Summary It is well established that the early malignant tumor invades surrounding extracellular matrix (ECM) in a manner that depends upon material properties of constituent cells, surrounding ECM, and their interactions. Recent studies have established the capacity of the invading tumor spheroids to evolve into coexistent solid-like, fluid-like, and gas-like phases. Using breast cancer cell lines invading into engineered ECM, here we show that the spheroid interior develops spatial and temporal heterogeneities in material phase which, depending upon cell type and matrix density, ultimately result in a variety of phase separation patterns at the invasive front. Using a computational approach, we further show that these patterns are captured by a novel jamming phase diagram. We suggest that non-equilibrium phase separation based upon jamming and unjamming transitions may provide a unifying physical picture to describe cellular migratory dynamics within, and invasion from, a tumor.

Cell migration is essential for regulating many biological processes in physiological or pathological conditions, including embryonic development and cancer invasion. In vitro and in silico studies suggest that collective cell migration is associated with some biomechanical particularities, such as restructuring of extracellular matrix (ECM), stress and force distribution profiles, and reorganization of cytoskeleton. Therefore, the phenomenon could be understood by an in-depth study of cells' behavior determinants, including but not limited to mechanical cues from the environment and from fellow "travelers". This review article aims to cover the recent development of experimental and computational methods for studying the biomechanics of collective cell migration during cancer progression and invasion. We also summarized the tested hypotheses regarding the mechanism underlying collective cell migration enabled by these methods. Together, the paper enables a broad overview on the methods and tools currently available to unravel the biophysical mechanisms pertinent to cell collective migration, as well as providing perspectives on future development towards eventually deciphering the key mechanisms behind the most lethal feature of cancer. I.

TWO-SENTENCE SUMMARY: Using a multicellular spheroid embedded within an engineered threedimensional matrix, we show here the potential for coexistence of solid-like, fluid-like, and gas-like phases of the cellular collective described by a jamming phase diagram. Depending upon cell type and matrix density, moreover, invasion into matrix from the tumor periphery can switch from a continuous cellular collective that flows like a fluid to discrete cells that scatter individually like a gas. ASTRACT:The early malignant tumor invades surrounding extracellular matrix (ECM) in a manner that depends upon material properties of constituent cells and ECM. Biophysical mechanisms remain unclear, however. Using a multicellular spheroid embedded within an engineered three-dimensional matrix, we show here the potential for coexistence of solid-like, fluid-like, and gas-like phases of the cellular collective described by a jamming phase diagram. Depending upon cell type (MCF-10A vs. MDA-MB-231) and ECM density (1 to 4 mg/ml collagen), cancer cells within the spheroid display a variety of collective behaviors, including a nonmigratory jammed phase and a migratory unjammed phase. At a critical collagen density, unjammed cancer cells at the spheroid periphery transition in an almost switch-like fashion between distinct modes of invasion. In the case of MDA-MB-231, for example, we find that when ECM density is 2 mg/ml or smaller single cells and cell clusters scatter from the spheroid periphery in the form of discrete gas-like particles, but when ECM density is 3 mg/ml or greater these cells flow collectively from the spheroid periphery in continuous fluid-like invasive branches. These findings suggest coexistence within the spheroid mass of multiple material phases of the cellular collective -solid-like, fluid-like, and gas-like-in a manner that is superficially similar to common inanimate multiphasic systems at thermodynamic equilibrium, but here arising in living cellular systems, all of which are displaced far from thermodynamic equilibrium. We conclude that non-equilibrium phase separation based upon jamming dynamics may provide a new physical picture to describe cellular migratory dynamics within and invasion from a tumor mass.Quantum Photonics. D.R. acknowledges the Department of Defense (DoD grant W81XWH-15-1-0070). We also gratefully acknowledge Elizabeth Bartolak-Suki (Boston University) for expert assistance with spheroid histology, and Lauren O'Keeffe (Cornell University) for assistance with spheroid embedding and cell counting. METHODSCell lines and culture media. Non-tumorigenic MCF-10A and metastatic MDA-MB-231 breast epithelial cell lines were purchased from American Type Cell Culture Collection (ATCC) and cultured using standardized media and conditions [21,52]. MCF-10A cells were cultured in DMEM/F-12 (ThermoFisher, No. 11330032) supplemented with 5% horse serum (Invitrogen, No. 16050122), 20 ng/ml EGF (Peprotech, AF10015; ThermoFisher, No. 10605HNAE), 0.5 mg/ml hydrocortisone (Sigma-Aldrich, No. H0888), 100 ng/ml ...

Barium titanate nanoparticles (BTNPs) are gaining popularity in biomedical research because of their piezoelectricity, nonlinear optical properties, and high biocompatibility. However, the potential of BTNPs is limited by the ability to create stable nanoparticle dispersions in water and physiological media. In this work, we report a method of surface modification of BTNPs based on surface hydroxylation followed by covalent attachment of hydrophilic poly(ethylene glycol) (PEG) polymers. This polymer coating allows for additional modifications such as fluorescent labeling, surface charge tuning, or directional conjugation of IgG antibodies. We demonstrate the conjugation of anti-EGFR antibodies to the BTNP surface and show efficient molecular targeting of the nanoparticles to A431 cells. Overall, the reported modifications aim to expand the BTNP applications in molecular imaging, cancer therapy, or noninvasive neurostimulation.

This study presents the design of novel composites nanogels, based on poly(ethylene glycol) diacrylate and natural zeolite particles, that are able to act as materials with controlled drug delivery properties. Natural zeolite–nanogels composite, with varying zeolite contents, were obtained by an inverse mini-emulsion technique and loaded with 5-fluorouracil, a widely used chemotherapeutic drug. Herein, the possibility of adjusting final properties by means of modifying the preparation conditions was investigated. The prepared composite nanogels are characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). In light of this tunable drug-loading capability, swelling behaviour, and cytotoxicity, these composite nanogels could be highly attractive as drug reservoirs.

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Phase-changing nanodroplets have been studied as externally activatable in situ microbubble precursors. The nanodroplets can be triggered to vaporize with an external optical or acoustic energy source, and the resulting microbubbles can be visualized with high sensitivity using ultrasound imaging. Because of their nanoscale size, this type of construct is attractive for the encapsulation and on-site, on-demand release of therapeutics. Here, we develop a double-drug loaded nanodroplet platform that can coencapsulate paclitaxel and doxorubicin, and release them upon external laser activation. Nanodroplets are characterized in terms of size, stability, protein interaction, and drug release. Their capacity to concurrently release the two drugs and generate ultrasound contrast is demonstrated in vitro. The efficacy of dual-drug loaded nanodroplets is compared in vitro with that of free drug formulations, and potential mechanisms of their enhanced cytotoxic behavior are explored. Overall, the results show that the nanodroplets are a versatile platform for on-demand image-guided drug delivery.

New nanogels (NGs) with tailored properties were obtained using a mini-emulsion technique, from poly(ethylene glycol) diacrylate (PEGDA) self-crosslinking macromers of various molecular weight. By modifying synthesis parameters (hydrophilic-lipophilic balance, emulsifier and the ratio of organic-aqueous medium), optimum recipes of NGs were selected. Therefore, the molecular weight distribution and the functionalization degree of the PEGDA2000 macromer were assessed by Gel Permeation Chromatography (GPC) and Nuclear Magnetic Resonance (NMR), respectively. Furthermore, the PEGDA-NGs were investigated by Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM) for size distributions and morphology. DLS and TEM results confirm that these new PEGDA-NGs hold potential for biomedical applications.