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Principal Investigator: Brian R Meckes
Organization: UNIVERSITY OF NORTH TEXAS
Fiscal Year: 2024
Award: $359,614
Funding agency: National Institute of General Medical Sciences
Summary Statement
An evolving extracellular mechanical landscape accompanies the progression of multiple diseases including
cancer, pulmonary fibrosis, and hypertension. While the influence of stiffening tissue on gene expression, cell
migration, and phenotype is well established, how these changes affect delivery of nanoparticle therapeutics is
less well understood, especially for materials that experience dynamic force (e.g., stretch). Conventional in vitro
nanoparticle discovery models use plastics that do not have mechanical properties reflecting tissue. These
models limit the effectiveness of conventional screening processes. Therefore, my research program will
examine how dynamic forces impact nanoparticle uptake and fate and apply this information to design more
efficient nanoparticles for cellular entry. Specifically, we will focus on lung epithelial tissue and vascular
endothelium, two tissues with important delivery routes for nanotherapeutics. In support of this goal, research
theme 1 will examine how substrate mechanics modulate the nanoparticle uptake pathway of cells. Nearly all
nanoparticles enter through endocytosis. However, the productivity of different endocytosis routes can vary,
especially when stiffness and dynamic forces are included. Our goal is to identify and understand how
mechanically-linked regulatory processes direct nanoparticles to different uptake pathways. To achieve this goal,
we will utilize tissue models that include 2D and 3D stretches that are observed in
physiological/pathophysiological tissue environments. Theme 2 focuses on understanding how cell surface
structures, particularly the glycocalyx, change when cells experience different forces. Identifying key changes in
glycocalyx structures will present potential routes for targeting specific cells based on the underlying
dysfunctional physical environment. These models will be combined with liposomal nanoparticle designs that
facilitate delivery to target cells within complex cell environments. Taken together, this research program will
allow us to reimagine cellular targeting by factoring in the mechanical characteristics of cells and multicellular
interactions to redesign NP formulations with enhanced efficacy, safety, and control.
Terms: <3-D><3-Dimensional><3D><Affect><Body Tissues><Cancers><Cell Body><Cell Coat><Cell Communication><Cell Interaction><Cell Locomotion><Cell Migration><Cell Movement><Cell surface><Cell-to-Cell Interaction><Cells><Cellular Migration><Cellular Motility><Characteristics><Complex><Disease><Disorder><Effectiveness><Endocytosis><Environment><Epithelium><Formulation><Gene Expression><Glycocalyx><Goals><Hypertension><In Vitro><Link><Liposomal><Liposomes><Lung><Lung Respiratory System><Lung Tissue Fibrosis><Malignant Neoplasms><Malignant Tumor><Mechanics><Modeling><Pathway interactions><Phenotype><Physical environment><Physiologic><Physiological><Plastics><Play><Process><Productivity><Pulmonary Fibrosis><Research><Role><Route><Safety><Stretching><Structure><Tissue Model><Tissues><Vascular Endothelium><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><cell motility><cellular targeting><design><designing><experience><extracellular><fibrosis in the lung><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><improved><lung fibrosis><malignancy><mechanic><mechanical><mechanical properties><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanoparticle therapy><nanosized particle><nanotherapeutic><neoplasm/cancer><novel><pathway><physical property><programs><pulmonary><screening><screenings><social role><therapeutic nanoparticles><three dimensional><trafficking><uptake>