Liposomes in Anticancer Strategies

Separation of avibactam by gemini quaternary ammonium salt: Extraction, precipitation, and application in large-scale production

Application of Gemini quaternary ammonium with ester groups in cationic P(St-co-BA) nanolatex and study on its antibacterial properties

We developed a three-dimensional (3D) engineered model of a solid human breast tumor to study the effects of interstitial fluid pressure (IFP) on collective invasion and the expression levels of epithelial-mesenchymal transition (EMT) markers. Many solid tumors exhibit elevated IFP; as these tumors grow, intra-tumoral vascular and lymphatic vessels collapse. The non-functioning lymphatic system impairs drainage, and immature hyperpermeable blood vessels cause fluid to accumulate within the interstitial space. As a result, IFP rises steeply beyond the tumor periphery and plateaus at pressures as high as 50 mm Hg above normal at the tumor core. This pressure profile, in turn, leads to outward fluid flow from the core of the tumor. IFP has been shown to affect the migratory behavior of individual cells in 3D cell culture models, though its role in collective cancer invasion remains unknown. Moreover, the underlying molecular mechanisms linking IFP to changes in cell motility remain unclear. We sought to address these questions using our engineered model. Our 3D culture model consists of an aggregate of MDA-MB-231 breast cancer cells (mimicking a solid tumor) embedded within a 3D collagen gel that is flanked by two media reservoirs. The IFP profile experienced by the cancer cells is established by altering the heights of the media reservoirs on either side of the collagen, creating a hydrostatic pressure gradient. Transcript levels of EMT markers in the aggregates subjected to a variety of pressure profiles were determined using quantitative real-time PCR. Expression of these markers was also manipulated ectopically through the creation of stable cell lines. Time-lapse imaging and cell tracking were used to determine the persistence and motility of individual cells within the aggregates. We found that the direction of IFP-induced flow determines the invasive phenotype of tumor cells. Additionally, high expression levels of both mesenchymal (Snail1, vimentin) and epithelial (E-cadherin, keratin-8) markers were characteristic of collectively invading aggregates, suggesting that partial EMT is important for collective invasion. Ectopic expression and knockdown of EMT markers revealed that they are necessary and sufficient for collective invasion in response to IFP. Time-lapse imaging analysis demonstrated that IFP and EMT marker expression also affect the motility and persistence of individual cells within the aggregates, further confirming that IFP is an important regulator of collective invasion. In conclusion, we used a robust culture model of a human breast tumor to gain insight into the mechanisms guiding collective invasion from primary tumors in response to IFP; IFP alters expression levels of EMT markers, thereby regulating collective invasion. Citation Format: Alexandra S. Piotrowski-Daspit, Joe Tien, Celeste M. Nelson. Interstitial fluid pressure alters cell motility and collective invasion via EMT marker expression in an engineered model of a human breast tumor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4269.

Effect of microvascular distribution and its density on interstitial fluid pressure in solid tumors: A computational model

Surface, thermodynamic and biological activities of some synthesized Gemini quaternary ammonium salts based on polyethylene glycol

Characteristics of the tumor microenvironment (TME) such as the leaky intratumoral vascular network and the density and composition of the desmoplastic extracellular matrix (ECM) contain essential information that determine the possibly heterogeneous interstitial fluid (IF) velocity field and interstitial fluid pressure (IFP). This information plays an important role for how anticancer drug that is delivered through the blood vasculature will distribute and possibly affect the tumor. The main question we deal with in this work is: Can we lure the cancer cells to reveal such information to us? By means of an in silico tumor model we demonstrate that subject to the condition that the tumor progression behavior is dominated by a cancer cell phenotype which moves by fluid-sensitive migration mechanisms as reported from experimental works, such information about the TME can be acquired by measuring the change in the cancer cell volume fraction distribution between two times T0 and T1, e.g., based on MRI images. We demonstrate this principle by using a continuum based multiphase model for tumor progression combined with assimilation of observed data through an ensemble Kalman filter approach which has been extensively and successfully used for updating advanced multiphase flow models in the context of reservoir simulation. Our results based on a synthetic dataset demonstrate how the methodology can be used to extract valuable quantitative information (e.g., interstitial fluid velocity field and fluid pressure, tissue conductivity reflecting ECM status, and effective vasculature conductivity) for which direct measurements may not be possible or impractical.

