Structural characterization of functionalized gold nanoparticles for drug delivery in cancer therapy: a NMR based approach

In the present paper, we report results from a study of the structure and physicochemical properties of gold nanoparticles modified with poly(ethylene glycol) (PEG) designed for the drug delivery of the proteasome inhibitor Bortezomib (BTZ) in cancer therapy. A number of advanced analytical techniques were used to define important physicochemical characteristics such as composition, structure, surface properties, particle size and morphology. A new approach based on detailed NMR studies was employed to define specific intermolecular interactions and mechanisms of drug immobilization and location into surface modified gold nanoparticles (AuNPs). Particularly important information was gained from analysis of NMR spectroscopic parameters such as the spectral line shape, translation diffusion, the nuclear Overhauser effect (NOE) and spin-lattice relaxation (T-1). The results confirmed the coexistence of two different types of BTZ inclusion into polyethylene glycol coated gold nanoparticles: (i) association with the polymer chains by weak H-bonds and/or dipole-charge interactions and (ii) adsorption on the surface of the gold nanoparticles. The results allowed for determination of the overall structure of Bortezomib loaded PEG coated AuNPs, which is related to the therapeutic drug efficacy and activity in the treatment of cancer

Factorial design as a tool for the optimization of plga nanoparticles for the co-delivery of temozolomide and o6-benzylguanine

Poly(D,L-lactic-co-glycolic) (PLGA) nanoparticles (NPs) have been widely studied for several applications due to their advantageous properties, such as biocompatibility and biodegradability. Therefore, these nanocarriers could be a suitable approach for glioblastoma multiforme (GBM) therapy. The treatment of this type of tumours remains a challenge due to intrinsic resistance mechanisms. Thus, new approaches must be envisaged to target GBM tumour cells potentially providing an efficient treatment. Co-delivery of temozolomide (TMZ) and O6-benzylguanine (O6BG), an inhibitor of DNA repair, could provide good therapeutic outcomes. In this work, a fractional factorial design (FFD) was employed to produce an optimal PLGA-based nanoformulation for the co-loading of both molecules, using a reduced number of observations. The developed NPs exhibited optimal physicochemical properties for brain delivery (dimensions below 200 nm and negative zeta potential), high encapsulation efficiencies (EE) for both drugs, and showed a sustained drug release for several days. Therefore, the use of an FFD allowed for the development of a nanoformulation with optimal properties for the co-delivery of TMZ and O6BG to the brain

Gold nanoparticles for targeting varlitinib to human pancreatic cancer cells

Colloidal gold nanoparticles are targeting probes to improve varlitinib delivery into cancer cells. The nanoconjugates were designed by the bioconjugation of pegylated gold nanoparticles with varlitinib via carbodiimide-mediated cross-linking and characterized by infrared and X-ray photoelectron spectroscopy. The drug release response shows an initial delay and a complete drug release after 72 h is detected. In vitro experiments with MIA PaCa-2 cells corroborate that PEGAuNPsVarl conjugates increase the varlitinib toxic effect at very low concentrations (IC50 = 80 nM) if compared with varlitinib alone (IC50 = 259 nM). Our results acknowledge a decrease of drug side effects in normal cells and an enhancement of drug efficacy against to the pancreatic cancer cells reported. (c) 2018 by the authors. Licensee MDPI, Basel, Switzerland

PLGA nanoparticles as a platform for vitamin D-based cancer therapy

Poly(lactic-co-glycolic acid) (PLGA) nanoparticles were studied as drug delivery vehicles for calcitriol, the active form of vitamin D-3. In vitro effects of calcitriol encapsulated in PLGA nanoparticles were evaluated with respect to free calcitriol on human pancreatic cell lines, S2-013 and hTERT-HPNE, and the lung cancer cell line A549. Encapsulated calcitriol retained its biological activity, reducing the cell growth. Cytotoxicity assays demonstrated that encapsulation of calcitriol enhanced its inhibitory effect on cell growth at a concentration of 2.4 mu M for the S2-013 cells (91%) and for A549 cells (70%) comparared to the free calcitriol results. At this concentration the inhibitory effect on nontumor cells (hTERT-HPNE) decreased to 65%. This study highlights the ability of PLGA nanoparticles to deliver vitamin D-3 into cancer cells, with major effects regarding cancer cell cycle arrest and major changes in the cell morphological features

