Statische und dynamische Magnetfelder für die Nanopartikel-basierte zielgerichtete Wirkstofffreisetzung

Although medicine has made great progress in the last centuries and decades, it is still facing basic challenges that make doctors fail to efficiently and successfully treat the continuously emerging diseases and ailments due to ageing, industrialization, pollution and resulting biological mutations. In this context, the systemic chemotherapeutic treatment of cancer seems to be one of the most fitting examples for the wide gap between the usually followed medical approach and the theoretically optimal solution. Extrapolating from in vitro experiments and mouse models to humans, treating children as “miniaturized” adults when analyzing therapeutic effects, estimating drug doses based on relatively coarse processes like up scaling on weight, volume or area, and flooding the human body with drugs to solely achieve a minimal effect at the ailment site are just few examples for improvement needs in medical methods. One of the most promising approaches intended to bring more specificity and precision into the therapeutic toolbox is the directed delivery of drugs, already prophesized and described one hundred years ago by the German immunologist and Nobel Laureate in Medicine (1908) Paul Ehrlich (1854-1915) as the “magic bullet” principle. It is a visionary medical method in which active agents -such as drugs or antibodies- are guided within the human body and brought to bind directly and exclusively to their biological target. This approach was triggered and has been remarkably promoted by the introduction and continuous development of nano-sized medical systems since the 1950s, and is expected to experience a real breakthrough by the clinical validation of the so called “Magnetic Drug Targeting”. According to this technique, magnetically active nanoparticles are coated with a therapeutically active biomaterial and guided through external magnetic fields in the natural transport pathways of the body, then retained and concentrated at target sites where the biologically active load is set free. The delivered dose is augmented, side effects are lowered and the overall therapeutic efficiency is enhanced. Especially for cancer treatment, the magnetically guided drug delivery represents a huge potential. In fact, conventional chemotherapy methods are used systemically and succeed in best cases in delivering only a fractional amount of the drug to the target sites, while the rest is absorbed by the healthy tissue of the treated body. This is so inefficient that dose levels of about 50 to 100-fold those of conventional doses need to be administered to achieve cures of cancer cells (T. A. Connors 1995). As a result, blood filtering and trafficking organs, such as the liver, the kidneys, the spleen and most importantly the heart, are the direct victims of the highly toxic substances used in chemotherapy. Even the apparently more gentle approach of applying the maximum tolerated dose at defined intervals -in order to avoid toxicity- can unintentionally lead to a chemoresistance of the tumor (C. Damyanov 2009). These shortcomings of the chemical therapy further aggravate the fact that cancer is still the worldwide deadliest disease, with an upward trend. For instance, around 25 % of all registered death cases in the European Union are reported by the World Health Organization to be caused by tumors. Despite the development of advanced anti-cancer medicine, it still remains a difficult challenge to keep costs at an affordable level. For that reason, new and more efficient cancer treatment methods with higher success rates and lower side effects and costs are urgently needed and would help physicians cope with an ever ageing world population. In this work, we report improvements achieved in the understanding and control of the magnetically targeted drug delivery, mainly realized by the consideration of time issues and the investigation of dynamic magnetic fields. New approaches to assess the magnetic behavior of nanoparticles in suspensions as well as an advanced examination of the lung drug targeting and the mechanisms of cellular drug uptake after successful localized delivery represent the major achievements compiled in this manuscript. The registered improvements are an important contribution to the further development of the idea of directed therapies promoted by the emerging