The consequences of particle uptake on immune cells.

Particle-based systems are becoming ubiquitous in the clinic. When administered in the body, phagocytic immune cells recognize these particles as foreign substances, resulting in their cellular engulfment for degradation and elimination. However, the internalization of particles may induce unintended effects on the functions of these immune cells. Understanding the consequences of particle uptake on immune cells is imperative to design biocompatible and efficient particulate formulations for diagnostic and therapeutic use. Here, we review the recent literature that describes the changes induced in immune cells following internalization of cargo-free particles. We also discuss how the inherent immunomodulatory properties of particles may be leveraged for therapeutic applications. We conclude with suggestions on newer methods to evaluate the effects of particles on immune cells.

Sterile inflammation alters neutrophil kinetics in mice.

Neutrophils play a crucial role in establishing inflammation in response to an infection or injury, but their production rates, as well as blood and tissue residence times, remain poorly characterized under these conditions. Herein, using a biomaterial implant model to establish inflammation followed by in vivo tracking of newly formed neutrophils, we determine neutrophil kinetics under inflammatory conditions. To obtain quantifiable information from our experimental observations, we develop an ordinary differential equation-based mathematical model to extract kinetic parameters. Our data show that in the presence of inflammation resulting in emergency granulopoiesis-like conditions, neutrophil maturation time in the bone marrow reduces by around 60% and reduced half-life in the blood, compared with noninflammatory conditions. Additionally, neutrophil residence time at the inflammatory site increases by 2-fold. Together, these data improve our understanding of neutrophil kinetics under inflammatory conditions, which could pave the way for therapies that focus on modulating in vivo neutrophil dynamics.

Surface-Coated Cerium Nanoparticles to Improve Chemotherapeutic Delivery to Tumor Cells.

The antioxidant property of cerium oxide nanoparticles has increased their demand as a nanocarrier to improve the delivery and therapeutic efficacy of anticancer drugs. Here, we report the synthesis of alginate-coated ceria nanoformulations (ceria NPs) and characterization using FTIR spectroscopy, Raman microscopy, and X-ray diffraction. The synthesized ceria NPs show negligible inherent in vitro toxicity when tested on a MDA-MB-231 breast cancer cell line at higher particle concentrations. Upon loading these particles with doxorubicin (Dox) and paclitaxel (PTX) drugs, we observe a potential synergistic cytotoxic effect mediated by the drug and the ceria NPs, resulting in the better killing capacity as well as suppression of cell migration against the MDA-MB-231 cell line. Further, to verify the immune-escaping capacity before targeting cancer cells, we coated the drug-loaded ceria NPs with the membrane of MDA-MB-231 cells using an extrusion method. The resultant delivery system exhibited in vitro preferential uptake by the MDA-MB-231 cell line and showed reduced uptake by the murine macrophage cell line (RAW 264.7), assigning its potential application as non-immunogenic personalized therapy in targeting and killing of cancer cells.

Particle uptake driven phagocytosis in macrophages and neutrophils enhances bacterial clearance.

Humans are exposed to numerous synthetic foreign particles in the form of drug delivery systems and diagnostic agents. Specialized immune cells (phagocytes) clear these particles by phagocytosing and attempting to degrade them. The process of recognition and internalization of the particles may trigger changes in the function of phagocytes. Some of these changes, especially the ability of a particle-loaded phagocyte to take up and neutralize pathogens, remains poorly studied. Herein, we demonstrate that the uptake of non-stimulatory cargo-free particles enhances the phagocytic ability of monocytes, macrophages and neutrophils. The enhancement in phagocytic ability was independent of particle properties, such as size or the base material constituting the particle. Additionally, we show that the increased phagocytosis was not a result of cellular activation or cellular heterogeneity but was driven by changes in cell membrane fluidity and cellular compliance. A consequence of the enhanced phagocytic activity was that particulate-laden immune cells neutralize Escherichia coli (E. coli) faster in culture. Moreover, when administered in mice as a prophylactic, particulates enable faster clearance of E. coli and Staphylococcus epidermidis. Together, we demonstrate that the process of uptake induces cellular changes that favor additional phagocytic events. This study provides insights into using non-stimulatory cargo-free particles to engineer immune cell functions for applications involving faster clearance of phagocytosable abiotic and biotic material.

Aging associated altered response to intracellular bacterial infections and its implication on the host.

The effects of senescence on geriatric disorders are well explored, but how it influences infections in the elderly is poorly addressed. Here, we show that several anti-microbial responses are elevated in senescent epithelial cells and old mice, which results in decreased bacterial survival in the host after infection. We identify higher levels of iNOS as a crucial host response and show that p38 MAPK in senescent epithelial cells acts as a negative regulator of iNOS transcription. However, in older mice, the ability to impede bacterial infection does not result in enhanced survival, possibly because elevated pro-inflammatory responses are not countered by a robust host protective anti-inflammatory response. Overall, while addressing an alternate advantage of senescent cells, our study demonstrates that infection-associated morbidity in the elderly may not be the sole outcome of pathogen loads but may also be influenced by the host's ability to resolve inflammation-induced damage.