A Review on the Rheological Properties of Single Amino Acids and Short Dipeptide Gels.

Self-assembled peptide-based hydrogels have attracted considerable interest from the research community. Particularly, low molecular weight gelators (LMWGs) consisting of amino acids and short peptides are highly suitable for biological applications owing to their facile synthesis and scalability, as well as their biocompatibility, biodegradability, and stability in physiological conditions. However, challenges in understanding the structure-property relationship and lack of design rules hinder the development of new gelators with the required properties for several applications. Hereby, in the plethora of peptide-based gelators, this review discusses the mechanical properties of single amino acid and dipeptide-based hydrogels. A mutual analysis of these systems allows us to highlight the relationship between the gel mechanical properties and amino acid sequence, preparation methods, or N capping groups. Additionally, recent advancements in the tuning of the gels' rheological properties are reviewed. In this way, the present review aims to help bridge the knowledge gap between structure and mechanical properties, easing the selection or design of peptides with the required properties for biological applications.

Multifunctional magneto-plasmonic lipogel based on peptide hydrogel for application in combined cancer therapy.

Supramolecular hydrogels, particularly low-molecular-weight peptide hydrogels, are promising drug delivery systems due to their ability to change the solubility, targeting, metabolism and toxicity of drugs. Magneto-plasmonic liposomes, in addition to being remotely controllable with the application of an external magnetic field, also increase the efficiency of encapsulated drug release through thermal stimulation, for example, with magnetic and optical hyperthermia. Thus, the combination of those two materials-giving magneto-plasmonic lipogels-brings together several functionalities, among which are hyperthermia and spatiotemporally controlled drug delivery. In this work, a novel dehydrodipeptide hydrogelator was synthesised, and the respective hydrogel was functionalized with magneto-plasmonic liposomes. After individually characterising the components with regard to their rheological, spectroscopic and magnetic properties, the magneto-plasmonic lipogel was equally characterised and evaluated concerning its ability to deliver drugs in a controlled fashion. To this end, the response of the 5(6)-carboxyfluorescein-loaded magneto-plasmonic lipogel to near-infrared light was assessed. The results showed that the system is a proper carrier of hydrophilic drugs and allows to envisage photo-responsive drug delivery. These facts, together with the magnetic guidance and hyperthermia capabilities of the developed composite gel, may pave the way to a new era in the treatment of cancer and other diseases.

Chitosan/Alginate Nanogels Containing Multicore Magnetic Nanoparticles for Delivery of Doxorubicin.

In this study, multicore-like iron oxide (Fe3O4) and manganese ferrite (MnFe2O4) nanoparticles were synthesized and combined with nanogels based on chitosan and alginate to obtain a multimodal drug delivery system. The nanoparticles exhibited crystalline structures and displayed sizes of 20 ± 3 nm (Fe3O4) and 11 ± 2 nm (MnFe2O4). The Fe3O4 nanoparticles showed a higher saturation magnetization and heating efficiency compared with the MnFe2O4 nanoparticles. Functionalization with citrate and bovine serum albumin was found to improve the stability and modified surface properties. The nanoparticles were encapsulated in nanogels, and provided high drug encapsulation efficiencies (~70%) using doxorubicin as a model drug. The nanogels exhibited sustained drug release, with enhanced release under near-infrared (NIR) laser irradiation and acidic pH. The nanogels containing BSA-functionalized nanoparticles displayed improved sustained drug release at physiological pH, and the release kinetics followed a diffusion-controlled mechanism. These results demonstrate the potential of synthesized nanoparticles and nanogels for controlled drug delivery, offering opportunities for targeted and on-demand release in biomedical applications.

Cellulose Nanocrystal (CNC) Gels: A Review.

The aim of this article is to review the research conducted in the field of aqueous and polymer composites cellulose nanocrystal (CNC) gels. The experimental techniques employed to characterize the rheological behavior of these materials will be summarized, and the main advantages of using CNC gels will also be addressed in this review. In addition, research devoted to the use of numerical simulation methodologies to describe the production of CNC-based materials, e.g., in 3D printing, is also discussed. Finally, this paper also discusses the application of CNC gels along with additives such as cross-linking agents, which can represent an enormous opportunity to develop improved materials for manufacturing processes.

