Antenna and system design for controlled delivery of microwave thermal ablation

Doctor of PhilosophyDepartment of Electrical and Computer EngineeringPunit PrakashMicrowave ablation is an established minimally invasive modality for thermal ablation of unresectable tumors and other diseases. The goal of a microwave ablation procedure is to deliver microwave power in a manner localized to the targeted tissue, with the objective of raising the target tissue to ablative temperatures (~60 °C). Engineering efforts in microwave applicator design have largely been focused on the design of microwave antennas that yield large, near-spherical ablation zones, and can fit within rigid needles or flexible catheters. These efforts have led to significant progress in the development and clinical application of microwave ablation systems, particularly for treating tumors in the liver and other highly vascular organs. However, currently available applicator designs are ill-suited to treating targets of diverse shapes and sizes. Furthermore, there are a lack of non-imaging-based techniques for monitoring the transient progression of the ablation zone as a means for providing feedback to the physician. This dissertation presents the design, implementation, and experimental evaluation of microwave ablation antennas for site-specific therapeutic applications with these issues in mind. A deployable 915 MHz loop antenna is presented, providing a minimally-invasive approach for thermal ablation of the endometrial lining of the uterus for treatment of heavy menstrual bleeding. The antenna incorporates a radiating loop, which can be deployed to adjustable shapes within the uterine cavity, and a passive element, to enable thermal ablation, to 5.7–9.6 mm depth, of uterine cavities ranging in size from 4–6.5 cm in length and 2.5–4.5 cm in width. Electromagnetic–bioheat transfer simulations were employed for design optimization of the antennas, and proof-of-concept applicators were fabricated and extensively evaluated in ex vivo tissue. Finally, feasibility of using the broadband antenna reflection coefficient for monitoring the ablation progress during the course of ablation was evaluated. Experimental studies demonstrated a shift in antenna resonant frequency of 50 MHz correlated with complete ablation. For treatment of 1–2 cm spherical targets, water-cooled monopole antennas operating at 2.45 and 5.8 GHz were designed and experimentally evaluated in ex vivo tissue. The technical feasibility of using these applicators for treating 1–2 cm diameter benign adrenal adenomas was demonstrated. These studies demonstrated the potential of using minimally-invasive microwave ablation applicators for treatment of hypertension caused by benign aldosterone producing adenomas. Since tissue dielectric properties have been observed to change substantially at elevated temperatures, knowledge of the temperature-dependence of tissue dielectric properties may provide a means for estimating treatment state from changes in antenna reflection coefficient during a procedure. The broadband dielectric properties of bovine liver, an established tissue for experimental characterization of microwave ablation applicators, were measured from room temperature to ablative temperatures. The measured dielectric data were fit to a parametric model using piecewise linear functions, providing a means for readily incorporating these data into computational models. These data represent the first report of changes in broadband dielectric properties of liver tissue at ablative temperatures and should help enable additional studies in ablation system development

Photodynamic Therapy of Inorganic Complexes for the Treatment of Cancer

Photodynamic therapy (PDT) is a medicinal tool that uses a photosensitiser and a light source to treat several conditions, including cancer. PDT uses reactive oxygen species (ROS) such as cytotoxic singlet oxygen 1O2 to induce cell death in cancer cells. Chemotherapy has historically utilized the cytotoxic effects of many metals, especially transition-metal complexes. However, chemotherapy is a systemic treatment so all cells in a patient\u27s body are exposed to the same cytotoxic effects. Transition metal complexes have also shown high cytotoxicity as PDT agents. PDT is a potential localized method for treating several cancer types by using inorganic complexes as photosensitizing agents. This review covers several in vitro and in vivo studies, as well as clinical trials that reported on the anti-cancer properties of inorganic pharmaceuticals used in PDT against different types of cancer

Nanoparticles in combination with Radiotherapy and/or Hyperthermia, in the treatment of Head & Neck cancer – A critical appraisal

