Reprogramming Tumor-Associated Macrophage Using Nanocarriers: New Perspectives to Halt Cancer Progression.

Cancer remains a significant challenge for public healthcare systems worldwide. Within the realm of cancer treatment, considerable attention is focused on understanding the tumor microenvironment (TME)-the complex network of non-cancerous elements surrounding the tumor. Among the cells in TME, tumor-associated macrophages (TAMs) play a central role, traditionally categorized as pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. Within the TME, M2-like TAMs can create a protective environment conducive to tumor growth and progression. These TAMs secrete a range of factors and molecules that facilitate tumor angiogenesis, increased vascular permeability, chemoresistance, and metastasis. In response to this challenge, efforts are underway to develop adjuvant therapy options aimed at reprogramming TAMs from the M2 to the anti-tumor M1 phenotype. Such reprogramming holds promise for suppressing tumor growth, alleviating chemoresistance, and impeding metastasis. Nanotechnology has enabled the development of nanoformulations that may soon offer healthcare providers the tools to achieve targeted drug delivery, controlled drug release within the TME for TAM reprogramming and reduce drug-related adverse events. In this review, we have synthesized the latest data on TAM polarization in response to TME factors, highlighted the pathological effects of TAMs, and provided insights into existing nanotechnologies aimed at TAM reprogramming and depletion.

Physiologically based pharmacokinetic model for predicting the biodistribution of albumin nanoparticles after induction and recovery from acute lung injury.

The application of nanomedicine in the treatment of acute lung injury (ALI) has great potential for the development of new therapeutic strategies. To gain insight into the kinetics of nanocarrier distribution upon time-dependent changes in tissue permeability after ALI induction in mice, we developed a physiologically based pharmacokinetic model for albumin nanoparticles (ANP). The model was calibrated using data from mice treated with intraperitoneal LPS (6 mg/kg), followed by intravenous ANP (0.5 mg/mouse or about 20.8 mg/kg) at 0.5, 6, and 24 h. The simulation results reproduced the experimental observations and indicated that the accumulation of ANP in the lungs increased, reaching a peak 6 h after LPS injury, whereas it decreased in the liver, kidney, and spleen. The model predicted that LPS caused an immediate (within the first 30 min) dramatic increase in lung and kidney tissue permeability, whereas splenic tissue permeability gradually increased over 24 h after LPS injection. This information can be used to design new therapies targeting specific organs affected by bacterial infections and potentially by other inflammatory insults.

The Intricate Balance between Life and Death: ROS, Cathepsins, and Their Interplay in Cell Death and Autophagy.

Cellular survival hinges on a delicate balance between accumulating damages and repair mechanisms. In this intricate equilibrium, oxidants, currently considered physiological molecules, can compromise vital cellular components, ultimately triggering cell death. On the other hand, cells possess countermeasures, such as autophagy, which degrades and recycles damaged molecules and organelles, restoring homeostasis. Lysosomes and their enzymatic arsenal, including cathepsins, play critical roles in this balance, influencing the cell's fate toward either apoptosis and other mechanisms of regulated cell death or autophagy. However, the interplay between reactive oxygen species (ROS) and cathepsins in these life-or-death pathways transcends a simple cause-and-effect relationship. These elements directly and indirectly influence each other's activities, creating a complex web of interactions. This review delves into the inner workings of regulated cell death and autophagy, highlighting the pivotal role of ROS and cathepsins in these pathways and their intricate interplay.

Smart Delivery Systems Responsive to Cathepsin B Activity for Cancer Treatment.

Cathepsin B is a lysosomal cysteine protease, contributing to vital cellular homeostatic processes including protein turnover, macroautophagy of damaged organelles, antigen presentation, and in the extracellular space, it takes part in tissue remodeling, prohormone processing, and activation. However, aberrant overexpression of cathepsin B and its enzymatic activity is associated with different pathological conditions, including cancer. Cathepsin B overexpression in tumor tissues makes this enzyme an important target for smart delivery systems, responsive to the activity of this enzyme. The generation of technologies which therapeutic effect is activated as a result of cathepsin B cleavage provides an opportunity for tumor-targeted therapy and controlled drug release. In this review, we summarized different technologies designed to improve current cancer treatments responsive to the activity of this enzyme that were shown to play a key role in disease progression and response to the treatment.