Advances in Nanomaterials for Drug Delivery.

In recent years, nanomedicine has provided several high-performance tools for overcoming biomedical challenges, resulting in numerous patents [...].

Synthesis and Cytotoxicity Assessment of Citrate-Coated Calcium and Manganese Ferrite Nanoparticles for Magnetic Hyperthermia.

Calcium-doped manganese ferrite nanoparticles (NPs) are gaining special interest in the biomedical field due to their lower cytotoxicity compared with other ferrites, and the fact that they have improved magnetic properties. Magnetic hyperthermia (MH) is an alternative cancer treatment, in which magnetic nanoparticles promote local heating that can lead to the apoptosis of cancer cells. In this work, manganese/calcium ferrite NPs coated with citrate (CaxMn1-xFe2O4 (x = 0, 0.2, 1), were synthesized by the sol-gel method, followed by calcination, and then characterized regarding their crystalline structure (by X-ray diffraction, XRD), size and shape (by Transmission Electron Microscopy, TEM), hydrodynamic size and zeta potential (by Dynamic Light Scattering, DLS), and heating efficiency (measuring the Specific Absorption Rate, SAR, and Intrinsic Loss Power, ILP) under an alternating magnetic field. The obtained NPs showed a particle size within the range of 10 nm to 20 nm (by TEM) with a spherical or cubic shape. Ca0.2Mn0.8Fe2O4 NPs exhibited the highest SAR value of 36.3 W/g at the lowest field frequency tested, and achieved a temperature variation of ~7 °C in 120 s, meaning that these NPs are suitable magnetic hyperthermia agents. In vitro cellular internalization and cytotoxicity experiments, performed using the human cell line HEK 293T, confirmed cytocompatibility over 0-250 µg/mL range and successful internalization after 24 h. Based on these studies, our data suggest that these manganese-calcium ferrite NPs have potential for MH application and further use in in vivo systems.

Oxidative Precipitation Synthesis of Calcium-Doped Manganese Ferrite Nanoparticles for Magnetic Hyperthermia.

Superparamagnetic nanoparticles are of high interest for therapeutic applications. In this work, nanoparticles of calcium-doped manganese ferrites (CaxMn1-xFe2O4) functionalized with citrate were synthesized through thermally assisted oxidative precipitation in aqueous media. The method provided well dispersed aqueous suspensions of nanoparticles through a one-pot synthesis, in which the temperature and Ca/Mn ratio were found to influence the particles microstructure and morphology. Consequently, changes were obtained in the optical and magnetic properties that were studied through UV-Vis absorption and SQUID, respectively. XRD and Raman spectroscopy studies were carried out to assess the microstructural changes associated with stoichiometry of the particles, and the stability in physiological pH was studied through DLS. The nanoparticles displayed high values of magnetization and heating efficiency for several alternating magnetic field conditions, compatible with biological applications. Hereby, the employed method provides a promising strategy for the development of particles with adequate properties for magnetic hyperthermia applications, such as drug delivery and cancer therapy.

Plasmonic lipogels: driving co-assembly of composites with peptide-based gels for controlled drug release.

Supramolecular short peptide-based gels are promising materials for the controlled release of drugs (e.g. chemotherapeutic drugs) owing to the biocompatibility and similarity to cell matrix. However, the drug encapsulation and control over its release, mainly the hydrophilic drugs, can be a cumbersome task. This can be overcome through encapsulation/compartmentalization of drugs in liposomes, which can also enable spatiotemporal control and enhanced drug release through a trigger, such as photothermia. Having this in mind, we explored the assembly of silica-coated gold nanoparticles and liposomes (storage units) with dehydropeptide-based hydrogels as a proof-of-concept to afford peptide-based NIR light-responsive lipogels. Several liposomes compositions were assessed that displayed influence on the final assembly properties by combining with silica-coated gold nanorods (∼106 nm). Gold nanospheres (∼11 nm) were used to study the preparation method, which revealed the importance of initially combine liposomes with nanoparticles and then the gelator solution to achieve a closer proximity of the nanoparticles to the liposomes. The control over a hydrophilic model drug, 5(6)-carboxyfluorescein, was only achieved by its encapsulation in liposomes, in which the presence of silica-coated nanorods further enabled the use of photothermia to induce the liposomes phase transition and stimulate the drug release. Further, both composites, the liposomes and silica-coated gold nanorods, induced a lower elastic modulus, but also provided an enhanced gelation kinetics. Hereby, this work advances fabrication strategies for the development of short peptide-based hydrogels towards on-demand, sustained and controlled release of hydrophilic drugs through photothermia under NIR light irradiation.

