Intercellular pathways of cancer treatment-related cardiotoxicity and their therapeutic implications: The paradigm of radiotherapy.

Advances in cancer therapeutics have improved patient survival rates. However, cancer survivors may suffer from adverse events either at the time of therapy or later in life. Cardiovascular diseases (CVD) represent a clinically important, but mechanistically understudied complication, which interfere with the continuation of best-possible care, induce life-threatening risks, and/or lead to long-term morbidity. These concerns are exacerbated by the fact that targeted therapies and immunotherapies are frequently combined with radiotherapy, which induces durable inflammatory and immunogenic responses, thereby providing a fertile ground for the development of cardiovascular diseases (CVDs). Stressed and dying irradiated cells produce 'danger' signals including, but not limited to, major histocompatibility complexes, cell-adhesion molecules, proinflammatory cytokines, and damage-associated molecular patterns. These factors activate intercellular signaling pathways which have potentially detrimental effects on the heart tissue homeostasis. Herein, we present the clinical crosstalk between cancer and heart diseases, describe how it is potentiated by cancer therapies, and highlight the multifactorial nature of the underlying mechanisms. We particularly focus on radiotherapy, as a case known to often induce cardiovascular complications even decades after treatment. We provide evidence that the secretome of irradiated tumors entails factors that exert systemic, remote effects on the cardiac tissue, potentially predisposing it to CVDs. We suggest how diverse disciplines can utilize pertinent state-of-the-art methods in feasible experimental workflows, to shed light on the molecular mechanisms of radiotherapy-related cardiotoxicity at the organismal level and untangle the desirable immunogenic properties of cancer therapies from their detrimental effects on heart tissue. Results of such highly collaborative efforts hold promise to be translated to next-generation regimens that maximize tumor control, minimize cardiovascular complications, and support quality of life in cancer survivors.

Optimization of Extracellular Vesicle Release for Targeted Drug Delivery.

Targeted drug delivery is a promising approach for many serious diseases, such as glioblastoma multiforme, one of the most common and devastating brain tumor. In this context, this work addresses the optimization of the controlled release of drugs which are carried by extracellular vesicles. Towards this goal, we derive and numerically verify an analytical solution for the end-to-end system model. We then apply the analytical solution either to reduce the disease treatment time or to reduce the amount of required drugs. The latter is formulated as a bilevel optimization problem, whose quasiconvex/quasiconcave property is proved here. For solving the optimization problem, we propose and utilize a combination of bisection method and golden-section search. The numerical results demonstrate that the optimization can significantly reduce the treatment time and/or the required drugs carried by extracellular vesicles for a therapy compared to the steady state solution.

Molecular Communication Transmitter Design in Limited-Capacity Storage Regime.

The limited storage capacity at the transmitters of a molecular communication (MC) system can affect the system's performance. One of the reasons for this limitation is the size restriction of the transmitter, which the storage must be replenished so that the transmitter has enough molecules for future transmission. This paper proposes a biologically inspired transmitter model based on neurons for MC whose storage charging and discharging follow differential equations. The proposed transmitter opens its outlet for a specific time in each time frame to exponentially release a portion of stored molecules to code bit-1 and remains silent to code bit-0. We analyze our model based on different transmission parameters. These parameters are the symbol duration, the release time duration, the storage capacity, and the release and replenishment rate of the storage. We find that the storage outlet must be open for a certain period within the time slot duration in order to improve the performance of the proposed system. Additionally, we demonstrate that determining the effect of storage capacity size can be important for practical MC due to the significant differences between the ideal transmitter and the proposed one, which have a limited size. We show that increases in the transmitter storage size can improve the system performance. As a result, taking a closer look at these practical transmitters is essential to solving the problems and challenges of molecular communication systems.

Targeted Drug Delivery for Cardiovascular Disease: Modeling of Modulated Extracellular Vesicle Release Rates.

Invasive and medical therapy has led to major improvements in cardiovascular disease management, but important challenges remain open. The discovery of a nano-sized system of extracellular vesicles (EVs) is opening new possibilities for reprogramming malfunctioning cells and indicates that EVs can be employed in therapeutic biomedical applications as engineered drug vehicles. Molecular communication (MC) has applications for treating cells with directed drug delivery, employing special targeting transmembrane proteins. In this paper, we propose a novel drug delivery system for cardiovascular diseases using an EV-mediated MC platform and exemplify the potential use in hypertrophic cardiomyopathy. We utilize intracellular calcium signaling as a natural mediator of EVs released from synthetic cells and model the release rate. We propose to use the cells as a therapeutic release system with a control signal input which modulates the EVs release rate as the output signal. We also study the frequency domain of the proposed model and estimate the transfer function of the therapeutic release system model numerically where the root-mean-square error for two separate estimated output signals are 0.0353 and 0.0124. The proposed EV-mediated targeted drug delivery system can make breakthroughs in future healthcare, in cardiovascular and other diseases where targeting is required.