the CIP. The complexes obtained in the solid state were broadly characterized using FTIR spectroscopy, XRP diffraction, DSC-TG analysis and optical microscopy techniques. Gels based on the DP-CIP complexes were easily prepared and presented excellent mechanical behaviors. In addition, optimal properties for application on mucosal membranes and skin were achieved due to their high biocompatibility and acute skin non-irritation. Slow and sustained release of CIP toward simulated physiological fluids was observed in the assays (in vitro), attributed to ion exchange phenomenon and to the drug reservoir effect. An in vitro bacterial growth inhibition assay showed significant CIP activity, corresponding to 38 and 58% of that exhibited by a CIP hydrochloride solution at similar CIP concentrations, against Staphylococcus aureus and Pseudomonas aeruginosa, respectively. However, CIP delivery was appropriate, both in terms of magnitude and velocity to allow for a bactericidal effect. In conclusion, the final product showed promising behavior, which could be exploited for the treatment of topical and mucosal opportunistic infections in human or veterinary applications.

Polymer gel dosimeter based on itaconic acid.

A new polymeric dosimeter based on itaconic acid and N, N'-methylenebisacrylamide was studied. The preparation method, compositions of monomer and crosslinking agent and the presence of oxygen in the dosimetric system were analyzed. The resulting materials were irradiated with an X-ray tube at 158cGy/min, 226cGymin and 298cGy/min with doses up to 1000Gy. The dosimeters presented a linear response in the dose range 75-1000Gy, sensitivities of 0.037 1/Gyat 298cGy/min and an increase in the sensitivity with lower dose rates. One of the most relevant outcomes in this study was obtaining different monomer to crosslinker inclusion in the formed gel for the dosimeters where oxygen was purged during the preparation method. This effect has not been reported in other typical dosimeters and could be attributed to the large differences in the reactivity among these species.

Molecular structure effects on the post irradiation diffusion in polymer gel dosimeters.

Polymer gel dosimeters have specific advantages for recording 3D radiation dose distribution in diagnostic and therapeutic medical applications. But, even in systems where the 3D structure is usually maintained for long periods of time after irradiation, it is still not possible to eliminate the diffusion of the different species in the regions of dose gradients within the gel. As a consequence, information of the dose loses quality over time. In the pursuit of a solution and to improve the understanding of this phenomenon a novel system based on itaconic acid and N-N'-methylene-bisacrylamide (BIS) is hereby proposed. Effects of changes in the chemical structure of the monomers over the dosimetric sensitivity and over the post-irradiation diffusion of species was studied. In this study, one of the carboxylic groups of the itaconic acid molecule was modified with aniline to obtain molecules with similar reactivity but different molecular sizes. Then, dosimeters based on these modified species and on the original ITA molecules were irradiated in an X-ray tomography apparatus at different doses up to 173Gy. Afterwards, the resulting dosimeters were characterized by Raman spectroscopy and optical absorbance in order to study their feasibility and capabilities as dosimetric systems, and by optical-CT to analyze the post irradiation diffusion.