RESUMO
Mechanical cues in the tumor microenvironment interplay with internal cellular processes to control cancer cell migration. Microscale pores present in tumor tissue confer varying degrees of confinement on migrating cells, increasing matrix contact and inducing cytoskeletal rearrangement. Previously, we observed that increased collagen matrix contact significantly increased cell migration speed and cell-induced strains within the matrix. However, the effects of this confinement on future cell migration are not fully understood. Here, we use a collagen microtrack platform to determine the effect of confinement on priming MDA-MB-231 cancer cells for fast migration. We show that migration through a confined track results in increased speed and accumulation of migratory machinery, including actin and active mitochondria, in the front of migrating breast cancer cells. By designing microtracks that allow cells to first navigate a region of high confinement, then a region of low confinement, we assessed whether migration in high confinement changes future migratory behavior. Indeed, cells maintain their speed attained in high confinement even after exiting to a region of low confinement, indicating that cells maintain memory of previous matrix cues to fuel fast migration. Active mitochondria maintain their location at the front of the cell even after cells leave high confinement. Furthermore, knocking out vinculin to disrupt focal adhesions disrupts active mitochondrial localization and disrupts the fast migration seen upon release from confinement. Together, these data suggest that active mitochondrial localization in confinement may facilitate fast migration post-confinement. By better understanding how confinement contributes to future cancer cell migration, we can identify potential therapeutic targets to inhibit breast cancer metastasis.
RESUMO
Autoimmune diseases are a group of debilitating illnesses that are often idiopathic in nature. The steady rise in the prevalence of these conditions warrants new approaches for diagnosis and treatment. Stimuli-responsive biomaterials also known as "smart", "intelligent" or "recognitive" biomaterials are widely studied for their applications in drug delivery, biosensing and tissue engineering due to their ability to produce thermal, optical, chemical, or structural changes upon interacting with the biological environment. This critical analysis highlights studies within the last decade that harness the recognitive capabilities of these biomaterials towards the development of novel detection and treatment options for autoimmune diseases.
RESUMO
Environmentally responsive nanomaterials have been developed for drug delivery applications, in an effort to target and accumulate therapeutic agents at sites of disease. Within a biological system, these nanomaterials will experience diverse conditions which encompass a variety of solute identities and concentrations. In this study, we developed a new quartz crystal microbalance with dissipation (QCM-D) assay, which enabled the quantitative analysis of nanogel swelling, protein adsorption, and biodegradation in a single experiment. As a proof of concept, we employed this assay to characterize non-degradable and biodegradable poly(acrylamide-co-methacrylic acid) nanogels. We compared the QCM-D results to those obtained by dynamic light scattering to highlight the advantages and limitations of each method. We detailed our protocol development and practical recommendations, and hope that this study will serve as a guide for others to design application-specific QCM-D assays within the nanomedicine domain.
RESUMO
Formulations and devices for precision medicine applications must be tunable and multiresponsive to treat heterogeneous patient populations in a calibrated and individual manner. We engineered modular poly(acrylamide-co-methacrylic acid) copolymers, cross-linked into multiresponsive nanogels with either a nondegradable or degradable disulfide cross-linker, that were customized via orthogonal chemistries to target biomarkers of an individual patient's disease or deliver multiple therapeutic modalities. Upon modification with functional small molecules, peptides, or proteins, these nanomaterials delivered methylene blue with environmental responsiveness, transduced visible light for photothermal therapy, acted as a functional enzyme, or promoted uptake by cells. In addition to quantifying the nanogels' composition, physicochemical characteristics, and cytotoxicity, we used a QCM-D method for characterizing nanomaterial degradation and a high-throughput assay for cellular uptake. In conclusion, we generated a tunable nanogel composition for precision medicine applications and new quantitative protocols for assessing the bioactivity of similar platforms.
