Role of Vascular Normalization in Benefit from Metronomic Chemotherapy

Metronomic dosing of chemotherapy—defined as frequent administration at lower doses—has been shown to be more efficacious than maximum tolerated dose treatment in preclinical studies, and is currently being tested in the clinic. Although multiple mechanisms of benefit from metronomic chemotherapy have been proposed, how these mechanisms are related to one another and which one is dominant for a given tumor–drug combination is not known. To this end, we have developed a mathematical model that incorporates various proposed mechanisms, and report here that improved function of tumor vessels is a key determinant of benefit from metronomic chemotherapy. In our analysis, we used multiple dosage schedules and incorporated interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature. We found that metronomic chemotherapy induces functional normalization of tumor blood vessels, resulting in improved tumor perfusion. Improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation and improves drug delivery and therapeutic outcomes. Indeed, in our model, improved vessel function enhanced the delivery of oxygen and drugs, increased the number of effector immune cells, and decreased the number of regulatory T cells, which in turn killed a larger number of cancer cells, including cancer stem-like cells. Vessel function was further improved owing to decompression of intratumoral vessels as a result of increased killing of cancer cells, setting up a positive feedback loop. Our model enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of metronomic therapy

Normalizing Tumor Microenvironment with Nanomedicine and Metronomic Therapy to Improve Immunotherapy

Nanomedicine offered hope for improving the treatment of cancer but the survival benefits of the clinically approved nanomedicines are modest in many cases when compared to conventional chemotherapy. Metronomic therapy, defined as the frequent, low dose administration of chemotherapeutics – is being tested in clinical trials as an alternative to the conventional maximum tolerated dose (MTD) chemotherapy schedule. Although metronomic chemotherapy has not been clinically approved yet, it has shown better survival than MTD in many preclinical studies. When beneficial, metronomic therapy seems to be associated with normalization of the tumor microenvironment including improvements in tumor perfusion, tissue oxygenation and drug delivery as well as activation of the immune system. Recent preclinical studies suggest that nanomedicines can cause similar changes in the tumor microenvironment. Here, by employing a mathematical framework, we show that both approaches can serve as normalization strategies to enhance treatment. Furthermore, employing murine breast and fibrosarcoma tumor models as well as ultrasound shear wave elastography and contrast-enhanced ultrasound, we provide evidence that the approved nanomedicine Doxil can induce normalization in a dose-dependent manner by improving tumor perfusion as a result of tissue softening. Finally, we show that pretreatment with a normalizing dose of Doxil can improve the efficacy of immune checkpoint inhibition

Role of Constitutive Behavior and Tumor-Host Mechanical Interactions in the State of Stress and Growth of Solid Tumors

<div><p>Mechanical forces play a crucial role in tumor patho-physiology. Compression of cancer cells inhibits their proliferation rate, induces apoptosis and enhances their invasive and metastatic potential. Additionally, compression of intratumor blood vessels reduces the supply of oxygen, nutrients and drugs, affecting tumor progression and treatment. Despite the great importance of the mechanical microenvironment to the pathology of cancer, there are limited studies for the constitutive modeling and the mechanical properties of tumors and on how these parameters affect tumor growth. Also, the contribution of the host tissue to the growth and state of stress of the tumor remains unclear. To this end, we performed unconfined compression experiments in two tumor types and found that the experimental stress-strain response is better fitted to an exponential constitutive equation compared to the widely used neo-Hookean and Blatz-Ko models. Subsequently, we incorporated the constitutive equations along with the corresponding values of the mechanical properties - calculated by the fit - to a biomechanical model of tumor growth. Interestingly, we found that the evolution of stress and the growth rate of the tumor are independent from the selection of the constitutive equation, but depend strongly on the mechanical interactions with the surrounding host tissue. Particularly, model predictions - in agreement with experimental studies - suggest that the stiffness of solid tumors should exceed a critical value compared with that of the surrounding tissue in order to be able to displace the tissue and grow in size. With the use of the model, we estimated this critical value to be on the order of 1.5. Our results suggest that the direct effect of solid stress on tumor growth involves not only the inhibitory effect of stress on cancer cell proliferation and the induction of apoptosis, but also the resistance of the surrounding tissue to tumor expansion.</p></div

Stress-strain response of tumors.

<p>Experimentally measured elastic stress-strain response of MCF10CA1a and SW620 tumors in unconfined compression. Data show individual tumor behavior.</p

Effect of tumor constitutive behavior on tumor growth and state of stress.

<p>A) Model fit to the experimentally measured growth curve of SW620 tumors using the neo-Hookean and the exponential equation. B) Evolution of bulk solid stress in the tumor interior does not depend on the selection of the constitutive equation. Results using the Blatz-Ko material are omitted for clarity.</p

Values of the mechanical properties of the two tumor types derived by fitting the model to the experimental stress-strain curves.

<p>Standard errors are shown in parenthesis.</p>a<p>The Poisson’s ratio was taken to be 0.2 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104717#pone.0104717-Roose1" target="_blank">[22]</a>.</p

Effect of tumor-host mechanical interactions on tumor state of stress and growth.

<p>Dependence of A) state of stress and B) growth rate of tumors on the mechanical properties of the host tissue. The host tissue was modeled as a compressible neo-Hookean material with Poisson’s ratio of 0.2 and three values of the shear modulus were used, <i>µ</i> = 10, 15 and 30 kPa. The stiffer the host tissue is, the higher the stress in the tumor and the lower its growth rate becomes.</p

Evaluation of novel, cationic electrospun microfibrous membranes as adsorbents in bacteria removal

Electrospun microfibrous membranes comprised of poly(methyl methacrylate)-poly((2-diethylamino)ethyl methacrylate) random copolymers (PMMA-co-PDEAEMA) of various chemical compositions blended together with a commercially available PMMA have been fabricated with diameters between 4.0-6.4 μm and further evaluated as adsorbents for bacteria removal from aqueous media. The morphology and thermal stability of the membranes were determined by scanning electron microscopy (SEM) and thermal gravimetric analysis (TGA), respectively. Tensile tests were also performed in order to investigate their mechanical properties. Membrane evaluation as adsorbents against two Gram-negative bacteria namely Pseudomonas aeruginosa and Advenella species revealed that the membranes containing the highest percentage of the cationic moieties (DEAEMA) exhibited the highest adsorption efficiency. The bacteria removal by the microfibrous membranes was studied by UV-vis spectrophotometry upon measuring the optical density (OD) of the microorganisms. The highest recorded bacteria removal percentages after 8 h were approximately 70% and 45%, for the Pseudomonas aeruginosa and Advenella species respectively, whereas in both cases complete (100%) bacteria removal was observed after 24 h of membrane immersion in bacteria-containing aqueous solutions. The experimental adsorption isotherms for P. aeruginosa and Advenella sp. were well-fitted with the Langmuir isotherm model indicating a monolayer adsorption process. SEM was also used to confirm the adhesion of the bacteria onto the electrospun microfibers. Most importantly, these materials exhibited great performance for the removal of microorganisms from urban wastewater as determined via the standard plating technique prepared by agar