Data-Driven Modeling of the Cellular Pharmacokinetics of Degradable Chitosan-Based Nanoparticles

Nanoparticle drug delivery vehicles introduce multiple pharmacokinetic processes, with the delivery, accumulation, and stability of the therapeutic molecule influenced by nanoscale processes. Therefore, considering the complexity of the multiple interactions, the use of data-driven models has critical importance in understanding the interplay between controlling processes. We demonstrate data simulation techniques to reproduce the time-dependent dose of trimethyl chitosan nanoparticles in an ND7/23 neuronal cell line, used as an in vitro model of native peripheral sensory neurons. Derived analytical expressions of the mean dose per cell accurately capture the pharmacokinetics by including a declining delivery rate and an intracellular particle degradation process. Comparison with experiment indicates a supply time constant, τ = 2 h. and a degradation rate constant, b = 0.71 h−1. Modeling the dose heterogeneity uses simulated data distributions, with time dependence incorporated by transforming data-bin values. The simulations mimic the dynamic nature of cell-to-cell dose variation and explain the observed trend of increasing numbers of high-dose cells at early time points, followed by a shift in distribution peak to lower dose between 4 to 8 h and a static dose profile beyond 8 h

Utilizing in vitro drug release assays to predict in vivo drug retention in micelles

In the present work, we aim at developing an in vitro release assay to predict circulation times of hydrophobic drugs loaded into polymeric micelles (PM), upon intravenous (i.v.) administration. PM based on poly (ethylene glycol)-b-poly (N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)) block copolymer were loaded with a panel of hydrophobic anti-cancer drugs and characterized for size, loading efficiency and release profile in different release media. Circulation times in mice of two selected drugs loaded in PM were evaluated and compared to the in vitro release profile. Release of drugs from PM was evaluated over 7 days in PBS containing Triton X-100 and in PBS containing albumin at physiological concentration (40 g/L). The results were utilized to identify crucial molecular features of the studied hydrophobic drugs leading to better micellar retention. For the best and the worst retained drugs in the in vitro assays (ABT-737 and BCI, respectively), the circulation of free and entrapped drugs into PM was examined after i.v. administration in mice. We found in vivo drug retention at 24 h post-injection similar to the retention found in the in vitro assays. This demonstrates that in vitro release assay in buffers supplemented with albumin, and to a lesser degree Triton X-100, can be employed to predict the in vivo circulation kinetics of drugs loaded in PM. Utilizing media containing acceptor molecules for hydrophobic compounds, provide a first screen to understand the stability of drug-loaded PM in the circulation and, therefore, can contribute to the reduction of animals used for circulation kinetics studies

Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression

Despite available targeted treatments for the disease, drug-resistant chronic lymphocytic leukemia (CLL) poses a clinical challenge. The objective of this study is to examine whether the dual-specific phosphatases DUSP1 and DUSP6 are required to negatively regulate mitogen-activated protein kinases (MAPKs) and thus counterbalance excessive MAPK activity. We show that high expression of DUSP6 in CLL correlates with poor clinical prognosis. Importantly, genetic deletion of the inhibitory phosphatase DUSP1 or DUSP6 and blocking DUSP1/6 function using a small-molecule inhibitor reduces CLL cell survival in vitro and in vivo. Using global phospho-proteome approaches, we observe acute activation of MAPK signaling by DUSP1/6 inhibition. This promotes accumulation of mitochondrial reactive oxygen species and, thereby, DNA damage and apoptotic cell death in CLL cells. Finally, we observe that DUSP1/6 inhibition is particularly effective against treatment-resistant CLL and therefore suggest transient DUSP1/6 inhibition as a promising treatment concept to eliminate drug-resistant CLL cells

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Π-π Stacked Polymeric Micelles as Carriers of Anticancer Therapeutics for Hematological Malignancies

The research presented in this thesis explores mPEG-b-p(HPMA-Bz)-based micelles as nanocarriers for cancer treatment, with focus on hematological cancers. PM showed good circulation and attractive tissue distribution in clinically relevant models of multiple myeloma and chronic lymphocytic leukemia. However, therapeutic outcome of the developed formulations was minimally improved. This is most likely due to the poor pharmacokinetic profile of drug-loaded PM in blood and consequently advantages attributed to nanocarriers, such as target tissue accumulation, could not be fully explored. Finally, physicochemical parameters of drug molecules that influence drug loading and retention in vivo were examined. Further in vivo studies to evaluate therapeutic effect of drugs with favorable drug retention can elucidate the potential of this micellar system

