Nanovehículos basados en albúmina para terapia contra el cáncer

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, leída el 15-12-2021Cancer is one of the major health problems worldwide and suitable therapies with enhanced efficacy and reduced side effects are hence being searched. In recent years, nanocarriers are gaining tremendous attention for the delivery of various therapeutic agents (both chemotherapeutics and nucleic acids) in cancer therapy. They offer multiple advantages, including improved drug delivery, targeted accumulation due to enhanced permeability and retention (EPR) effect, controlled release, improvement of circulation half-lives, biodistribution, and efficacy of encapsulated cargos, and flexibility in administration routes.This thesis is focused on the use of albumin-based nanocarriers for cancer therapy. Albumin is a versatile protein and provides biocompatibility, tumor specificity, the possibility for surface modification, and reduces toxicity. Some of the widely investigated albumin nanocarriers include polyplexes, nanoconjugates, and nanoparticles. Despite their broad potential in oncology, many studies still need to be done regarding their safety and tumor targeting enhancement. Anyhow, the potential of albumin nanocarriers is clearly supported by the FDA and EMA approved formulation, Abraxane, which is currently used for metastatic breast cancer. Therefore, further developments based on related strategies can have a dramatic impact on cancer therapy...El cáncer es uno de los principales problemas de salud en todo el mundo y la busqueda de terapias con mejor eficacia y menores efectos secundarios es un reto prioritario para la sociedad. En este sentido, en los últimos años, los nanovehiculos han mostrado excelentes propiedades para la administración de varios agentes terapéuticos (tanto quimioterapéuticos como ácidos nucleicos) en la terapia del cáncer. Estos sistemas ofrecen varias ventajas, como son una administración mejorada del fármaco, acumulación dirigida debido al efecto de permeabilidad y retención (EPR), liberación controlada, mejora de la vida media de la circulación, biodistribución y eficacia de las cargas encapsuladas y flexibilidad en las vías de administración. Esta tesis se centra en el uso de nanovehiculos a base de albúmina para la terapia del cáncer. La albúmina es una proteína versátil y proporciona biocompatibilidad, especificidad tumoral, la posibilidad de modificación de la superficie y reduce la toxicidad. Algunos de los nanopovehiculos de albúmina ampliamente investigados incluyen polyplexes, nanoconjugados y nanopartículas. A pesar de su amplio potencial en oncología, aún deben realizarse muchos estudios en términos de estudios de seguridad y mejora de la orientación tumoral. En este sentido merece la pena recordar que el potencial de los nanovehiculos de albúmina ya se refleja en una formulación aprobada por la FDA y la EMA, el Abraxane, utilizado para el cáncer de mama metastásico. Por tanto, es de esperar que futuros desarrollos basados en estos sistemas tengan un gran impacto en las terapias contra el cáncer...Fac. de FarmaciaTRUEunpu

Albumin-based nanocarriers for cancer therapy

Cancer is one of the major health problems worldwide and suitable therapies with enhanced efficacy and reduced side effects are hence being searched. In recent years, nanocarriers are gaining tremendous attention for the delivery of various therapeutic agents (both chemotherapeutics and nucleic acids) in cancer therapy. They offer multiple advantages, including improved drug delivery, targeted accumulation due to enhanced permeability and retention (EPR) effect, controlled release, improvement of circulation half-lives, biodistribution, and efficacy of encapsulated cargos, and flexibility in administration routes.This thesis is focused on the use of albumin-based nanocarriers for cancer therapy. Albumin is a versatile protein and provides biocompatibility, tumor specificity, the possibility for surface modification, and reduces toxicity. Some of the widely investigated albumin nanocarriers include polyplexes, nanoconjugates, and nanoparticles. Despite their broad potential in oncology, many studies still need to be done regarding their safety and tumor targeting enhancement. Anyhow, the potential of albumin nanocarriers is clearly supported by the FDA and EMA approved formulation, Abraxane, which is currently used for metastatic breast cancer. Therefore, further developments based on related strategies can have a dramatic impact on cancer therapy..

pH-responsive nano-self-assemblies of the anticancer drug 2-hydroxyoleic acid

pH-responsive lipid nanocarriers have the potential to selectively target the acidic extracellular pH environment of cancer tissues and may further improve the efficacy of chemotherapeutics by minimizing their toxic side-effects. Here, we present the design and characterization of pH-sensitive nano-self-assemblies of the poorly water-soluble anticancer drug 2-hydroxyoleic acid (2OHOA) with glycerol monooleate (GMO). pH- triggered nanostructural transformations from 2OHOA/GMO nanoparticles with an internal inverse hexagonal structure (hexosomes) at pH around 2.0–3.0, via nanocarriers with an internal inverse bicontinuous cubic structure (cubosomes) at pH 2.0–4.5, to vesicles at pH 4.5–7.4 were observed with synchrotron small-angle X-ray scattering, and cryogenic transmission electron microscopy. ζ-potential measurements highlight that the pH-driven deprotonation of the carboxylic group of 2OHOA, and the resulting charge-repulsions at the lipid–water interface account for these nanostructural alterations. The study provides detailed insight into the pH-dependent self-assembly of 2OHOA with GMO in excess buffer at physiologically relevant pH values, and discusses the effects of pH alterations on modulating their nanostructure. The results may guide the further development of pH-responsive anticancer nanocarriers for the targeted delivery of chemotherapeutics to the local microenvironment of tumor cells