Quaternary ammonium salts for water treatment with balanced rate of sterilization and degradation

Growth of most human tumors leads to elevated interstitial fluid pressure (IFP). The mechanisms underlying the high tumor IFP are still not fully understood, but may include increased vascular permeability and abnormal lymph drainage leading to increased fluid volume, followed by elevated IFP. The resultant IFP may lead to poor and heterogeneous uptake of macromolecular and nanoparticle therapeutic agents, thus leading to resistance to immunotherapy and gene therapy. Here we show that tumor cells were inoculated in groin lymph nodes, and the variation of IFP with time was measured by using MXH/lpr mice with human size lymph nodes. The IFP was increased in tumor bearing mouse. Corresponding changes in lymph vessels area, tumor volume, and IFP suggest that the increased pressure is caused by defective lymph drainage and solid stress generated by tumor cells growing in a low compliant environment. This study suggests a possibility for future studies of cancer metastasis.

The effect of interstitial pressure on tumor growth: Coupling with the blood and lymphatic vascular systems

The anti-fungal activities of four self-prepared rosinyl quaternary ammonium salts (QAS), QASA, BQAS1, BQAS2 and DQAS, were evaluated with paper disc method in this paper. The result showed that, all the QAS of rosin were bioactive to the selected fungi, Irpex lacteus, Trametes versicolor, Phanerochaete chrysosporium, Gloeophyllum trabeum, Chaetomium globosum, and Paecilomyces variotii. There were obvious inhibition halos for all QAS to the fungi. The result proved that the QAS of rosin were broad-spectrum anti-fungal. Especially, to white rot fungus Trametes versicolor, brown rot fungus Gloeophyllum trabeum and soft rot fungus Chaetomium globosum, they were more effective. When the concentration reached 3.2% (w/w), the inhibition halo diameters all met or exceeded 25mm. Among these four anti-fungal derivatives of rosin, the Gemini QAS (BQAS1 and BQAS2) had bigger inhibition halo diameters than the others, which indicated that the Gemini QAS of rosin were more anti-fungal than the normal QAS of rosin.

Simple SummaryHigh vessel permeability, poor perfusion, low lymphatic drainage, and dense abundant stroma elevate interstitial fluid pressures (IFP) in pancreatic ductal adenocarcinoma (PDAC). The present study aims to monitor longitudinal changes in simulated tumor IFP and velocity (IFV) values using a dynamic contrast-enhanced (DCE)-MRI-based computational fluid modeling (CFM) approach in PDAC. Nine PDAC patients underwent DCE-MRI acquisition on a 3-Tesla MRI scanner at pre-treatment (TX (0)), immediately after the first fraction of stereotactic body radiotherapy (SBRT, (D1-TX)), and six weeks post-TX (D2-TX). The partial differential equation of IFP formulated from the continuity equation using the Starling Principle of fluid exchange and Darcy velocity–pressure relationship was solved in COMSOL Multiphysics software to generate IFP and IFV parametric maps using relevant tumor tissue physiological parameters. Initial results suggest that after validation, IFP and IFV can be imaging biomarkers of early response to therapy that may guide precision medicine in PDAC.The present study aims to monitor longitudinal changes in simulated tumor interstitial fluid pressure (IFP) and velocity (IFV) values using dynamic contrast-enhanced (DCE)-MRI-based computational fluid modeling (CFM) in pancreatic ductal adenocarcinoma (PDAC) patients. Nine PDAC patients underwent MRI, including DCE-MRI, on a 3-Tesla MRI scanner at pre-treatment (TX (0)), after the first fraction of stereotactic body radiotherapy (SBRT, (D1-TX)), and six weeks post-TX (D2-TX). The partial differential equation of IFP formulated from the continuity equation, incorporating the Starling Principle of fluid exchange, Darcy velocity, and volume transfer constant (Ktrans), was solved in COMSOL Multiphysics software to generate IFP and IFV maps. Tumor volume (Vt), Ktrans, IFP, and IFV values were compared (Wilcoxon and Spearman) between the time- points. D2-TX Ktrans values were significantly different from pre-TX and D1-TX (p < 0.05). The D1-TX and pre-TX mean IFV values exhibited a borderline significant difference (p = 0.08). The IFP values varying <3.0% between the three time-points were not significantly different (p > 0.05). Vt and IFP values were strongly positively correlated at pre-TX (ρ = 0.90, p = 0.005), while IFV exhibited a strong negative correlation at D1-TX (ρ = −0.74, p = 0.045). Vt, Ktrans, IFP, and IFV hold promise as imaging biomarkers of early response to therapy in PDAC.