Nanomedicines for the treatment of hematological malignancies

Hematological malignancies (HM) are a collection of malignant transformations originating from cells in the primary or secondary lymphoid organs. Leukemia, lymphoma, and multiple myeloma comprise the three major types of HM. Current treatment consists of bone marrow transplantation, radiotherapy, immunotherapy and chemotherapy. Although, many chemotherapeutic drugs are clinically available for the treatment of HM, the use of these agents is limited due to dose-related toxicity and lack of specificity to tumor tissue. Moreover, the poor pharmacokinetic profile of most of the chemotherapeutics requires high dosage and frequent administration to maintain therapeutic levels at the target site, both increasing adverse effects. This underlines an urgent need for a suitable drug delivery system to improve efficacy, safety, and pharmacokinetic properties of conventional therapeutics. Nanomedicines have proven to enhance these properties for anticancer therapeutics. The most extensively studied nanomedicine systems are lipid-based nanoparticles and polymeric nanoparticles. Typically, nanomedicines are small sub-micron sized particles in the size range of 20-200 nm. The biocompatible and biodegradable nature of nanomedicines makes them attractive vehicles to improve drug delivery. Their small size allows them to extravasate and accumulate at malignant sites passively by means of the enhanced permeability and retention (EPR) effect, resulting from rapid angiogenesis and inflammation. Moreover, the specificity to the target tissue can be further enhanced by surface modification of nanoparticles. This review describes currently available therapies as well as limitations and potential advantages of nanomedicine formulations for treatment of various types of HM. Additionally, recent investigational and approved nanomedicine formulations and their limited applications in HM are discussed

Nanomedicines for the treatment of hematological malignancies

Hematological malignancies (HM) are a collection of malignant transformations originating from cells in the primary or secondary lymphoid organs. Leukemia, lymphoma, and multiple myeloma comprise the three major types of HM. Current treatment consists of bone marrow transplantation, radiotherapy, immunotherapy and chemotherapy. Although, many chemotherapeutic drugs are clinically available for the treatment of HM, the use of these agents is limited due to dose-related toxicity and lack of specificity to tumor tissue. Moreover, the poor pharmacokinetic profile of most of the chemotherapeutics requires high dosage and frequent administration to maintain therapeutic levels at the target site, both increasing adverse effects. This underlines an urgent need for a suitable drug delivery system to improve efficacy, safety, and pharmacokinetic properties of conventional therapeutics. Nanomedicines have proven to enhance these properties for anticancer therapeutics. The most extensively studied nanomedicine systems are lipid-based nanoparticles and polymeric nanoparticles. Typically, nanomedicines are small sub-micron sized particles in the size range of 20-200 nm. The biocompatible and biodegradable nature of nanomedicines makes them attractive vehicles to improve drug delivery. Their small size allows them to extravasate and accumulate at malignant sites passively by means of the enhanced permeability and retention (EPR) effect, resulting from rapid angiogenesis and inflammation. Moreover, the specificity to the target tissue can be further enhanced by surface modification of nanoparticles. This review describes currently available therapies as well as limitations and potential advantages of nanomedicine formulations for treatment of various types of HM. Additionally, recent investigational and approved nanomedicine formulations and their limited applications in HM are discussed

Nanomedicines for the treatment of hematological malignancies

Hematological malignancies (HM) are a collection of malignant transformations originating from cells in the primary or secondary lymphoid organs. Leukemia, lymphoma, and multiple myeloma comprise the three major types of HM. Current treatment consists of bone marrow transplantation, radiotherapy, immunotherapy and chemotherapy. Although, many chemotherapeutic drugs are clinically available for the treatment of HM, the use of these agents is limited due to dose-related toxicity and lack of specificity to tumor tissue. Moreover, the poor pharmacokinetic profile of most of the chemotherapeutics requires high dosage and frequent administration to maintain therapeutic levels at the target site, both increasing adverse effects. This underlines an urgent need for a suitable drug delivery system to improve efficacy, safety, and pharmacokinetic properties of conventional therapeutics. Nanomedicines have proven to enhance these properties for anticancer therapeutics. The most extensively studied nanomedicine systems are lipid-based nanoparticles and polymeric nanoparticles. Typically, nanomedicines are small sub-micron sized particles in the size range of 20-200 nm. The biocompatible and biodegradable nature of nanomedicines makes them attractive vehicles to improve drug delivery. Their small size allows them to extravasate and accumulate at malignant sites passively by means of the enhanced permeability and retention (EPR) effect, resulting from rapid angiogenesis and inflammation. Moreover, the specificity to the target tissue can be further enhanced by surface modification of nanoparticles. This review describes currently available therapies as well as limitations and potential advantages of nanomedicine formulations for treatment of various types of HM. Additionally, recent investigational and approved nanomedicine formulations and their limited applications in HM are discussed