An injectable, naproxen-conjugated, supramolecular hydrogel with ultra-low critical gelation concentration-prepared from a known folate receptor ligand.

Short peptides capped on the N-terminus with aromatic groups are often able to form supramolecular hydrogels-self-assembled networks of fibrils able to trap water molecules. Typically, these hydrogelators can form stiff gels at concentrations of 0.1 to 1.0 wt%-i.e. they consist of mainly water. The properties of these soft materials mimic those of the extracellular matrix (ECM) of biological tissue and therefore they have found many biomedical uses in tissue engineering, wound healing, drug delivery, biosensing and bioprinting applications. In drug delivery strategies related to cancer therapy, injectable hydrogels can serve as a depot formulation, where a sustained release of the chemotherapeutic from near the tumour site allows reduced doses and, therefore, decreased side effects. To further target cancer cells, folic acid-conjugated hydrogels and nanostructures are often sought, to exploit the overexpression of folate receptors on cancer cells-an approach which can allow the selective cellular uptake of an encapsulated drug. In this present study, two known dipeptide folate receptor ligands (1 and 2) recently identified from a screen of a DNA-encoded compound library, were synthesised and investigated for their hydrogelation ability and cytotoxicity. Compound 1, containing a naproxen capping group, rapidly forms hydrogels at concentrations as low as 0.03 wt%-one of the lowest critical gelation concentrations (CGCs) known for a supramolecular hydrogelator. In contrast, compound 2, which contains a 3-indolepropionic acid capping group, was unable to form hydrogels under a range of conditions and concentrations, instead forming nanospheres with diameters of 0.5 µm. Hydrogels of 1 were characterised by STEM microscopy, rheology, fluorescence spectroscopy and circular dichroism. Both compounds 1 and 2 had no impact on the proliferation of kerotinocytes (HaCaT cells) at concentrations up to 100 µM. Compound 1, containing the NSAID, was tested for anti-inflammatory activity in a human cyclooxygenase-1/2 model. The rate of the release of model drug compounds from within hydrogels of 1 was also investigated.

Tuning the drug multimodal release through a co-assembly strategy based on magnetic gels.

Self-assembled short peptide-based gels are highly promising drug delivery systems. However, implementing a stimulus often requires screening different structures to obtain gels with suitable properties, and drugs might not be well encapsulated and/or cause undesirable effects on the gel's properties. To overcome this challenge, a new design approach is presented to modulate the release of doxorubicin as a model chemotherapeutic drug through the interplay of (di)phenylalanine-coated magnetic nanoparticles, PEGylated liposomes and doxorubicin co-assembly in dehydropeptide-based gels. The composites enable an enhancement of the gelation kinetics in a concentration-dependent manner, mainly through the use of PEGylated liposomes. The effect of the co-assembly of phenylalanine-coated nanoparticles with the hydrogel displays a concentration and size dependence. Finally, the integration of liposomes as doxorubicin storage units and of nanoparticles as composites that co-assemble with the gel matrix enables the tuneability of both passive and active doxorubicin release through a thermal, and a low-frequency alternating magnetic field-based trigger. In addition to the modulation of the gel properties, the functionalization with (di)phenylalanine improves the cytocompatibility of the nanoparticles. Hereby, this work paves a way for the development of peptide-based supramolecular systems for on-demand and controlled release of drugs.

Epidemiological trends of HIV/HCV coinfection in Spain, 2015-2019.

