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Register a new userKinetic limitations of cooperativity based drug delivery systems
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We study theoretically a novel drug delivery system that utilizes the overexpression of certain proteins in cancerous cells for cell specific chemotherapy. The system consists of dendrimers conjugated with keys (ex: folic acid) which key-lock bind to particular cell membrane proteins (ex: folate receptor). The increased concentration of locks on the surface leads to a longer residence time for the dendrimer and greater incorporation into the cell. Cooperative binding of the nanocomplexes leads to an enhancement of cell specificity. However, both our theory and detailed analysis of in-vitro experiments indicate that the degree of cooperativity is kinetically limited. We demonstrate that cooperativity and hence the specificity to particular cell type can be increased by making the strength of individual bonds weaker, and suggest a particular implementation of this idea. The implications of the work for optimizing the design of drug delivery vehicles are discussed.
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In this work we investigate the use of nanoporous carrier as drug delivery systems for hydrophobic molecules. By studying a model system made of porous silicon loaded with beta-carotene, we unveil a fundamental limitation of these carriers that is due to heterogeneous nucleation that imposes a tradeoff between the amount of drug loaded and the reproducibility of the release. Nonetheless, such issue is an alternative and improved method, compared with the standard induction time, to monitor the formation of heterogenously nucleated aggregates.
We present a mechanistic model of drug release from a multiple emulsion into an external surrounding fluid. We consider a single multi-layer droplet where the drug kinetics are described by a pure diffusive process through different liquid shells. The multi-layer problem is described by a system of diffusion equations coupled via interlayer conditions imposing continuity of drug concentration and flux. Mass resistance is imposed at the outer boundary through the application of a surfactant at the external surface of the droplet. The two-dimensional problem is solved numerically by finite volume discretization. Concentration profiles and drug release curves are presented for three typical round-shaped (circle, ellipse and bullet) droplets and the dependency of the solution on the mass transfer coefficient at the surface analyzed. The main result shows a reduced release time for an increased elongation of the droplets.
We propose two-dimensional organic poly(heptazine imide) (PHI) carbon nitride microparticles as light-driven microswimmers in various ionic and biological media. Their demonstrated high-speed (15-23 $mu$m/s) swimming in multi-component ionic solutions with concentrations up to 1 M and without dedicated fuels is unprecedented, overcoming one of the bottlenecks of previous light-driven microswimmers. Such high ion tolerance is attributed to a favorable interplay between the particles textural and structural nanoporosity and optoionic properties, facilitating ionic interactions in solutions with high salinity. Biocompatibility of the microswimmers is validated by cell viability tests with three different cell types and primary cells. The nanopores of the swimmers are loaded with a model cancer drug, doxorubicin (DOX), in high (185%) loading efficiency without passive release. Controlled drug release is reported in different pH conditions and can be triggered on-demand also by illumination. Light-triggered, boosted release of DOX and its active degradation products is demonstrated in oxygen-poor conditions using the intrinsic, environmentally sensitive and light-induced charge storage properties of PHI, which could enable future theranostic applications in oxygen-deprived tumor regions. These organic PHI microswimmers simultaneously solve the current light-driven microswimmer challenges of high ion tolerance, fuel-free high-speed propulsion in biological media, biocompatibility and controlled on-demand cargo release towards their biomedical, environmental and other potential future applications.
In vitro cell proliferation assays are widely used in pharmacology, molecular biology, and drug discovery. Using theoretical modeling and experimentation, we show that current antiproliferative drug effect metrics suffer from time-dependent bias, leading to inaccurate assessments of parameters such as drug potency and efficacy. We propose the drug-induced proliferation (DIP) rate, the slope of the line on a plot of cell population doublings versus time, as an alternative, time-independent metric.
Increasing number in global COVID-19 cases demands for mathematical model to analyze the interaction between the virus dynamics and the response of innate and adaptive immunity. Here, based on the assumption of a weak and delayed response of the innate and adaptive immunity in SARS-CoV-2 infection, we constructed a mathematical model to describe the dynamic processes of immune system. Integrating theoretical results with clinical COVID-19 patients data, we classified the COVID-19 development processes into three typical modes of immune responses, correlated with the clinical classification of mild & moderate, severe and critical patients. We found that the immune efficacy (the ability of host to clear virus and kill infected cells) and the lymphocyte supply (the abundance and pool of naive T and B cell) play important roles in the dynamic process and determine the clinical outcome, especially for the severe and critical patients. Furthermore, we put forward possible treatment strategies for the three typical modes of immune response. We hope our results can help to understand the dynamical mechanism of the immune response against SARS-CoV-2 infection, and to be useful for the treatment strategies and vaccine design.
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