Search for: All records

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. 

Abstract While plasma concentration kinetics has traditionally been the predictor of drug pharmacological effects, it can occasionally fail to represent kinetics at the site of action, particularly for solid tumors. This is especially true in the case of delivery of therapeutic macromolecules (drug‐loaded nanomaterials or monoclonal antibodies), which can experience challenges to effective delivery due to particle size‐dependent diffusion barriers at the target site. As a result, disparity between therapeutic plasma kinetics and kinetics at the site of action may exist, highlighting the importance of target site concentration kinetics in determining the pharmacodynamic effects of macromolecular therapeutic agents. Assessment of concentration kinetics at the target site has been facilitated by non‐invasive in vivo imaging modalities. This allows for visualization and quantification of the whole‐body disposition behavior of therapeutics that is essential for a comprehensive understanding of their pharmacokinetics and pharmacodynamics. Quantitative non‐invasive imaging can also help guide the development and parameterization of mathematical models for descriptive and predictive purposes. Here, we present a review of the application of state‐of‐the‐art imaging modalities for quantitative pharmacological evaluation of therapeutic nanoparticles and monoclonal antibodies, with a focus on their integration with mathematical models, and identify challenges and opportunities. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic DiseaseDiagnostic Tools > in vivo Nanodiagnostics and ImagingNanotechnology Approaches to Biology > Nanoscale Systems in Biology