Παρά την πρόοδο που έχει επιτευχθεί στις μεθόδους θεραπείας του καρκίνου, ο καρκίνος της κεφαλής και του τραχήλου εξακολουθεί να παραμένει μια σημαντική αιτία νοσηρότητας και θνησιμότητας. Η ακτινοθεραπεία εξελίχθηκε σε μεγάλο βαθμό την τελευταία δεκαετία, αλλά υπάρχουν πολλοί παράγοντες που περιορίζουν την αποτελεσματικότητά της, όπως η ακτινο-ανθεκτικότητα των καρκινικών κυττάρων και οι ανεπιθύμητες ενέργειες που προκαλούνται από τη βλάβη των υγιών ιστών. Η εφαρμογή της νανοτεχνολογίας στη θεραπεία του καρκίνου παρουσιάζει μεγάλες δυνατότητες βελτίωσης των θεραπευτικών αποτελεσμάτων της ακτινοθεραπείας, ενισχύοντας την αποτελεσματικότητά της και καταπολεμώντας την ακτινο-ανθεκτικότητα των καρκινικών κυττάρων. Επιπλέον, περιορίζει τη δόση που απορροφάται από τους υγιείς ιστούς, με αποτέλεσμα τη μείωση των ανεπιθύμητων ενεργειών. Επιπλέον, η εφαρμογή νανοσωματιδίων σε διάφορες μεθόδους υπερθερμίας μπορεί να επαναφέρει αυτή τη μορφή θεραπείας ως επικουρική θεραπεία για τον καρκίνο της κεφαλής και του τραχήλου. Ο συνδυασμός ακτινοθεραπείας και υπερθερμίας που ενισχύεται από νανοσωματιδιακούς παράγοντες μπορεί να οδηγήσει σε επανάσταση στη θεραπεία του καρκίνου κεφαλής και τραχήλου, με αποτέλεσμα τη δραματική βελτίωση των ποσοστών επιβίωσης και της ποιότητας ζωής αυτών των ασθενών.Despite the progress that has been made in cancer therapy methods, head and neck cancer still remains a major cause of morbidity and mortality. Radiation therapy has evolved greatly the last decade, but there are many factors that limit its efficacy, such as the radioresistance of cancer cells and the adverse effects that are produced from healthy tissue damage. The application of nanotechnology in cancer treatment shows great potential in improving the therapeutic outcomes of radiation therapy, by enhancing its efficiency and counteracts the radioresistance of cancer cells. Furthermore it limits the dose absorbed by healthy tissue, resulting in the reduction of the adverse effects. In addition, the implementation of nanoparticles in various hyperthermia methods may restore this treatment modality as an adjuvant therapy for head and neck cancer. The combination of radiotherapy and hyperthermia enhanced by nanoparticle-agents, may lead to a revolution in head and neck cancer therapy, resulting in a dramatic improvement of the survival rates and the quality of life of these patients

Hyperthermia and smart drug delivery systems for solid tumor therapy

Chemotherapy is a cornerstone of cancer therapy. Irrespective of the administered drug, it is crucial that adequate drug amounts reach all cancer cells. To achieve this, drugs first need to be absorbed, then enter the blood circulation, diffuse into the tumor interstitial space and finally reach the tumor cells. Next to chemoresistance, one of the most important factors for effective chemotherapy is adequate tumor drug uptake and penetration. Unfortunately, most chemotherapeutic agents do not have favorable properties. These compounds are cleared rapidly, distribute throughout all tissues in the body, with only low tumor drug uptake that is heterogeneously distributed within the tumor. Moreover, the typical microenvironment of solid cancers provides additional hurdles for drug delivery, such as heterogeneous vascular density and perfusion, high interstitial fluid pressure, and abundant stroma. The hope was that nanotechnology will solve most, if not all, of these drug delivery barriers. However, in spite of advances and decades of nanoparticle development, results are unsatisfactory. One promising recent development are nanoparticles which can be steered, and release content triggered by internal or external signals. Here we discuss these so-called smart drug delivery systems in cancer therapy with emphasis on mild hyperthermia as a trigger signal for drug delivery

PLGA Based Drug Carrier and Pharmaceutical Applications

Poly(lactic-co-glycolic acid) (PLGA) is one of the most successful polymers used for producing therapeutic devices, such as drug carriers (DC). PLGA is one of the few polymers that the Food and Drug Administration (FDA) has approved for human administration due to its biocompatibility and biodegradability. In recent years, DC produced with PLGA has gained enormous attention for its versatility in transporting different type of drugs, e.g., hydrophilic or hydrophobic small molecules, or macromolecules with a controlled drug release without modifying the physiochemical properties of the drugs. These drug delivery systems have the possibility/potential to modify their surface properties with functional groups, peptides, or other coatings to improve the interactions with biological materials. Furthermore, they present the possibility to be conjugated with specific target molecules to reach specific tissues or cells. They are also used for different therapeutic applications, such as in vaccinations, cancer treatment, neurological disorder treatment, and as anti-inflammatory agents. This book aims to focus on the recent progress of PLGA as a drug carrier and their new pharmaceutical applications