An optimized nanoparticle delivery system based on chitosan and chondroitin sulfate molecules reduces the toxicity of amphotericin B and is effective in treating tegumentary leishmaniasis

Amphotericin B (AmpB) is active against leishmaniasis, but its use is hampered due to its high toxicity observed in patients. In this study, a nanoparticles-delivery system for AmpB (NQC-AmpB), containing chitosan and chondroitin sulfate molecules, was evaluated in BALB/c mice against Leishmania amazonensis. An in vivo biodistribution study, including biochemical and toxicological evaluations, was performed to evaluate the toxicity of AmpB. Nanoparticles were radiolabeled with technetium-99m and injected in mice. The products presented a similar biodistribution in the liver, spleen, and kidneys of the animals. Free AmpB induced alterations in the body weight of the mice, which, in the biochemical analysis, indicated hepatic and renal injury, as well as morphological damage to the kidneys of the animals. In general, no significant organic alteration was observed in the animals treated with NQC-AmpB. Mice were infected with L. amazonensis and treated with the nanoparticles or free AmpB; then, parasitological and immunological analyses were performed. The NQC-AmpB group, as compared to the control groups, presented significant reductions in the lesion size and in the parasite burden in all evaluated organs. These animals presented significantly higher levels of IFN-γ and IL-12, and low levels of IL-4 and IL-10, when compared to the control groups. The NQC-AmpB system was effective in reducing the infection in the animals, and proved to be effective in diminishing the toxicity evoked by AmpB, which was observed when it was administered alone. In conclusion, NQC-AmpB could be considered a viable possibility for future studies in the treatment of leishmaniasisThis work was supported by grants from Pró-Reitoria de Pesquisa from UFMG (Edital 01/2014), Instituto Nacional de Ciência e Tecnologia em Nano-biofarmacêutica (INCT-Nanobiofar), FAPEMIG (CBB-APQ-00496-11 and CBB-APQ-00819-12), and CNPq (APQ-472090/2011-9 and APQ-482976/2012-8). MACF is a grant recipient of FAPEMIG/CAPES. EAFC, VNC, and AAGF are grant recipients of CNPq. Eduardo AF Coelho and André AG Faraco are co-senior authors of this stud

Recent updates and perspectives on approaches for the development of vaccines against visceral leishmaniasis

All rights reserved. Visceral leishmaniasis (VL) is one of the most important tropical diseases worldwide. Although chemotherapy has been widely used to treat this disease, problems related to the development of parasite resistance and side effects associated with the compounds used have been noted. Hence, alternative approaches for VL control are desirable. Some methods, such as vector control and culling of infected dogs, are insufficiently effective, with the latter not ethically recommended. The development of vaccines to prevent VL is a feasible and desirable measure for disease control, for example, some vaccines designed to protect dogs against VL have recently been brought to market. These vaccines are based on the combination of parasite fractions or recombinant proteins with adjuvants that are able to induce cellular immune responses, however, their partial efficacy and the absence of a vaccine to protect against human leishmaniasis underline the need for characterization of new vaccine candidates. This review presents recent advances in control measures for VL based on vaccine development, describing extensively studied antigens, as well as new antigenic proteins recently identified using immuno-proteomic techniquesThis work was supported by grants from Instituto Nacional de Ciência e Tecnologia em Nano-Biofarmacêutica, Rede Nanobiotec/Brasil-Universidade Federal de Uberlândia/CAPES, PRONEX-FAPEMIG (APQ-01019-09), FAPEMIG (CBB-APQ-00819-12 and CBB-APQ-01778-2014), and CNPq (APQ-482976/2012-8, APQ-488237/2013-0, and APQ-467640/2014-9). EAFC and LRG are recipients of the grant from CNPq. MACF is the recipient of grants from FAPEMIG/CAPE

Coadministration of the Three Antigenic Leishmania infantum Poly (A) Binding Proteins as a DNA Vaccine Induces Protection against Leishmania major Infection in BALB/c Mice

