Requirements for designing an effective metallic nanoparticle (NP)-boosted radiation therapy (RT)

Many different tumor-targeted strategies are under development worldwide to limit the side effects and improve the effectiveness of cancer therapies. One promising method is to enhance the radiosensitization of the cancer cells while reducing or maintaining the normal tissue complica-tion probability during radiation therapy using metallic nanoparticles (NPs). Radiotherapy with MV photons is more commonly available and applied in cancer clinics than high LET particle radi-otherapy, so the addition of high-Z NPs has the potential to further increase the efficacy of photon radiotherapy in terms of NP radiosensitization. Generally, when using X-rays, mainly the inner electron shells are ionized, which creates cascades of both low and high energy Auger electrons. When using high LET particles, mainly the outer shells are ionized, which give electrons with lower energies than when using X-rays. The amount of the produced low energy electrons is higher when exposing NPs to heavy charged particles than when exposing them to X-rays. Since ions traverse the material along tracks, and therefore give rise to a much more inhomogeneous dose distributions than X-rays, there might be a need to introduce a higher number of NPs when using ions compared to when using X-rays to create enough primary and secondary electrons to get the desired dose escalations. This raises the questions of toxicity. This paper provides a review of the fundamental processes controlling the outcome of metallic NP-boosted photon beam and ion beam radiation therapy and presents some experimental procedures to study the biological effects of NPs’ radio-sensitization. The overview shows the need for more systematic studies of the behavior of NPs when exposed to different kinds of ionizing radiation before applying metallic-based NPs in clinical practice to improve the effect of IR therapy

Biophysical applications of laser and development of methodology for nanoparticles micromanipulation using optical tweezers

The present thesis studies the photo-biophysical applications of laser in macroscopic and microscopic level. The laser light was applied to tissues, implant materials, cells and nanoparticles. In particular, the laser beam was used as a tool for ablation and micromanipulation of biostructures. The aim was to study several applications of the laser radiation on the rapidly evolving fields of photorefractive surgery and biotechnology. The thesis is divided into two parts. In the first part was examined the interaction of laser radiation with ocular tissues and intraocular lenses (IOLs). The photorefractive surgery uses laser light for cornea reshaping in order to correct refractive errors such as myopia, astigmatism and hyperopia. The cataract surgery uses polymeric implants (lenses) to restore vision in cases of clouding of the natural lens of the eye. On top of refractive surgery with excimer laser is the optimization of quality of vision and the minimization of postoperative complications. In cataract surgery new polymeric materials, techniques and patterns have been studied for forming and etching IOLs to reduce diffractive aberrations and improve multifocal focusingΣτην παρούσα διατριβή μελετήθηκαν οι φωτο-βιοφυσικές εφαρμογές των laser σε μακροσκοπικό και μικροσκοπικό επίπεδο. Η ακτινοβολία laser εφαρμόστηκε σε ιστούς, σε υλικά εμφυτεύματα, σε κύτταρα και νανοσωματίδια. Συγκεκριμένα, χρησιμοποιήθηκε η δέσμη laser ως εργαλείο αποδόμησης αλλά και μικροχειρισμού βιοδομών. Στόχος ήταν η μελέτη εφαρμογής της ακτινοβολίας laser στους ραγδαία εξελισσόμενους τομείς της φωτοδιαθλαστικής χειρουργικής, της βιοφυσικής και της βιοτεχνολογίας. Η διατριβή χωρίζεται σε δύο μέρη. Στο Α΄ μέρος μελετήθηκε για πρώτη φορά στο εργαστήριο και σε επίπεδο βασικής έρευνας η αλληλεπίδραση της ακτινοβολίας laser με οφθαλμικούς ιστούς και ενδοφακούς. Η φωτοδιαθλαστική χειρουργική χρησιμοποιεί την ακτινοβολία laser για την μορφοποίηση του κερατοειδούς χιτώνα με σκοπό την διόρθωση διαθλαστικών σφαλμάτων, όπως η μυωπία, ο αστιγματισμός και η υπερμετρωπία. Στην κορυφή της διαθλαστικής χειρουργικής με excimer laser βρίσκεται η βελτιστοποίηση της ποιότητας της όρασης και η ελαχιστοποίηση των μετεγχειρητικών επιπλοκών. Η χειρουργική του καταρράκτη χρησιμοποιεί πολυμερικά εμφυτεύματα (ενδοφακούς) για την αποκατάσταση της όρασης σε περιπτώσεις θόλωσης του φυσικού φακού του ματιού. Στη σύγχρονη χειρουργική του καταρράκτη μελετούνται νέα πολυμερικά υλικά, τεχνικές παραγωγής και μορφοποίησης των ενδοφακών με σκοπό την βελτίωση των διαθλαστικών εκτροπών και της αδυναμίας πολυεστιακής ικανότητας του οφθαλμού