Immuno Magnetic Thermosensitive Liposomes For Cancer Therapy

The present work describes the encapsulation of the drug doxorubicin (DOX) in immuno paramagnetic thermosensitive liposomes. DOX is the most common chemotherapeutic agent for the treatment of a variety of carcinomas. However, the pure drug has high cytotoxicity and therefore requires a targeted and biocompatible delivery system. The introduction includes concepts, modalities, and functionalities of the project. First, a detailed description of the cell type (triple-negative breast cancer) is given. Furthermore, the importance of liposomal doxorubicin is explained and the current state of research is shown. The importance of modification to achieve thermosensitive properties and the procedure for co-encapsulation with Gd chelate to achieve paramagnetic properties is also discussed. In addition, the first part describes the surface modification with ADAM8 antibodies, which leads to improved targeting. The second part of the thesis covers the different materials and methods used in this paper. The production of the liposomes LipTS, LipTS-GD, LipTS-GD-CY, LipTS-GD-CY-MAB and the loading of DOX using an ammonium sulfate gradient method were described in detail. The results part deals with the physicochemical characterization using dynamic light scattering and laser Doppler velocimetry, which confirmed a uniform monodisperse distribution of the liposomes. These properties facilitate the approach of liposomes to target cancer cells. The influence of lipid composition of liposomes, co-encapsulation with Gd chelate and surface modification of liposomes was evaluated and described accordingly. The size and structure of the individual liposomal formulations were determined by atomic force microscopy and transmission electron microscopy. Morphological examination of the liposomes confirmed agreement with the sizes obtained by dynamic light scattering. Temperature-dependent AFM images showed an intact liposome structure at 37 °C, whereas heating by UHF-MRI led to a lipid film indicating the destruction of the lipid bilayer. Furthermore, TEM images showed the morphological properties of the liposomes and gave a more precise indication of how Gd-chelate accumulates within the liposomes. Liposomes with Gd-chelate showed well-separated vesicles, suggesting that Gd- chelate is deposited in the lipid bilayer of the liposomes. Gd was encapsulated in the hydrophilic core whereas chelate was extended into the lipid bilayer. By differential scanning calorimetry and drug release, the heat-sensitive functionality of the liposomes could be determined. Liposomes showed a beginning of phase transition temperature at about 38 °C, which can be achieved by UHF-MRI exposure. The maximum phase transition temperature in the case of LipTS-GD and LipTS-GD-CY-MAB was 42 °C and 40 °C, respectively. A proof of concept study for the thermosensitive properties of liposomes and a time-dependent DOX release profile in hyperthermia was performed. Gd-chelate is encapsulated in both LipTS-GD and LipTS-GD-CY-MAB and led to paramagnetic properties of the liposomes. This facilitates imaging mediated DOX delivery and diagnosis of the solid tumor and metastatic cells. The change in relaxation rate R1 of liposomes was quantified before and after heating above Tm (T> Tm). The relaxivity of the liposomes was obtained from the adapted slope of the relaxation rate against the Gd concentration. Remarkably, the relaxation rate and relaxivity increased after heating the liposomes above Tm (T> Tm), suggesting that the liposomes opened, released Gd chelate, and the exchange of water molecules became faster and more practicable. Toxicity studies describe the different mechanisms for induced DOX toxicity. The increased cytotoxic effect at elevated temperatures showed that the induced toxicity is thermally dependent, i.e. DOX was released from the liposomes. The high viability of the cells at 37 °C indicates that the liposomes were intact at normal physiological temperatures. Under UHF-MRI treatment, cell toxicity due to elevated temperature was observed. The cellular uptake of liposomes under UHF-MRI was followed by a confocal laser scanning microscope. An increase in fluorescence intensity was observed after UHF-MRI exposure. The study of the uptake pathway showed that the majority of liposomes were mainly uptake by clathrin-mediated endocytosis. In addition, the liposomes were modified with anti-ADAM8 antibodies (MAB 1031) to allow targeted delivery. The cellular binding capabilities of surface-modified and non-modified liposomes were tested on cells that had ADAM8 overexpression and on ADAM8 knockdown cells. Surface-modified liposomes showed a significant increase in binding ability, indicating significant targeting against cells that overexpress ADAM8 on their surface. In addition, cells with knockdown ADAM8 could not bind a significant amount of modified liposomes. The biocompatibility of liposomes was assessed using a hemolysis test, which showed neglected hemolytic potential and an activated thromboplastin time (aPTT), where liposomes showed minimal interference with blood clotting. Hemocompatibility studies may help to understand the correlation between in vitro and in vivo. The chorioallantois model was used in ovo to evaluate systematic biocompatibility in an alternative animal model. In the toxicity test, liposomes were injected intravenously into the chicken embryo. The liposomes showed a neglectable harmful effect on embryo survival. While free DOX has a detrimental effect on the survival of chicken embryos, this confirms the safety profile of liposomes compared to free DOX. LipTS-GD-CY-MAB were injected into the vascular system of the chicken embryo on egg development day 11 and scanned under UHF-MRI to evaluate the magnetic properties of the liposomes in a biological system with T2-weighted images (3D). The liposomal formulation had distinct magnetic properties under UHF MRI and the chick survived the scan. In summary, immunomagnetic heat-sensitive liposomes are a novel drug for the treatment of TNBC. It is used both for the diagnosis and therapy of solid and metastasizing tumors without side effects on the neighboring tissue. Furthermore, a tumor in the CAM model will be established. Thereafter, the selective targeting of the liposomes will be visualized and quantitated using fluorescence and UHF-MRI. Liposomes are yet to be tested on mice as a xenograft triple-negative breast cancer model, in which further investigation on the effect of DOX-LipTS-GD-CY-MAB is evaluated. On one hand, the liposomes will be evaluated regarding their targetability and their selective binding. On the other hand, the triggered release of DOX from the liposomes after UHF-MRI exposure will be quantitated, as well as evaluate the DOX-Liposomes therapeutic effect on the tumor