Highly conserved intracellular proteins from Leishmania have been described as antigens in natural and experimental infected mammals. The present study aimed to evaluate the antigenicity and prophylactic properties of the Leishmania infantum Poly (A) binding proteins (LiPABPs). Three different members of the LiPABP family have been described. Recombinant tools based on these proteins were constructed: recombinant proteins and DNA vaccines. The three recombinant proteins were employed for coating ELISA plates. Sera from human and canine patients of visceral leishmaniasis and human patients of mucosal leishmaniasis recognized the three LiPABPs. In addition, the protective efficacy of a DNA vaccine based on the combination of the three Leishmania PABPs has been tested in a model of progressive murine leishmaniasis: BALB/c mice infected with Leishmania major. The induction of a Th1-like response against the LiPABP family by genetic vaccination was able to down-regulate the IL-10 predominant responses elicited by parasite LiPABPs after infection in this murine model. This modulation resulted in a partial protection against L. major infection. LiPABP vaccinated mice showed a reduction on the pathology that was accompanied by a decrease in parasite burdens, in antibody titers against Leishmania antigens and in the IL-4 and IL-10 parasite-specific mediated responses in comparison to control mice groups immunized with saline or with the non-recombinant plasmid. The results presented here demonstrate for the first time the prophylactic properties of a new family of Leishmania antigenic intracellular proteins, the LiPABPs. The redirection of the immune response elicited against the LiPABP family (from IL-10 towards IFN-γ mediated responses) by genetic vaccination was able to induce a partial protection against the development of the disease in a highly susceptible murine model of leishmaniasisThe study was supported in Spain by grants from Ministerio de Ciencia e Innovación FIS PI11/00095 and FISPI14/00366 from the Instituto de Salud Carlos III within the Network of TropicalDiseases Research (VI P I+D+I 2008-2011, ISCIII -Subdirección General de Redes y Centros de Investigación Cooperativa (RD12/0018/0009)). This work was also supported in Brazil by a grant from CNPq (Ciencia sem Fronteiras-PVE 300174/2014-4). A CBMSO institutional grant from Fundación Ramón Areces is also acknowledged. EAFC is a grant recipient of CNPq. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip

Is diet partly responsible for differences in COVID-19 death rates between and within countries?

Correction: Volume: 10 Issue: 1 Article Number: 44 DOI: 10.1186/s13601-020-00351-w Published: OCT 26 2020Reported COVID-19 deaths in Germany are relatively low as compared to many European countries. Among the several explanations proposed, an early and large testing of the population was put forward. Most current debates on COVID-19 focus on the differences among countries, but little attention has been given to regional differences and diet. The low-death rate European countries (e.g. Austria, Baltic States, Czech Republic, Finland, Norway, Poland, Slovakia) have used different quarantine and/or confinement times and methods and none have performed as many early tests as Germany. Among other factors that may be significant are the dietary habits. It seems that some foods largely used in these countries may reduce angiotensin-converting enzyme activity or are anti-oxidants. Among the many possible areas of research, it might be important to understand diet and angiotensin-converting enzyme-2 (ACE2) levels in populations with different COVID-19 death rates since dietary interventions may be of great benefit.Peer reviewe

Evolutionary Heritage Influences Amazon Tree Ecology

Lineages tend to retain ecological characteristics of their ancestors through time. However, for some traits, selection during evolutionary history may have also played a role in determining trait values. To address the relative importance of these processes requires large-scale quantification of traits and evolutionary relationships among species. The Amazonian tree flora comprises a high diversity of angiosperm lineages and species with widely differing life-history characteristics, providing an excellent system to investigate the combined influences of evolutionary heritage and selection in determining trait variation. We used trait data related to the major axes of life-history variation among tropical trees (e.g. growth and mortality rates) from 577 inventory plots in closed-canopy forest, mapped onto a phylogenetic hypothesis spanning more than 300 genera including all major angiosperm clades to test for evolutionary constraints on traits. We found significant phylogenetic signal (PS) for all traits, consistent with evolutionarily related genera having more similar characteristics than expected by chance. Although there is also evidence for repeated evolution of pioneer and shade tolerant life-history strategies within independent lineages, the existence of significant PS allows clearer predictions of the links between evolutionary diversity, ecosystem function and the response of tropical forests to global change

Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

BACKGROUND: Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions. OBJECTIVE: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management. DATA SOURCES: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach. KEY RECOMMENDATIONS: We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early