nanomedicine. This modern medicine is expected to provide techniques that can act on a cellular and even sub-cellular level, treating ailments with considerably more accuracy. Gradually, modern diagnostic and therapeutic techniques should elevate us slowly to the point where we can start thinking more in terms of real “regenerative” medicine. That means, we should be able to precisely and directly address pathologic tissues, save cells and organs, repair and heal them, rather than extinguish them.Mehr als hundert Jahre nach dem Tod von Paul Ehrlich, dem bedeutendsten deutschen Immunologen, verfolgt die "Nachwelt" noch mit großen Schritten eine seiner wichtigsten Visionen, die er während seiner Arbeiten zur Behandlung der Syphilis entwickelte: eine „Zauberkugel“ (magic bullet), die einen gegebenen krankmachenden Erreger gezielt abtöten kann. Ganz nach diesem noch -mehr denn je- aktuellen Prinzip, entwickeln Forscher heutzutage weltweit neue Methoden, um nicht nur Krankheitserreger, sondern auch befallene Gewebe, spezifisch zu behandeln. In den letzten Jahren entwickelte sich dadurch die Medizin von der konventionellen Anwendung, über die personalisierte Behandlung, wo die genetische Information eines jeden Patienten präventiv untersucht werden kann und die Ergebnisse zur Auswahl und Anpassung der Therapie-Art herangezogen werden, bis hin zur "Nanomedizin", einer neuen Ära der Arzneimittel-Konzipierung, -Synthese, -Dosierung und -Verabreichung, die Therapien auf zellulärer und sub-zellulärer Ebene ermöglichen sollte. Mediziner sind heutzutage weit entfernt von der Darstellung von Christian Friedrich Hebbel (18.03.1813 - 13.12.1863), dass "ein Arzt eine Aufgabe hat, als ob ein Mensch in einem dunklen Zimmer in einem Buche lesen sollte". Sie sind in der Lage, durch die Integration der Nanotechnologie im biomedizinischen Bereich, Gewebe und Zellen, die durchschnittliche Dimensionen von 10 µm haben, mit Nanosystemen im Submikrometer-Bereich zu adressieren und gezielt zu behandeln. In diesem Rahmen präsentiert sich das Magnetic Drug Targeting (MDT) als besonders wirksamer Therapie-Ansatz. Dabei werden Wirkstoff-beladene magnetische Nanopartikel über externe Magnetfelder im Körper geführt und an einem gegebenen Krankheitsort lokal angereichert. Die verabreichte Wirkdosis wird dadurch erhöht, Nebeneffekte minimiert. Besonders in der Krebsbekämpfung verspricht dieser Ansatz hohe Erfolgsquoten und eine Reduzierung der ohnehin enormen Chemo- und Radiotherapie-Kosten, die meistens einen bremsenden Effekt auf die Entwicklung und Verbreitung zahlreicher Behandlungsmethoden haben. An dieser Stelle sei daran erinnert, dass Krebs nach wie vor die weltweit wichtigste Todesursache ist, an der schätzungsweise 11.5 Millionen Weltbewohner im Jahre 2030 sterben werden, was einem Anstieg von 45% zum Jahre 2007 darstellt. Die zielgerichtete Arzneimittel-Applikation, zu Englisch "Directed Drug Delivery", soll hierfür Lösungen anbieten, die Tumore spezifisch angreifen und ausschalten können. Durch eine magnetische Lenkung und Anreicherung wird dieses Verfahren weiter optimiert. Die somit entstehende MDT-Methode eignet sich für Anwendungen in der Blutbahn, sowie in den Atemwegen von Patienten, mit entsprechenden Anpassungen. Entscheidend ist hierbei vor Allem das eingesetzte Magnetfeld, in Bezug auf Amplitude, Homogenität und Dynamik. In zahlreichen wissenschaftlichen Arbeiten, wurden bisher Erfolg versprechende Ergebnisse präsentiert, die überwiegend durch die Manipulation und Aufkonzentrierung von Nanopartikel-Wirkstoff-Komplexen mit statischen Magnetfeldern realisiert wurden. Eine hierzu komplementäre Betrachtung mit dynamischen Magnetfeldern wird in dieser Arbeit untersucht. Im Rahmen dieses Forschungsprojekts wurden Ansätze mit statischen und dynamischen Magnetfeldern zur Verbesserung des Magnetic Drug Targeting theoretisch überprüft, simulativ validiert und systemtechnisch umgesetzt. Nach einer ausführlichen Untersuchung der Nanopartikel-Eigenschaften, die den MDT-Effekt überhaupt ermöglichen und besonders beeinflussen, wurde der Anreicherungsprozess unter Magnetkraftwirkung modelliert und ein für Anwendungen in der Blutbahn optimiertes Magnetsystem simuliert, konstruiert und bei in-vivo-Versuchen eingesetzt. Dadurch konnte eine aktive und vor Allem reproduzierbare Retention von beladenen Nanopartikel-Komplexen in den Arterien und Venen der Rückenhaut einer Maus verzeichnet werden

