Improvement in Therapeutic Efficacy and Reduction in Cellular Toxicity: Introduction of a Novel Anti-PSMA-Conjugated Hybrid Antiandrogen Nanoparticle.

Second generation antiandrogens have improved overall survival for men with metastatic castrate resistant prostate cancer; however, the antiandrogens result in suppression of androgen receptor (AR) activity in all tissues resulting in dose limiting toxicity. We sought to overcome this limitation through encapsulation in a prostate specific membrane antigen (PSMA)-conjugated nanoparticle. We designed and characterized a novel nanoparticle containing an antiandrogen, enzalutamide.

Evaluation of MUC1-Aptamer Functionalized Hybrid Nanoparticles for Targeted Delivery of miRNA-29b to Nonsmall Cell Lung Cancer.

The objective of this study was to evaluate the therapeutic efficacy and pharmacokinetic study of mucin1-aptamer functionalized miRNA-29b-loaded hybrid nanoparticles (MAFMILHNs) in lung tumor-bearing SCID mice. MAFMILHNs were manufactured using an isoelectric point based nanotechnology. They were then fully characterized for particle size, loading capacity, zeta potential, and encapsulation efficiency.

Therapeutic Challenge with a CDK 4/6 Inhibitor Induces an RB-Dependent SMAC-Mediated Apoptotic Response in Non-Small Cell Lung Cancer.

The retinoblastoma tumor suppressor (RB), a key regulator of cell-cycle progression and proliferation, is functionally suppressed in up to 50% of non-small cell lung cancer (NSCLC). RB function is exquisitely controlled by a series of proteins, including the CyclinD-CDK4/6 complex. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function.

siRNA-Encapsulated Hybrid Nanoparticles Target Mutant K-ras and Inhibit Metastatic Tumor Burden in a Mouse Model of Lung Cancer.

There is an unmet need in the development of an effective therapy for mutant K-ras-expressing non-small-cell lung cancer (NSCLC). Although various small molecules have been evaluated, an effective therapy remains a dream. siRNAs have the potential to downregulate mutant K-ras both at the protein and mRNA levels.

Aptamer-hybrid nanoparticle bioconjugate efficiently delivers miRNA-29b to non-small-cell lung cancer cells and inhibits growth by downregulating essential oncoproteins.

MicroRNAs (miRNAs) are potentially attractive candidates for cancer therapy. However, their therapeutic application is limited by lack of availability of an efficient delivery system to stably deliver these potent molecules intracellularly to cancer cells while avoiding healthy cells. We developed a novel aptamer-hybrid nanoparticle bioconjugate delivery system to selectively deliver miRNA-29b to MUC1-expressing cancer cells.

Gradually softening hydrogels for modeling hepatic stellate cell behavior during fibrosis regression.

The extracellular matrix (ECM) presents an evolving set of mechanical cues to resident cells. We developed methacrylated hyaluronic acid (MeHA) hydrogels containing both stable and hydrolytically degradable crosslinks to provide cells with a gradually softening (but not fully degradable) milieu, mimicking physiological events such as fibrosis regression. To demonstrate the utility of this cell culture system, we studied the phenotype of rat hepatic stellate cells, the major liver precursors of fibrogenic myofibroblasts, within this softening environment.

Stiffening hydrogels for investigating the dynamics of hepatic stellate cell mechanotransduction during myofibroblast activation.

Tissue fibrosis contributes to nearly half of all deaths in the developed world and is characterized by progressive matrix stiffening. Despite this, nearly all in vitro disease models are mechanically static. Here, we used visible light-mediated stiffening hydrogels to investigate cell mechanotransduction in a disease-relevant system.

Biodistribution and Pharmacokinetics Study of siRNA-loaded Anti-NTSR1-mAb-functionalized Novel Hybrid Nanoparticles in a Metastatic Orthotopic Murine Lung Cancer Model.

Small interfering RNA (siRNA) is effective in silencing critical molecular pathways in cancer. The use of this tool as a treatment modality is limited by lack of an intelligent carrier system to enhance the preferential delivery of this molecule to specific targets in vivo. In the present study, the in vivo behavior of novel anti-NTSR1-mAb-functionalized antimutant K-ras siRNA-loaded hybrid nanoparticles, delivered by i.

Normal and Fibrotic Rat Livers Demonstrate Shear Strain Softening and Compression Stiffening: A Model for Soft Tissue Mechanics.

Tissues including liver stiffen and acquire more extracellular matrix with fibrosis. The relationship between matrix content and stiffness, however, is non-linear, and stiffness is only one component of tissue mechanics. The mechanical response of tissues such as liver to physiological stresses is not well described, and models of tissue mechanics are limited.

Novel targeted siRNA-loaded hybrid nanoparticles: preparation, characterization and in vitro evaluation.

Background: siRNAs have a high potential for silencing critical molecular pathways that are pathogenic. Nevertheless, their clinical application has been limited by a lack of effective and safe nanotechnology-based delivery system that allows a controlled and safe transfection to cytosol of targeted cells without the associated adverse effects. Our group recently reported a very effective and safe hybrid nanoparticle delivery system composing human IgG and poloxamer-188 for siRNA delivery to cancer cells.

Hydrogels with differential and patterned mechanics to study stiffness-mediated myofibroblastic differentiation of hepatic stellate cells.

The differentiation of hepatic stellate cells (HSCs) into myofibroblasts is a key event in liver fibrosis. Due to the local stiffening of the extracellular matrix (ECM) during fibrosis, it is of great interest to develop mimics that can be used to investigate the cellular response to changes in mechanics. Here, we used a step-wise hydrogel crosslinking technique, where macromolecules are crosslinked using a sequence of addition then UV light-mediated radical crosslinking, to generate hydrogels with tunable stiffness.

Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury.

Liver fibrosis is characterized by excessive deposition of extracellular matrix proteins by myofibroblasts derived from hepatic stellate cells and portal fibroblasts. Activation of these precursors to myofibroblasts requires matrix stiffness, which results in part from increased collagen cross-linking mediated by lysyl oxidase (LOX) family proteins. The aims of this study were to characterize the mechanical changes of early fibrosis, to identify the cells responsible for LOX production in early injury, and to determine which cells in normal liver produce collagens and elastins, which serve as substrates for LOXs early after injury.

Isolation of rat portal fibroblasts by in situ liver perfusion.

Liver fibrosis is defined by the excessive deposition of extracellular matrix by activated myofibroblasts. There are multiple precursors of hepatic myofibroblasts, including hepatic stellate cells, portal fibroblasts and bone marrow derived fibroblasts. Hepatic stellate cells have been the best studied, but portal fibroblasts are increasingly recognized as important contributors to the myofibroblast pool, particularly in biliary fibrosis.