In order to obtain some novel cationic surfactants with high surface activity, n-octadecyldimethylamine and epichlorohydrin were used to synthesize 2-hydroxy-1, 3-dis (chloride octadecyl dimethyl ammonium) propane, which was a kind of gemini quaternary ammonium salt. N-octadecyldimethylamine and epichlorohydrin were used to prepare active epoxy intermediate glycidyloctadecyldimethyl ammonium chlorided, and then glycidyloctadecyldimethyl ammonium chlorided was reacted with octadecyldimethyl amine hydrochloride to synthesize the gemini cationic surfactant. FTIR and 1H NMR were used to represent structure of the gemini cationic surfactant. The interface characteristics were studied in detail. The critical micellar concentration (CMC) was determined by surface tension test to obtain the values of CMC and surface tension at CMC. The foam ability and foam stability of the gemini cationic surfactant were also discussed through contrast octadecyltrimethyl ammonium chloride and cetyltrimethyl ammonium chloride.

In this work, extensive lattice Monte Carlo simulations were performed to investigate the influence of confinement on critical micelle concentration (CMC). It is found that the CMC of surfactants in a confined space is shifted from its bulk value, and the shift is affected by the presence of the confining boundaries, which induces both the finite size effect and the wall-surfactant interaction. In general, for strongly confined system (the system with narrow pore size), the finite size effect dominates the CMC shift because the confined space cannot accommodate fully developed micelles, and the rapid increase of the entropic loss due to the decrease of the pore size results in the rapid increase of CMC. In contrast, for a weakly confined space, the CMC shift depends on the interaction between the walls and surfactants. For the systems with two weakly hydrophilic surfaces, the local density depletion of the surfactants near the walls results in lower CMCs than the bulk value, and the CMC shifts to a higher value as the pore size increases. For the systems with moderately hydrophilic surfaces, the shifts of CMCs show a similar behavior as those for weakly hydrophilic surfaces, but the CMCs are near their bulk values in the range of weak confinement. For the systems with strongly attractive wall-surfactant interactions, the strong adsorption also results in lower CMCs than their bulk value, but the CMCs decrease with the increase of pore size.

Interstitial fluid pressure (IFP) in most tumors is high, and this high pressure has been correlated with poor prognosis. Measurements of IFP in normal tongue and in tongue cancer are lacking. Recent research suggests the existence of a relationship between increased peritumoral lymph vessels (PTLV) and survival, and a correlation of increased lymphatic vessel density with an unfavorable prognosis has been reported. In the present study, tongue squamous cell carcinoma (SCC) was induced by adding the carcinogen 4-nitroquinoline oxide in drinking water for 19 weeks. The IFP was measured by micropuncture and immunohistochemistry was used to visualize lymph vessels. In normal tongue, IFP averaged 3.1 +/- 0.3 mmHg. The IFP, both in the tumor (29.1 +/- 2.9 mmHg) and 0.5 cm anterior to it (15.4 +/- 2.1 mmHg) was consistently increased (P < 0.005) with values ranging from 10 to 40 mmHg. The highest IFP values were measured in rats with large tumors (P < 0.05) and low body weight (P < 0.001), suggesting that IFP increases with cancer progression. Lymphatic vessel area (%), as determined with the lymphatic specific marker LYVE-1 antibody, was significantly increased in the peritumoral area when compared to intratumoral and control mucosa (P < 0.05). There was a significant positive correlation between IFP, PTLV area, tumor size and invasiveness. Our data show that IFP is increased in tongue cancer. Corresponding changes in PTLV area, invasiveness, tumor area and IFP suggest that the increased pressure is caused by defective lymph drainage and solid stress generated by tumor cells growing in a low compliant environment.

Interstitial fluid pressure gradients and interstitial flow have been shown to drive morphogenic processes that shape tissues and influence progression of diseases including cancer. The advent of porous media microfluidic approaches has enabled investigation of the cellular response to interstitial flow, but questions remain as to the critical biophysical and biochemical signals imparted by interstitial fluid pressure gradients and resulting flow on resident cells and extracellular matrix (ECM). Here, we introduce a low-cost method to maintain physiological interstitial fluid pressures that is built from commonly accessible laboratory equipment, including a laser pointer, camera, Arduino board, and a commercially available linear actuator. We demonstrate that when the system is connected to a microfluidic device containing a 3D porous hydrogel, physiologic pressure is maintained with sub-Pascal resolution and when basic feedback control is directed using an Arduino, constant pressure and pressure gradient can be maintained even as cells remodel and degrade the ECM hydrogel over time. Using this model, we characterized breast cancer cell growth and ECM changes to ECM fibril structure and porosity in response to constant interstitial fluid pressure or constant interstitial flow. We observe increased collagen fibril bundling and the formation of porous structures in the vicinity of cancer cells in response to constant interstitial fluid pressure as compared to constant interstitial flow. Collectively, these results further define interstitial fluid pressure as a driver of key pathogenic responses in cells, and the systems and methods developed here will allow for future mechanistic work investigating mechanotransduction of interstitial fluid pressures and flows.