Computational Fluid Dynamics as an Emerging Supporting Clinical Tool: Review on Human Airways

Objectives: The main objective of this review article is to evaluate the usability of Computational Fluid Dynamics (CFD) as a supporting clinical tool for respiratory system. Data Source: The English articles referred for this review paper were identified from various International peer reviewed journals indexed in Science citation index. Study Selection: 26 high quality articles most relevant to the highlighted topic which were published in last fifteen years were selected from almost 120 articles. Results: The analysis done and the outcome obtained by this computational method is as accurate as Spirometry and Pulmonary function test (PFT) result. CFD can be very useful in the cases where patents is unable to perform PFT. Pressure drop, Velocity profile, Wall shear stress & other flow parameter, respiratory resistance, Pattern of drug deposition, Particles transport/deposition, etc. had also been predicted accurately using CFD. The effect of tracheal stenosis on the flow parameters has been predicted. The size and location of tracheal stenosis has also been correlated with breathing difficulties. The distribution of air in various lobes of the lungs can be accurately predicted with CFD tool. Conclusion: Virtual surgery is eventually possible by using CFD after further research with validation. With the help of this multi - disciplinary and efficient tool we can obtain accurate result while reducing cost and time

Exploring the Role of Molecular Dynamics Simulations in Most Recent Cancer Research: Insights into Treatment Strategies

Cancer is a complex disease that is characterized by uncontrolled growth and division of cells. It involves a complex interplay between genetic and environmental factors that lead to the initiation and progression of tumors. Recent advances in molecular dynamics simulations have revolutionized our understanding of the molecular mechanisms underlying cancer initiation and progression. Molecular dynamics simulations enable researchers to study the behavior of biomolecules at an atomic level, providing insights into the dynamics and interactions of proteins, nucleic acids, and other molecules involved in cancer development. In this review paper, we provide an overview of the latest advances in molecular dynamics simulations of cancer cells. We will discuss the principles of molecular dynamics simulations and their applications in cancer research. We also explore the role of molecular dynamics simulations in understanding the interactions between cancer cells and their microenvironment, including signaling pathways, proteinprotein interactions, and other molecular processes involved in tumor initiation and progression. In addition, we highlight the current challenges and opportunities in this field and discuss the potential for developing more accurate and personalized simulations. Overall, this review paper aims to provide a comprehensive overview of the current state of molecular dynamics simulations in cancer research, with a focus on the molecular mechanisms underlying cancer initiation and progression.Comment: 49 pages, 2 figure

Magnetic Drug Targeting: Developing the Basics

Focusing medicine to disease locations is a needed ability to treat a variety of pathologies. During chemotherapy, for example, typically less than 0.1% of the drugs are taken up by tumor cells, with the remaining 99.9% going into healthy tissue. Physicians often select the dosage by how much a patient can physically withstand rather than by how much is needed to kill all the tumor cells. The ability to actively position medicine, to physically direct and focus it to specific locations in the body, would allow better treatment of not only cancer but many other diseases. Magnetic drug targeting (MDT) harnesses therapeutics attached to magnetizable particles, directing them to disease locations using magnetic fields. Particles injected into the vasculature will circulate throughout the body as the applied magnetic field is used to attempt confinement at target locations. The goal is to use the reservoir of particles in the general circulation and target a specific location by pulling the nanoparticles using magnetic forces. This dissertation adds three main advancements to development of magnetic drug targeting. Chapter 2 develops a comprehensive ferrofluid transport model within any blood vessel and surrounding tissue under an applied magnetic field. Chapter 3 creates a ferrofluid mobility model to predict ferrofluid and drug concentrations within physiologically relevant tissue architectures established from human autopsy samples. Chapter 4 optimizes the applied magnetic fields within the particle mobility models to predict the best treatment scenarios for two classes of chemotherapies for treating future patients with hepatic metastatic breast cancer microtumors

ESHO benchmarks for computational modeling and optimization in hyperthermia therapy