OBJECTIVES: We assessed the prevalence of anti-hepatitis C virus (HCV) antibodies and active HCV infection (HCV-RNA-positive) in people living with HIV (PLWH) in Spain in 2019 and compared the results with those of four similar studies performed during 2015-2018. METHODS: The study was performed in 41 centres. Sample size was estimated for an accuracy of 1%. Patients were selected by random sampling with proportional allocation. RESULTS: The reference population comprised 41 973 PLWH, and the sample size was 1325. HCV serostatus was known in 1316 PLWH (99.3%), of whom 376 (28.6%) were HCV antibody (Ab)-positive (78.7% were prior injection drug users); 29 were HCV-RNA-positive (2.2%). Of the 29 HCV-RNA-positive PLWH, infection was chronic in 24, it was acute/recent in one, and it was of unknown duration in four. Cirrhosis was present in 71 (5.4%) PLWH overall, three (10.3%) HCV-RNA-positive patients and 68 (23.4%) of those who cleared HCV after anti-HCV therapy (p = 0.04). The prevalence of anti-HCV antibodies decreased steadily from 37.7% in 2015 to 28.6% in 2019 (p < 0.001); the prevalence of active HCV infection decreased from 22.1% in 2015 to 2.2% in 2019 (p < 0.001). Uptake of anti-HCV treatment increased from 53.9% in 2015 to 95.0% in 2019 (p < 0.001). CONCLUSIONS: In Spain, the prevalence of active HCV infection among PLWH at the end of 2019 was 2.2%, i.e. 90.0% lower than in 2015. Increased exposure to DAAs was probably the main reason for this sharp reduction. Despite the high coverage of treatment with direct-acting antiviral agents, HCV-related cirrhosis remains significant in this population.

Tuning Peptide-Based Hydrogels: Co-Assembly with Composites Driving the Highway to Technological Applications.

Self-assembled peptide-based gels provide several advantages for technological applications. Recently, the co-assembly of gelators has been a strategy to modulate and tune gel properties and even implement stimuli-responsiveness. However, it still comprises limitations regarding the required library of compounds and outcoming properties. Hence, efforts have been made to combine peptide-based gels and (in)organic composites (e.g., magnetic nanoparticles, metal nanoparticles, liposomes, graphene, silica, clay, titanium dioxide, cadmium sulfide) to endow stimuli-responsive materials and achieve suitable properties in several fields ranging from optoelectronics to biomedical. Herein, we discuss the recent developments with composite peptide-based gels including the fabrication, tunability of gels' properties, and challenges on (bio)technological applications.

HIV/HBV coinfection: temporal trends and patient characteristics, Spain, 2002 to 2018.

BackgroundRecent and reliable estimates on the prevalence of coinfection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) in Europe are lacking.AimLeveraged on a study designed to assess HIV/HCV coinfection prevalence, we assessed the prevalence of HIV/HBV coinfection in Spain in 2018 and compared the results with five similar studies performed since 2002.MethodsThis cross-sectional prevalence study was carried out in 43 centres, and patients were selected using simple random sampling. The reference population comprised 40,322 patients and the sample size were 1,690 patients.ResultsThe prevalence of HIV/HBV coinfection in Spain at the end of 2018 was 3.2%. The prevalence in 2002, 2009, 2015, 2016 and 2017 was 4.9%, 3.4%, 3%, 3.9% and 3%, respectively. Among the HIV/HBV-coinfected patients identified in 2018, 16.7% had cirrhosis according to transient elastography and 26.3% tested positive for antibodies against hepatitis D virus. All HIV/HBV-coinfected patients were receiving drugs with activity against HBV, and 97% of those tested for HBV DNA had an HBV DNA load < 80 IU/mL.ConclusionsThe prevalence of HIV/HBV coinfection in Spain remained stable at around 3% for a decade. Our data could facilitate the design of national programmes to control HBV infection and help identify areas of patient management that need improvement.

Bolaamphiphilic Bis-Dehydropeptide Hydrogels as Potential Drug Release Systems.

