Prés Molecular Imaging - HES
publicité
Healthcare economics Shift of paradigm Transformation of medical paradigm New developments in Molecular Imaging • Détecteur à scintillations Applications in personalized medicine spectromètre Osman Ratib, MD, PhD • Treat disease before it becomes symptomatic • Four P PM cristal collimateur «name» - «studyName» Molecular Imaging Evolution of medical imaging Predictive Personalized Preemptive Participatory • We should better understand how the molecules we are giving to the patients really work (how cancer mutate, response, environment etc..) Division of Nuclear Medicine and Molecular Imaging Department of Medical Imaging and Information Sciences University Hospital of Geneva Image 1 • • • • Keynote Lecture Elias Zerhouni International Society for Strategic Studies in Radiology • • • Genomics, proteomics Molecular Imaging (quantitative…) Radiomics ©2016 Hôpitaux Universitaires de Genève asservissement mécanique imprimante HISTORY Evolution of molecular imaging 1958 2015 Planar scintigram Hybrid PET-CT ➩ scintigraphie ©2011 Hôpitaux Universitaires de Genève ©2016 Hôpitaux Universitaires de Genève Master Physique Médicale Lyon - Tomographie d’émission monophotonique - Irène Buvat – septembre 2011 - 26 Evolution of medical imaging Molecular Imaging Multidetector scanners The fifth dimension 3D 4D ©2014 Hôpitaux Universitaires de Genève Positron emission tomography Molecular imaging Anatomy (CT) Metabolism (PET) ©2014 Hôpitaux Universitaires de Genève PET vs CT Advantages CT Pre treatment Post treatment ©2014 Hôpitaux Universitaires de Genève ©2011 Hôpitaux Universitaires de Genève PET Positron Emission Tomography Evolution of hybrid Imaging Invention of hybrid PET-CT PET-CT scanners 1994 1998 University of Pittsburgh Medical Center ©2006 Hôpitaux Universitaires de Genève ©2008 Hôpitaux Universitaires de Genève PET-CT PET-CT Staging in oncology Treatment monitoring Follow up of treatment response Better characterization of lesions T.M. 3487591 ©2011 Hôpitaux Universitaires de Genève Staging Post therapy T.M. 3487591 ©2011 Hôpitaux Universitaires de Genève Staging Mobile PET-CT Hybrid imaging From PET-CT to PET-MR CT PET PET-CT PET-MRI CT PET PET-CT ©2009 Hôpitaux Universitaires de Genève ©2016 Hôpitaux Universitaires de Genève Hybrid PET-MRI Evolution... Evolution... PET ©2016 Hôpitaux Universitaires de Genève MRI PET-MRI Hybrid PET-MRI Separate MRI PET MRI Separate ©2016 Hôpitaux Universitaires de Genève ➟ Co-planar MRI Hybrid PET-MRI Evolution... PET-MR hybrid imaging PET MRI World premier in hybrid imaging... Separate ➟ Co-planar ➟ Integrated ©2016 Hôpitaux Universitaires de Genève ©2016 Hôpitaux Universitaires de Genève Hybrid whole-body PET-MRI Hybrid PET-MR Co-planar registration of standard scanners Clinical applications of hybrid PET-MR • Le PET-CT est un nouvel outil diagnostic pour la détection et le suivi des cancers 3m MRI • L’acquisition simultanée de CT et de PET offre des avantages de qualité diagnostique et de confort pour le patient • Le PET offre aussi des applications en neurologie, cardiologie et dans la détection des infections et des foyers inflammatoires PET • Le développement de nouveaux traceurs plus spécifiques ouvre de nouvelles perspectives dans le diagnostique précoce des tumeurs et dans l’étude des maladies neurodégénératives et cardiovasculaires ©2016 Hôpitaux Universitaires de Genève ©2016 Hôpitaux Universitaires de Genève Hybrid PET-MR Clinical applications of hybrid PET-MR Head & Neck Breast Prostate Sarcoma Pelvis from diagnostic to Theranostic A new paradigm in molecular imaging... PET$CT ©2016 Hôpitaux Universitaires de Genève THERANOSTICS FOR PERSONALIZED MOLECULAR TARGETED