Background: The success of cancer hyperthermia (HT) treatments is strongly dependent on the temperatures achieved in the tumor and healthy tissues as it correlates with treatment efficacy and safety, respectively. Hyperthermia treatment planning (HTP) simulations have become pivotal for treatment optimization due to the possibility for pretreatment planning, optimization and decision making, as well as real-time treatment guidance. Materials and methods: The same computational methods deployed in HTP are also used for in silico studies. These are of great relevance for the development of new HT devices and treatment approaches. To aid this work, 3 D patient models have been recently developed and made available for the HT community. Unfortunately, there is no consensus regarding tissue properties, simulation settings, and benchmark applicators, which significantly influence the clinical relevance of computational outcomes. Results and discussion: Herein, we propose a comprehensive set of applicator benchmarks, efficacy and safety optimization algorithms, simulation settings and clinical parameters, to establish benchmarks for method comparison and code verification, to provide guidance, and in view of the 2021 ESHO Grand Challenge (Details on the ESHO grand challenge on HTP will be provided at https://www.esho.info/). Conclusion: We aim to establish guidelines to promote standardization within the hyperthermia community such that novel approaches can quickly prove their benefit as quickly as possible in clinically relevant simulation scenarios. This paper is primarily focused on radiofrequency and microwave hyperthermia but, since 3 D simulation studies on heating with ultrasound are now a reality, guidance as well as a benchmark for ultrasound-based hyperthermia are also included

Mathematical Model on Magnetic Drug Targeting in Microvessel

Drug targeting is a process by which the distribution of drug in an organism is deployed in such a manner that its major fraction interacts exclusively with the target tissue at the cellular or subcellular level. Magnetic drug targeting is one of the major drug delivery methods due to its noninvasiveness, high targeting efficiency, and minimized toxic side effects on healthy cells and tissues. There are several experimental works on the magnetic drug targeting through microvessel, but very few works are carried out on the mathematical models on magnetic drug delivery. The aim of the present chapter is to discuss all major and minor factors, such as fluidic force, magnetic force, particle-particle interaction, inertia force, Saffman lift force, permeability of the microvessel and carrier particle, and so on, which influenced the drug targeting through microvessel by considering the nature of blood flow as Newtonian, non-Newtonian, single phase, and two phase model. A brief details of fluidic force, magnetic force, particle-particle interaction, Saffman force, buoyancy force, etc. Mathematical models on the fluidic force are discussed for Newtonian, non-Newtonian fluid, single phase, and two-phase fluid model including other forces that influence the magnetic drug targeting in microvessel

Inverse-Consistent Determination of Young\u27s Modulus of Human Lung

Human lung undergoes respiration-induced deformation due to sequential inhalation and exhalation. Accurate determination of lung deformation is crucial for tumor localization and targeted radiotherapy in patients with lung cancer. Numerical modeling of human lung dynamics based on underlying physics and physiology enables simulation and virtual visualization of lung deformation. Dynamical modeling is numerically complicated by the lack of information on lung elastic behavior, structural heterogeneity as well as boundary constrains. This study integrates physics-based modeling and image-based data acquisition to develop the patient-specific biomechanical model and consequently establish the first consistent Young\u27s modulus (YM) of human lung. This dissertation has four major components: (i) develop biomechanical model for computation of the flow and deformation characteristics that can utilize subject-specific, spatially-dependent lung material property; (ii) develop a fusion algorithm to integrate deformation results from a deformable image registration (DIR) and physics-based modeling using the theory of Tikhonov regularization; (iii) utilize fusion algorithm to establish unique and consistent patient specific Young\u27s modulus and; (iv) validate biomechanical model utilizing established patient-specific elastic property with imaging data. The simulation is performed on three dimensional lung geometry reconstructed from four-dimensional computed tomography (4DCT) dataset of human subjects. The heterogeneous Young\u27s modulus is estimated from a linear elastic deformation model with the same lung geometry and 4D lung DIR. The biomechanical model adequately predicts the spatio-temporal lung deformation, consistent with data obtained from imaging. The accuracy of the numerical solution is enhanced through fusion with the imaging data beyond the classical comparison of the two sets of data. Finally, the fused displacement results are used to establish unique and consistent patient-specific elastic property of the lung

Examining the effects of macrophage populations on cancerous tumor growth.

The most abundant immune cell types of the tumor microenvironment macrophages recruited there by tumor-eluted factors. The role of these immune cells in tumor progression, and the interplay between tumor and immune cells is an emerging field of research with potential for novel treatment strategies. Here, a TIE2 expressing macrophage (TEM) subtype is integrated into a virtual tumor model. Within the 2D microenvironment, the TEM will differentiate from an extravasated monocyte precursor, congregate around the abluminal side of the vasculature in response to a chemoattractant gradient, secrete cytokines which favor differentiation of a separate angiogenic macrophage subtype [1]. The effects of macrophage populations on tumor progression on angiogenic activity and tumor growth will be examined

Biodistribution, biocompatibility and targeted accumulation of magnetic nanoporous silica nanoparticles as drug carrier in orthopedics

