Sequential deconstruction of composite drug transport in metastatic breast cancer

Abstract

It is challenging to design effective drug delivery systems (DDS) that target metastatic breast cancers (MBC) because of lack of competent imaging and image analysis protocols that suitably capture the interactions between DDS and metastatic lesions. Here, we integrate high temporal resolution of in vivo whole-body PET-CT, ex vivo whole-organ optical imaging, high spatial resolution of confocal microscopy, and mathematical modeling, to systematically deconstruct the trafficking of injectable nanoparticle generators encapsulated with polymeric doxorubicin (iNPG-pDox) in pulmonary MBC. iNPG-pDox accumulated substantially in metastatic lungs, compared to healthy lungs. Intratumoral distribution and retention of iNPG-pDox varied with lesion size, possibly induced by locally remodeled microenvironment. We further used multiscale imaging and mathematical simulations to provide improved drug delivery strategies for MBC. Our work presents a multidisciplinary translational toolbox to evaluate transport and interactions of DDS within metastases. This knowledge can be recursively applied to rationally design advanced therapies for metastatic cancers.

Innate immunity plays a key role in controlling viral load in COVID-19: mechanistic insights from a whole-body infection dynamics model

“…Based on the estimated characteristic times (1-24 h) of the vascular transport processes (shown in Figure 1 and presented as rates in Table 2 ), it can be inferred that viral transport is permeability-limited and not perfusion-limited, i.e., capillary permeability and vascular surface area govern the rate of extravasation of virions from blood vessels into tissue interstitium to reach the target cells, and thus viral transport is not exclusively governed by the plasma flow rates into the organs. This is consistent with the in vivo behavior of nanomaterials of comparable size 35-40 , and is in contrast to the perfusion rate-limited kinetics of smaller lipophilic molecules. The variability in characteristic times of vascular transport can be explained by differences in the permeability of capillary endothelium due to differences in pore sizes of endothelial fenestrae 41 .…”

Innate Immunity Plays a Key Role in Controlling Viral Load in COVID-19: Mechanistic Insights from a Whole-Body Infection Dynamics Model

“…Based on the estimated characteristic times (1–24 h) of the vascular transport processes (shown in Figure 1 and presented as rates in Table 2 ), it can be inferred that viral transport is permeability-limited and not perfusion-limited, i.e., capillary permeability and vascular surface area govern the rate of extravasation of virions from blood vessels into tissue interstitium to reach the target cells, and thus viral transport is not exclusively governed by the plasma flow rates into the organs. This is consistent with the in vivo behavior of nanomaterials of comparable size 36 − 44 and is in contrast to the perfusion rate-limited kinetics of smaller lipophilic molecules. The variability in characteristic times of vascular transport can be explained by differences in the permeability of capillary endothelium due to differences in pore sizes of endothelial fenestrae.…”

Moving Beyond the Pillars of Cancer Treatment: Perspectives From Nanotechnology

“…It is important to thoroughly characterize and deconstruct nanoparticle transport and toxicity not only in the short term, but also long term. Continued progress of nanofabrication methodologies provides the potential for incorporating imaging labels onto therapeutic nanomaterials to develop modular designs that enable non-invasive delineation of nanoparticles kinetics in vivo in real time (Goel et al, 2020 ). Better understanding of NP transport in different animal models over longer timescales would function not only to improve treatment outcomes, but also to help anticipate long term off-target side effects during translational studies.…”