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

Albumin-Based Nanoparticles for the Delivery of Doxorubicin in Breast Cancer

Albumin-based nanoparticles are an emerging platform for the delivery of various chemotherapeutics because of their biocompatibility, safety, and ease of surface modification for specific targeting. The most widely used method for the preparation of albumin nanoparticles is by desolvation process using glutaraldehyde (GLU) as a cross-linker. However, limitations of GLU like toxicity and interaction with drugs force the need for alternative cross-linkers. In the present study, several cross-linking systems were evaluated for the preparation of Bovine Serum Albumin (BSA) nanoparticles (ABNs) encapsulating Doxorubicin (Dox). Based on the results obtained from morphological characterization, in vitro release, and therapeutic efficacy in cells, N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP)-modified ABNs (ABN-SPDP) was chosen. Since ABN-SPDP are formed with disulfide linkage, the drug release is facilitated under a highly reducing environment present in the tumor sites. The cytotoxicity studies of those ABN-SPDP were performed in three different breast cell lines, highlighting the mechanism of cell death. The Dox-encapsulated ABN-SPDP showed toxicity in both the breast cancer cells (MCF-7 and MDA-MB-231), but, remarkably, a negligible effect was observed in non-tumoral MCF-10A cells. In addition to the hydrophilic Dox, this system could be used as a carrier for hydrophobic drugs like SN38. The system could be employed for the preparation of nanoparticles based on human serum albumin (HSA), which further enhances the feasibility of this system for clinical use. Hence, the albumin nanoparticles developed herein present an excellent potential for delivering various drugs in cancer therapy

Albumin Nanostructures for Nucleic Acid Delivery in Cancer: Current Trend, Emerging Issues, and Possible Solutions

Cancer is one of the major health problems worldwide, and hence, suitable therapies with enhanced efficacy and reduced side effects are desired. Gene therapy, involving plasmids, small interfering RNAs, and antisense oligonucleotides have been showing promising potential in cancer therapy. In recent years, the preparation of various carriers for nucleic acid delivery to the tumor sites is gaining attention since intracellular and extracellular barriers impart major challenges in the delivery of naked nucleic acids. Albumin is a versatile protein being used widely for developing carriers for nucleic acids. It provides biocompatibility, tumor specificity, the possibility for surface modification, and reduces toxicity. In this review, the advantages of using nucleic acids in cancer therapy and the challenges associated with their delivery are presented. The focus of this article is on the different types of albumin nanocarriers, such as nanoparticles, polyplexes, and nanoconjugates, employed to overcome the limitations of the direct use of nucleic acids in vivo. This review also highlights various approaches for the modification of the surface of albumin to enhance its transfection efficiency and targeted delivery in the tumor sites

Spectral energy and angular distributions of bremsstrahlung radiation produced by 3.5 keV electrons in scattering with a free SF

Absolute double differential cross sections (DDCS) of bremsstrahlung (BS) radiation produced by 3.5 keV electrons in scattering with a free SF6 molecule were measured by using a Si-PIN photodiode detector in the angular detection range of 45°−110° relative to the direction of incident electrons. Angular distributions of the BS photons are found to be anisotropic. The experimental DDCS spectra are compared with the theoretical calculations obtained from atomic-field BS formulations of Kissel–Quarles–Pratt (KQP) using the “additivity hypothesis”. A fair agreement is observed between the measured results and those obtained from the KQP calculations for both the energy and the angular spectral distributions of BS radiation. The measured anisotropy of bremsstrahlung radiation is reproduced reasonably well by a modified Sommerfeld formula, if the relative velocity β is chosen to be half of the incident electron velocity β0. The measured anisotropy may be described by a parameter P, which is compared with the degree of polarisation obtained from theoretical calculations. Further, it is noted that the molecular weight, geometry and the number of constituent atoms present in the considered molecule do not seem to influence the usefulness of “additivity hypothesis”. In conclusion, the present results have once again corroborated the validity of “additivity hypothesis” for predicting the spectral distributions of molecular bremsstrahlung produced by keV-electrons

Electron excited multiply charged argon ions studied by means of an energy resolved electron-ion coincidence technique

Multiply charged argon ions produced from decay of L-shell hole states by impact of a continuous beam of 3.5 keV electrons are studied for the first time using an energy resolved electron-ion coincidence technique. The TOF spectra of argon ions are measured in coincidence with 18-energy selected electrons emitted in a wide energy range (126–242 eV). The coincidence measurement between the energy selected electrons and the correlated ions specifies the individual decay channel for various multiply charged ions. New experimental data are obtained and reported on the correlation probability for production of argon ions with charge states 1+ to 4+ as a function of ejected electrons in the considered energy range. The relative correlation probability of producing different charge state ions and corresponding physical processes involved in their production are presented and discussed. It has been found that the maximum probability for production of Ar2+ ions correlated to ejected Auger electrons in the energy range of 205–209 eV is 100%. No theoretical predictions are available to compare with these results. The present study shows further that not only the auto-ionization and normal Auger transitions but also several other decay processes including Coster-Kronig transitions followed by Auger cascades with a fraction of shake process play important role in producing ions with charge states 1+ to 4+