Combined anti-angiogenic and cytotoxic treatment of a solid tumour: in silico investigation of a xenograft animal model's digital twin.

Anti-angiogenic (AA) treatments have received significant research interest due to the key role of angiogenesis in cancer progression. AA agents can have a strong effect on cancer regression, by blocking new vessels and reducing the density of the existing vasculature. Moreover, in a process termed vascular normalisation, AA drugs can improve the abnormal structure and function of the tumour vasculature, enhancing the delivery of chemotherapeutics to the tumour site. Despite their promising potential, an improved understanding of AA treatments is necessary to optimise their administration as a monotherapy or in combination with other cancer treatments. In this work we present an in silico multiscale cancer model which is used to systematically interrogate the role of individual mechanisms of action of AA drugs in tumour regression. Focus is placed on the reduction of vascular density and on vascular normalisation through a parametric study, which are considered either as monotherapies or in combination with conventional/ metronomic chemotherapy. The model is specified to data from a mammary carcinoma xenograft in immunodeficient mice, to enhance the physiological relevance of model predictions. Our results suggest that conventional chemotherapy might be more beneficial when combined with AA treatments, hindering tumour growth without causing excessive damage on healthy tissue. Notably, metronomic chemotherapy has shown significant potential in stopping tumour growth with minimal toxicity, even as a monotherapy. Our findings underpin the potential of our in silico framework for non-invasive and cost-effective evaluation of treatment strategies, which can enhance our understanding of combined therapeutic strategies and contribute towards improving cancer treatment management.

Cell Electropermeabilisation Enhancement by Non-Thermal-Plasma-Treated PBS.

The effectiveness of electrochemotherapy (ECT) in local eradication of tumours in human and veterinary medicine has been proven. ECT consists of increasing the uptake of cytotoxic drugs by means of pulsed electric fields (PEFs) that transiently permeabilise the cell membrane. Still, this tumour treatment includes some drawbacks that are linked to the characteristics of the intense electric pulses (EPs) used. Meanwhile, the emerging field of cancer therapies that are based on the application of non-thermal plasmas (NTP) has recently garnered interest because of their potentialities as rich sources of reactive species. In this work, we investigated the potential capabilities of the combined application of indirect NTP treatment and microsecond PEFs (µsPEFs) to outperform in vitro cell electropermeabilisation, the basis of ECT. Thus, phosphate-buffered saline (PBS) was plasma-treated (pPBS) and used afterwards to explore the effects of its combination with µsPEFs. Analysis of two different cell lines (DC-3F Chinese hamster lung fibroblasts and malignant B16-F10 murine melanoma cells), by flow cytometry, revealed that this combination resulted in significant increases of the level of cell membrane electropermeabilisation, even at very low electric field amplitude. The B16-F10 cells were more sensitive to the combined treatment than DC-3F cells. Importantly, the percentage of permeabilised cells reached values similar to those of cells exposed to classical electroporation field amplitude (1100 V/cm) when the cells were treated with pPBS before and after being exposed only to very low PEF amplitude (600 V/cm). Although the level of permeabilisation of the cells that are treated by the pPBS and the PEFs at 600 V/cm is lower than the level reached after the exposure to µsPEFs alone at 1100 V/cm, the combined treatment opens the possibility to reduce the amplitude of the EPs used in ECT, potentially allowing for a novel ECT with reduced side-effects.

Correlations between gaseous and liquid phase chemistries induced by cold atmospheric plasmas in a physiological buffer.

The understanding of plasma-liquid interactions is of major importance, not only in physical chemistry, chemical engineering and polymer science, but in biomedicine as well as to better control the biological processes induced on/in biological samples by Cold Atmospheric Plasmas (CAPs). Moreover, plasma-air interactions have to be particularly considered since these CAPs propagate in the ambient air. Herein, we developed a helium-based CAP setup equipped with a shielding-gas device, which allows the control of plasma-air interactions. Thanks to this device, we obtained specific diffuse CAPs, with the ability to propagate along several centimetres in the ambient air at atmospheric pressure. Optical Emission Spectroscopy (OES) measurements were performed on these CAPs during their interaction with a liquid medium (phosphate-buffered saline PBS 10 mM, pH 7.4) giving valuable information about the induced chemistry as a function of the shielding gas composition (variable O2/(O2 + N2) ratio). Several excited species were detected including N2+(First Negative System, FNS), N2(Second Positive System, SPS) and HO˙ radical. The ratios between nitrogen/oxygen excited species strongly depend on the O2/(O2 + N2) ratio. The liquid chemistry developed after CAP treatment was investigated by combining electrochemical and UV-visible absorption spectroscopy methods. We detected and quantified stable oxygen and nitrogen species (H2O2, NO2-, NO3-) along with Reactive Nitrogen Species (RNS) such as the peroxynitrite anion ONOO-. It appears that the RNS/ROS (Reactive Oxygen Species) ratio in the treated liquid depends also on the shielding gas composition. Eventually, the composition of the surrounding environment of CAPs seems to be crucial for the induced plasma chemistry and consequently, for the liquid chemistry. All these results demonstrate clearly that for physical, chemical and biomedical applications, which are usually achieved in ambient air environments, it is necessary to realize an effective control of plasma-air interactions.