Background: In orthopedics, the treatment of implant-associated infections represents a high challenge. Especially, potent antibacterial effects at implant surfaces can only be achieved by the use of high doses of antibiotics, and still often fail. Drug-loaded magnetic nanoparticles are very promising for local selective therapy, enabling lower systemic antibiotic doses and reducing adverse side effects. The idea of the following study was the local accumulation of such nanoparticles by an externally applied magnetic field combined with a magnetizable implant. The examination of the biodistribution of the nanoparticles, their effective accumulation at the implant and possible adverse side effects were the focus. In a BALB/c mouse model (n = 50) ferritic steel 1.4521 and Ti90Al6V4 (control) implants were inserted subcutaneously at the hindlimbs. Afterwards, magnetic nanoporous silica nanoparticles (MNPSNPs), modified with rhodamine B isothiocyanate and polyethylene glycol-silane (PEG), were administered intravenously. Directly/1/7/21/42 day(s) after subsequent application of a magnetic field gradient produced by an electromagnet, the nanoparticle biodistribution was evaluated by smear samples, histology and multiphoton microscopy of organs. Additionally, a pathohistological examination was performed. Accumulation on and around implants was evaluated by droplet samples and histology. Results: Clinical and histological examinations showed no MNPSNP-associated changes in mice at all investigated time points. Although PEGylated, MNPSNPs were mainly trapped in lung, liver, and spleen. Over time, they showed two distributional patterns: early significant drops in blood, lung, and kidney and slow decreases in liver and spleen. The accumulation of MNPSNPs on the magnetizable implant and in its area was very low with no significant differences towards the control. Conclusion: Despite massive nanoparticle capture by the mononuclear phagocyte system, no significant pathomorphological alterations were found in affected organs. This shows good biocompatibility of MNPSNPs after intravenous administration. The organ uptake led to insufficient availability of MNPSNPs in the implant region. For that reason, among others, the nanoparticles did not achieve targeted accumulation in the desired way, manifesting future research need. However, with different conditions and dimensions in humans and further modifications of the nanoparticles, this principle should enable reaching magnetizable implant surfaces at any time in any body region for a therapeutic reason. © 2020 The Author(s)

Study of novel nanoparticle transport and drug release for cancer treatment.

Nano-scale particles sized 10—400 nm administered systemically preferentially extravasate from tumor vasculature due to the enhanced permeability and retention effect. Therapeutic success remains elusive, however, because of inhomogeneous particle distribution within tumor tissue. Insufficient tumor vascularization limits particle transport and also results in avascular hypoxic regions with non-proliferating cells, which can regenerate tissue after nanoparticle-delivered cytotoxicity or thermal ablation. In this study, gold nanoparticles were functionalized with phosphatidylcholine (two-layer) or phosphatidylcholine and HDL (three-layer) in the formation of “layered” nanoparticles. The diffusivity of both two- and three layered colloidal gold nanoparticles and silica gold nanoshells were examined in 3D cell cultures. Both two- and three layered nanoparticles showed enhanced diffusivity in comparison to previously developed PEGylated nanoparticles. As the two layer nanoparticles displayed enhanced diffusivity in comparison to three layer nanoparticles, the two layered nanoparticles were further examined in vivo using mice implanted with orthotopic pancreatic adenocarcinomas. The two layer colloidal gold nanoparticles showed enhanced diffusivity in comparison to silica gold nanoshells in vivo, suggesting that smaller nanoparticles were able to localize and diffuse from vasculature better than larger nanoparticles. Overall accumulation of solid gold nanoparticle accumulated in the tumor and filtering organs (liver and spleen) was 2X higher than silica gold nanoshells. Thus, two layer colloidal gold nanoparticles were loaded with cisplatin or paclitaxel to determine optimal drug release kinetics. Drug release from paclitaxel-loaded nanoparticles displayed a slower release while cisplatin-loaded nanoparticles experienced an initial burst of drug release followed by a slower release of remaining drug. Lastly, drug-loaded colloidal gold nanoparticles were tested in 3D cell cultures to determine their cytotoxicity. Both two and three layer nanoparticles loaded with cisplatin orpaclitaxel showed similar efficacy to drug alone, suggesting their viable use in vivo for cancer treatment. This study has demonstrated the potential use of layered nanoparticles for increasing the delivery of chemotherapeutics deeper into tumor tissue