Oncologic Thermoradiotherapy: Need for Evidence, Harmonisation, and Innovation

The road of acceptance of oncologic thermotherapy/hyperthermia as a synergistic modality in combination with standard oncologic therapies is still bumpy. This is partially due to the lack of level I evidence from international, multicentric, randomized clinical trials including large patient numbers and a long term follow-up. Therefore we need more level I EVIDENCE from clinical trials, we need HARMONISATION and global acceptance for existing technologies and a common language understood by all stakeholders and we need INNOVATION in the fields of biology, clinics and technology to move thermotherapy/hyperthermia forward. This is the main focus of this reprint. In this reprintyou find carefully selected and peer-reviewed contributions from Africa, America, Asia, and Europe. The published papers from leading scientists from all over the world covering a broad range of timely research topics might also help to strengthen thermotherapy on a global level

HIGH INTENSITY FOCUSED ULTRASOUND AND OXYGEN LOAD NANOBUBBLES: TWO DIFFERENT APPROCHES FOR CANCER TREATMENT

The study of applications based on the use of ultrasound in medicine and biology for therapeutic purposes is under strong development at international level and joins the notoriously well-established and widespread use of diagnostic applications [1]. In the past few years, High Intensity Focused Ultrasound (HIFU) has developed from a scientific curiosity to an accepted therapeutic modality. HIFU is a non invasive technique for the treatment of various types of cancer, as well as non-malignant pathologies, by inducing localized hyperthermia that causes necrosis of the tissue. Beside HIFU technology, other innovative therapeutic modalities to treat cancer are emerging. Among them, an extremely innovative technique is represented by oxygen loaded nanobubbles (OLNs): gas cavities confined by an appropriately functionalized coating. This is an oxygenating drugs aimed at re-oxygenation of cancerous tissue. Oxygen deficiency, in fact, is the main hallmark of cancerous solid tumors and a major factor limiting the effectiveness of radiotherapy. In this work, these two approaches to treat tumours are under study from a metrological point of view. In particular, a complete characterization of an HIFU fields regarding power, pressure and temperature is provided while oxygen load nanobubbles are synthesized, characterized and applied in in vitro and in vivo experiments

Engineered Therapeutic Plasmids and Nanoparticle Delivery Vehicles for Targeted Treatment of Hepatocellular Carcinoma

Nucleic acid-based therapies can be used to target the genetic basis of a disease and have been explored for the treatment of wide range of medical conditions, including cancer. However, many of these therapies have largely been ineffective in the clinic due to off-target toxicities and poor targeting properties, resulting in poor safety and efficacy outcomes. To address these challenges, there has been a strong effort over the past decades to develop delivery vehicles for targeted nucleic acid delivery. A high degree of targeting is particularly critical when delivering cytotoxic therapies for cancer cell killing, as off-target toxicities can lead to dangerous or deadly adverse events. In the case of liver cancer, off-target toxicity has a high risk of liver failure due to the prevalence of severe underlying liver disease in these patients. The aim of this thesis is to investigate multiple methods for targeted DNA delivery to hepatocellular carcinoma, the most common form of liver cancer. Polyplex nanoparticles (NPs) synthesized using poly(beta-amino ester) (PBAE) serve as a delivery vehicle to deliver plasmid DNA to target cells. This thesis uses PBAE NPs to explore multimodal targeting using (1) anatomical targeting of tissues, specifically HCC tumor vasculature, (2) optimization of delivery vehicle biomaterials for HCC cell-specific transfection, and (3) an HCC-specific promoter to restrict therapeutic gene expression. These methodologies are explored independently and in combination to specifically deliver DNA to HCC cells in vitro and in vivo. Importantly, these targeting principles are applied to develop two targeted therapeutics for HCC, which show therapeutic efficacy in preclinical rodent models of HCC. Altogether, these results highlight the clinical potential of PBAE NPs for targeted therapy for HCC