Characterization of new drug delivery nanosystems using atomic force microscopy

Liposomes are the most attractive lipid vesicles for targeted drug delivery in nanomedicine, behaving also as cell models in biophotonics research. The characterization of the micro-mechanical properties of drug carriers is an important issue and many analytical techniques are employed, as, for example, optical tweezers and atomic force microscopy. In this work, polyol hyperbranched polymers (HBPs) have been employed along with liposomes for the preparation of new chimeric advanced drug delivery nanosystems (Chi-aDDnSs). Aliphatic polyester HBPs with three different pseudogenerations G2, G3 and G4 with 16, 32, and 64 peripheral hydroxyl groups, respectively, have been incorporated in liposomal formulation. The atomic force microscopy (AFM) technique was used for the comparative study of the morphology and the mechanical properties of Chi-aDDnSs and conventional DDnS. The effects of both the HBPs architecture and the polyesters pseudogeneration number in the stability and the stiffness of chi-aDDnSs were examined. From the force-distance curves of AFM spectroscopy, the Young’s modulus was calculated

Recent Advances in Cancer Therapy Based on Dual Mode Gold Nanoparticles

Many tumor-targeted strategies have been used worldwide to limit the side effects and improve the effectiveness of therapies, such as chemotherapy, radiotherapy (RT), etc. Biophotonic therapy modalities comprise very promising alternative techniques for cancer treatment with minimal invasiveness and side-effects. These modalities use light e.g., laser irradiation in an extracorporeal or intravenous mode to activate photosensitizer agents with selectivity in the target tissue. Photothermal therapy (PTT) is a minimally invasive technique for cancer treatment which uses laser-activated photoabsorbers to convert photon energy into heat sufficient to induce cells destruction via apoptosis, necroptosis and/or necrosis. During the last decade, PTT has attracted an increased interest since the therapy can be combined with customized functionalized nanoparticles (NPs). Recent advances in nanotechnology have given rise to generation of various types of NPs, like gold NPs (AuNPs), designed to act both as radiosensitizers and photothermal sensitizing agents due to their unique optical and electrical properties i.e., functioning in dual mode. Functionalized AuNPS can be employed in combination with non-ionizing and ionizing radiation to significantly improve the efficacy of cancer treatment while at the same time sparing normal tissues. Here, we first provide an overview of the use of NPs for cancer therapy. Then we review many recent advances on the use of gold NPs in PTT, RT and PTT/RT based on different types of AuNPs, irradiation conditions and protocols. We refer to the interaction mechanisms of AuNPs with cancer cells via the effects of non-ionizing and ionizing radiations and we provide recent existing experimental data as a baseline for the design of optimized protocols in PTT, RT and PTT/RT combined treatment

Requirements for Designing an Effective Metallic Nanoparticle (NP)-Boosted Radiation Therapy (RT)

Simple Summary Recent advances in nanotechnology gave rise to trials with various types of metallic nanoparticles (NPs) to enhance the radiosensitization of cancer cells while reducing or maintaining the normal tissue complication probability during radiation therapy. This work reviews the physical and chemical mechanisms leading to the enhancement of ionizing radiation’s detrimental effects on cells and tissues, as well as the plethora of experimental procedures to study these effects of the so-called “NPs’ radiosensitization”. The paper presents the need to a better understanding of all the phases of actions before applying metallic-based NPs in clinical practice to improve the effect of IR therapy. More physical and biological experiments especially in vivo must be performed and simulation Monte Carlo or mathematical codes based on more accurate models for all phases must be developed. Many different tumor-targeted strategies are under development worldwide to limit the side effects and improve the effectiveness of cancer therapies. One promising method is to enhance the radiosensitization of the cancer cells while reducing or maintaining the normal tissue complication probability during radiation therapy using metallic nanoparticles (NPs). Radiotherapy with MV photons is more commonly available and applied in cancer clinics than high LET particle radiotherapy, so the addition of high-Z NPs has the potential to further increase the efficacy of photon radiotherapy in terms of NP radiosensitization. Generally, when using X-rays, mainly the inner electron shells are ionized, which creates cascades of both low and high energy Auger electrons. When using high LET particles, mainly the outer shells are ionized, which give electrons with lower energies than when using X-rays. The amount of the produced low energy electrons is higher when exposing NPs to heavy charged particles than when exposing them to X-rays. Since ions traverse the material along tracks, and therefore give rise to a much more inhomogeneous dose distributions than X-rays, there might be a need to introduce a higher number of NPs when using ions compared to when using X-rays to create enough primary and secondary electrons to get the desired dose escalations. This raises the questions of toxicity. This paper provides a review of the fundamental processes controlling the outcome of metallic NP-boosted photon beam and ion beam radiation therapy and presents some experimental procedures to study the biological effects of NPs’ radiosensitization. The overview shows the need for more systematic studies of the behavior of NPs when exposed to different kinds of ionizing radiation before applying metallic-based NPs in clinical practice to improve the effect of IR therapy

Consolidation of Gold and Gadolinium Nanoparticles: An Extra Step towards Improving Cancer Imaging and Therapy

