Modelling the Transport of Nanoparticles under Blood Flow using an Agent-based Approach.

Blood-mediated nanoparticle delivery is a new and growing field in the development of therapeutics and diagnostics. Nanoparticle properties such as size, shape and surface chemistry can be controlled to improve their performance in biological systems. This enables modulation of immune system interactions, blood clearance profile and interaction with target cells, thereby aiding effective delivery of cargo within cells or tissues. Their ability to target and enter tissues from the blood is highly dependent on their behaviour under blood flow. Here we have produced an agent-based model of nanoparticle behaviour under blood flow in capillaries. We demonstrate that red blood cells are highly important for effective nanoparticle distribution within capillaries. Furthermore, we use this model to demonstrate how nanoparticle size can selectively target tumour tissue over normal tissue. We demonstrate that the polydispersity of nanoparticle populations is an important consideration in achieving optimal specificity and to avoid off-target effects. In future this model could be used for informing new nanoparticle design and to predict general and specific uptake properties under blood flow

INFRARED MULTIPLE-PHOTON DISSOCIATION AS A SOURCE OF REACTIVE FREE-RADICALS - METHYLENE REVISITED

Rate constants for collisional removal of ã1 A 1 CH2 and CD2 have been directly measured for the first time, by using IR multiplephoton dissociation to produce the radicals and time-resolved laser-induced fluorescence to detect them. Contributions to the removal processes from both intersystem crossing and chemical reaction are discussed. © 1981 Società Italiana di Fisica

SINGLET METHYLENE KINETICS - DIRECT MEASUREMENTS OF REMOVAL RATES OF A1A1 AND B1B1 CH2 AND CD2

Rate constants for collisional removal of ã1A1 and b̃1B1 CH2 and CD2 have been directly measured, using IR laser induced multiple photon dissociation to prepare the radicals, and time resolved laser induced fluorescence to observe them. For CH2(ã1A1) removal by He, Ne, Ar, Kr, Xe, N2, H2, O2, CO and CH4, rate constants of 3.1, 4.2, 6.0, 7.0, 16, 8.8, 130, 30, 56 and 73 × 10-12 cm3 molecule-1 s-1 were found respectively. These represent significant increases over the previously accepted values. Essentially no isotope effect is observed in the removal of CD2(ã1A1) by the rare gases. The rate determining step in removal by the rare gases and N2 is thought to be singlet-triplet intersystem crossing controlled by long range attractive forces, and the results are discussed in terms of both isolated and mixed state theoretical models of these processes. For the other molecular collision partners, bimolecular chemical removal channels are possible, and may account for the relatively fast rates observed. Radiative lifetimes of five Σ vibronic levels of CH2(b̃1B1) and three Σ vibronic levels of CD2(b̃1B1) have been measured and found to lie in the range 2.5-6.0 μs, and collisional quenching rates for CH2(b̃1B1) are found to be of the order of the gas kinetic collisional frequency. © 1981

On the shuttling across the blood-brain barrier via tubule formation: Mechanism and cargo avidity bias

The blood-brain barrier is made of polarized brain endothelial cells (BECs) phenotypically conditioned by the central nervous system (CNS). Although transport across BECs is of paramount importance for nutrient uptake as well as ridding the brain of waste products, the intracellular sorting mechanisms that regulate successful receptor-mediated transcytosis in BECs remain to be elucidated. Here, we used a synthetic multivalent system with tunable avidity to the low-density lipoprotein receptor–related protein 1 (LRP1) to investigate the mechanisms of transport across BECs. We used a combination of conventional and super-resolution microscopy, both in vivo and in vitro, accompanied with biophysical modeling of transport kinetics and membrane-bound interactions to elucidate the role of membrane-sculpting protein syndapin-2 on fast transport via tubule formation. We show that high-avidity cargo biases the LRP1 toward internalization associated with fast degradation, while mid-avidity augments the formation of syndapin-2 tubular carriers promoting a fast shuttling across