Proteolytic Resistance Determines Albumin Nanoparticle Drug Delivery Properties and Increases Cathepsin B, D, and G Expression.

Proteolytic activity is pivotal in maintaining cell homeostasis and function. In pathological conditions such as cancer, it covers a key role in tumor cell viability, spreading to distant organs, and response to the treatment. Endosomes represent one of the major sites of cellular proteolytic activity and very often represent the final destination of internalized nanoformulations. However, little information about nanoparticle impact on the biology of these organelles is available even though they represent the major location of drug release. In this work, we generated albumin nanoparticles with a different resistance to proteolysis by finely tuning the amount of cross-linker used to stabilize the carriers. After careful characterization of the particles and measurement of their degradation in proteolytic conditions, we determined a relationship between their sensitivity to proteases and their drug delivery properties. These phenomena were characterized by an overall increase in the expression of cathepsin proteases regardless of the different sensitivity of the particles to proteolytic degradation.

Anticancer Nanotherapeutics in Clinical Trials: The Work behind Clinical Translation of Nanomedicine.

The ultimate goal of nanomedicine has always been the generation of translational technologies that can ameliorate current therapies. Cancer disease represented the primary target of nanotechnology applied to medicine, since its clinical management is characterized by very toxic therapeutics. In this effort, nanomedicine showed the potential to improve the targeting of different drugs by improving their pharmacokinetics properties and to provide the means to generate new concept of treatments based on physical treatments and biologics. In this review, we considered different platforms that reached the clinical trial investigation, providing an objective analysis about their physical and chemical properties and the working mechanism at the basis of their tumoritr opic properties. With this review, we aim to help other scientists in the field in conceiving their delivering platforms for clinical translation by providing solid examples of technologies that eventually were tested and sometimes approved for human therapy.

Investigation of Nonlinear Optical Properties of Quantum Dots Deposited onto a Sample Glass Using Time-Resolved Inline Digital Holography.

We report on the application of time-resolved inline digital holography in the study of the nonlinear optical properties of quantum dots deposited onto sample glass. The Fresnel diffraction patterns of the probe pulse due to noncollinear degenerate phase modulation induced by a femtosecond pump pulse were extracted from the set of inline digital holograms and analyzed. The absolute values of the nonlinear refractive index of both the sample glass substrate and the deposited layer of quantum dots were evaluated using the proposed technique. To characterize the inhomogeneous distribution of the samples' nonlinear optical properties, we proposed plotting an optical nonlinearity map calculated as a local standard deviation of the diffraction pattern intensities induced by noncollinear degenerate phase modulation.

Subclinical target organ damage in subjects with different components of metabolic syndrome.

BACKGROUND: To assess the association of metabolic syndrome (MS) and its components with target organ damage in a follow-up study of relatively healthy bank employers. METHODS: Out of 1600 random samples of office workers in Saint Petersburg (Russia), a group of 383 participants with at least one component of MS and without cardiovascular complications was selected (mean age 46.6 ± 9.0 years, 214 females (64.6%)). Follow-up visit was performed in 331 subjects. Target organ damage (TOD) was assessed by echocardiography, carotid ultrasound, applanational tonometry, brachial-ankle index, and urine albumin excretion measurements. Anthropometry, vital signs, and biochemistry were performed according to standard protocols. RESULTS: Presence of MS was not associated with higher probability of TOD. Multiple linear regression revealed significant association of all markers of TOD with older age. Hypertension was a significant predictor of left ventricular hypertrophy (LVH), increased arterial stiffness, and early signs of carotid atherosclerosis in logistic regression adjusted for age and gender. During follow-up, proportion of patients with LVH significantly decreased (from 46.7% to 32.9%, р = 0.003) and prevalence of patients with IMT > 0.09 сm increased (from 24.5% to 44.1%, p < 0.001) accompanying by significant declining of office blood pressure (BP) and total cholesterol. CONCLUSIONS: MS per se is not related to increased probability to TOD. Hypertension, female gender, and older age are main determinants of subclinical changes. After 2-years follow-up, significant LVH and renal damage regression was observed probably owing to BP reduction. Alternatively, early signs of carotid atherosclerosis increase with aging despite decreasing of the prevalence of hypercholesterolemia.