The multifactorial nature of cancer still classifies the disease as one of the leading causes of death worldwide. Modern medical sciences are following an interdisciplinary approach that has been fueled by the nanoscale revolution of the past years. The exploitation of high-Z materials, in combination with ionizing or non-ionizing radiation, promises to overcome restrictions in medical imaging and to augment the efficacy of current therapeutic modalities. Gold nanoparticles (AuNPs) have proven their value among the scientific community in various therapeutic and diagnostic techniques. However, the high level of multiparametric demands of AuNP experiments in combination with their biocompatibility and cytotoxicity levels remain crucial issues. Gadolinium NPs (GdNPs), have presented high biocompatibility, low cytotoxicity, and excellent hemocompatibility, and have been utilized in MRI-guided radiotherapy, photodynamic and photothermal therapy, etc. Τhe utilization of gadolinium bound to AuNPs may be a promising alternative that would reduce phenomena, such as toxicity, aggregation, etc., and could create a multimodal in vivo contrast and therapeutic agent. This review highlights multi-functionalization strategies against cancer where gold and gadolinium NPs are implicated. Their experimental applications and limitations of the past 5 years will be analyzed in the hope of enlightening the benefits and drawbacks of their proper combination

Raman Spectroscopy: A Personalized Decision-Making Tool on Clinicians’ Hands for In Situ Cancer Diagnosis and Surgery Guidance

Accurate in situ diagnosis and optimal surgical removal of a malignancy constitute key elements in reducing cancer-related morbidity and mortality. In surgical oncology, the accurate discrimination between healthy and cancerous tissues is critical for the postoperative care of the patient. Conventional imaging techniques have attempted to serve as adjuvant tools for in situ biopsy and surgery guidance. However, no single imaging modality has been proven sufficient in terms of specificity, sensitivity, multiplexing capacity, spatial and temporal resolution. Moreover, most techniques are unable to provide information regarding the molecular tissue composition. In this review, we highlight the potential of Raman spectroscopy as a spectroscopic technique with high detection sensitivity and spatial resolution for distinguishing healthy from malignant margins in microscopic scale and in real time. A Raman spectrum constitutes an intrinsic “molecular finger-print” of the tissue and any biochemical alteration related to inflammatory or cancerous tissue state is reflected on its Raman spectral fingerprint. Nowadays, advanced Raman systems coupled with modern instrumentation devices and machine learning methods are entering the clinical arena as adjunct tools towards personalized and optimized efficacy in surgical oncology

Clustered DNA Damage Patterns after Proton Therapy Beam Irradiation Using Plasmid DNA

Modeling ionizing radiation interaction with biological matter is a major scientific challenge, especially for protons that are nowadays widely used in cancer treatment. That presupposes a sound understanding of the mechanisms that take place from the early events of the induction of DNA damage. Herein, we present results of irradiation-induced complex DNA damage measurements using plasmid pBR322 along a typical Proton Treatment Plan at the MedAustron proton and carbon beam therapy facility (energy 137–198 MeV and Linear Energy Transfer (LET) range 1–9 keV/μm), by means of Agarose Gel Electrophoresis and DNA fragmentation using Atomic Force Microscopy (AFM). The induction rate Mbp−1 Gy−1 for each type of damage, single strand breaks (SSBs), double-strand breaks (DSBs), base lesions and non-DSB clusters was measured after irradiations in solutions with varying scavenging capacity containing 2-amino-2-(hydroxymethyl)propane-1,3-diol (Tris) and coumarin-3-carboxylic acid (C3CA) as scavengers. Our combined results reveal the determining role of LET and Reactive Oxygen Species (ROS) in DNA fragmentation. Furthermore, AFM used to measure apparent DNA lengths provided us with insights into the role of increasing LET in the induction of highly complex DNA damage

Advanced Raman Spectroscopy Based on Transfer Learning by Using a Convolutional Neural Network for Personalized Colorectal Cancer Diagnosis

Advanced Raman spectroscopy (RS) systems have gained new interest in the field of medicine as an emerging tool for in vivo tissue discrimination. The coupling of RS with artificial intelligence (AI) algorithms has given a boost to RS to analyze spectral data in real time with high specificity and sensitivity. However, limitations are still encountered due to the large amount of clinical data which are required for the pre-training process of AI algorithms. In this study, human healthy and cancerous colon specimens were surgically resected from different sites of the ascending colon and analyzed by RS. Two transfer learning models, the one-dimensional convolutional neural network (1D-CNN) and the 1D–ResNet transfer learning (1D-ResNet) network, were developed and evaluated using a Raman open database for the pre-training process which consisted of spectra of pathogen bacteria. According to the results, both models achieved high accuracy of 88% for healthy/cancerous tissue discrimination by overcoming the limitation of the collection of a large number of spectra for the pre-training process. This gives a boost to RS as an adjuvant tool for real-time biopsy and surgery guidance