The self-assembly of nanometric structures from molecular building blocks is an effective way to make new functional materials for biological and technological applications. In this work, four symmetrical bolaamphiphiles based on dehydrodipeptides (phenylalanyldehydrophenylalanine and tyrosyldehydrophenylalanine) linked through phenyl or naphthyl linkers (terephthalic acid and 2,6-naphthalenedicarboxylic acid) were prepared, and their self-assembly properties were studied. The results showed that all compounds, with the exception of the bolaamphiphile of tyrosyldehydrophenylalanine and 2,6-naphthalene dicarboxylic acid, gave self-standing hydrogels with critical gelation concentrations of 0.3 wt % and 0.4 wt %, using a pH trigger. The self-assembly of these hydrogelators was investigated using STEM microscopy, which revealed a network of entangled fibers. According to rheology, the dehydrodipeptide bolaamphiphilic hydrogelators are viscoelastic materials with an elastic modulus G' that falls in the range of native tissue (0.37 kPa brain-4.5 kPa cartilage). In viability and proliferation studies, it was found that these compounds were non-toxic toward the human keratinocyte cell line, HaCaT. In sustained release assays, we studied the effects of the charge present on model drug compounds on the rate of cargo release from the hydrogel networks. Methylene blue (MB), methyl orange (MO), and ciprofloxacin were chosen as cationic, anionic, and overall neutral cargo, respectively. These studies have shown that the hydrogels provide a sustained release of methyl orange and ciprofloxacin, while methylene blue is retained by the hydrogel network.

Magnetoliposomes: recent advances in the field of controlled drug delivery.

INTRODUCTION: Magnetoliposomes have gained increasing attention as delivery systems, as they surpass many limitations associated with liposomes. The combination with magnetic nanoparticles provides a means for development of multimodal and multifunctional theranostic agents that enable on-demand drug release and real-time monitoring of therapy. AREAS COVERED: Recently, several magnetoliposome structures have been reported to ensure efficient transport and delivery of therapeutics, while improving magnetic properties. Besides, novel techniques have been introduced to improve on-demand release, as well as to achieve sequential release of different therapeutic agents. This review presents the major types and methods of preparation of magnetoliposomes, and discusses recent strategies in the trigger of drug release, development of theranostic formulations, and delivery of drugs and biological entities. EXPERT OPINION: Despite significant advances in efficient drug delivery, current literature lacks an assessment of formulations as theranostic agents and complementary techniques to optimize thermotherapy efficiency. Plasmonic magnetoliposomes are highly promising multimodal and multifunctional systems, providing the required design versatility to optimize theranostic capabilities. Further, photodynamic therapy and delivery of proteins/genes can be improved with a deeper research on the employed magnetic material and associated toxicity. A scale-up procedure is also lacking in recent research, which is limiting their translation to clinical use.

Supramolecular ultra-short carboxybenzyl-protected dehydropeptide-based hydrogels for drug delivery.

Self-assembled peptide-based hydrogels are promising materials for biomedical research owing to biocompatibility and similarity to the extracellular matrix, amenable synthesis and functionalization and structural tailoring of the rheological properties. Wider developments of self-assembled peptide-based hydrogels in biomedical research and clinical translation are hampered by limited commercial availability allied to prohibitive costs. In this work a focused library of Cbz-protected dehydrodipeptides Cbz-L-Xaa-Z-ΔPhe-OH (Xaa= Met, Phe, Tyr, Ala, Gly) was synthesised and evaluated as minimalist hydrogels. The Cbz-L-Met-Z-ΔPhe-OH and Cbz-L-Phe-Z-ΔPhe-OH hydrogelators were comprehensively evaluated regarding molecular aggregation and self-assembly, gelation, biocompatibility and as drug carriers for delivery of the natural compound curcumin and the clinically important antitumor drug doxorubicin. Drug release profiles and FRET studies of drug transport into small unilamellar vesicles (as biomembrane models) demonstrated that the Cbz-protected dehydropeptide hydrogels are effective nanocarriers for drug delivery. The expedite and scalable synthesis (in 3 steps), using commercially available reagents and amenable reaction conditions, makes Cbz-protected dehydrodipeptide hydrogels, widely available at affordable cost to the research community.