THERAPY Shift of paradigm ©2016 Hôpitaux Universitaires de Genève HISTORY Radionuclide can cure cancer.. Theranostics • Theranostics is the combination of a Diagnostic Tool that also provides a Therapeutic Tool for a specific disease. • The right treatment, not anymore targeting the “specific disease” but the “specific disease expression of a given patient”. Personalized Medicine • The right treatment, for the right patient, at the right time, at the right dose. – first time • The concept of PM has been extended to Personalized Health Care that includes all steps from the first sign of disease up to full recovery Published: May 12th 1921 © The New York Times ©2016 Hôpitaux Universitaires de Genève ©2015 Hôpitaux Universitaires de Genève Targeted Radionuclide Therapy Targeted Radionuclide Therapy Radium-223 (Alpharadin) Radium-223 (Alpharadin) • 1921 223 Ra (Alpharadin) for treatment of bone metastases in patients with prostate cancer resistant to hormonotherapy 2015 ©2015 Hôpitaux Universitaires de Genève ©2016 Hôpitaux Universitaires de Genève Targeted Radionuclide Therapy Targeted Radionuclide Therapy Radium-223 (Alpharadin) Radium-223 (Alpharadin) • Phase II and phase III studies showed increase in overall survival rate of 3.5 months • Increase in time to first skeletal-related event of 5.5 months ©2016 Hôpitaux Universitaires de Genève Nilsson et al. Lancet Oncol 2007 ©2016 Hôpitaux Universitaires de Genève HISTORY Radionuclide therapy Theranostics in nuclear medicine 131 I Therapy for thyroid cancer Eur J Nucl Med Mol Imaging (2014) 41:199–201 DOI 10.1007/s00259-013-2609-2 EDITORIAL Nothing new under the nuclear sun: towards 80 years of theranostics in nuclear medicine • Well established since the 1950s • Beta and gamma rays • Self-targeting Frederik A. Verburg & Alexander Heinzel & Heribert Hänscheid & Felix M. Mottaghy & Markus Luster & Luca Giovanella Published online: 6 November 2013 # Springer-Verlag Berlin Heidelberg 2013 Some time in the early 2000s, the word “theranostics” (or “theragnostics”) started surfacing in the medical literature. Theranostics (from the Greek therapeuein “to treat medically” and gnosis “knowledge”) is the use of individual patient-level biological information in choosing the optimal therapy for that individual [1]. In the modern era of “personalized medicine”, theranostics is increasingly pursued in many branches of medicine in order to develop ever more effective treatment regimens. There are now many studies and reviews dedicated to theranostics, and even a journal bearing the name of this principle, detailing many different concepts on how to combine imaging and therapy using, for example, complex molecules [2] or nanotechnology [3]. However, it is rarely realized by either clinicians or scientists ©2016 Hôpitaux Universitaires de Genève that nuclear medicine has been employing theranostics for nearly 80 years now. In fact, the very foundations of targeted therapy in nuclear medicine are those that are only now being adopted by other medical disciplines under the designation “theranostics”. F. A. Verburg (*) : A. Heinzel : F. M. Mottaghy Department of Nuclear Medicine, RWTH University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany e-mail: [email protected] The cornerstones of theranostics can be traced back to some of the most illustrious names among the founding fathers of nuclear medicine. Soon after Chiewitz and de Hevesy [4] described the uptake of radioactive 32P in the bones of rats, Erf and J.H. Lawrence (brother of the physicist Ernest O. Lawrence, who built the first cyclotron) applied this same radioisotope to patients suffering from leukaemia and polycythaemia vera [5]. Although this treatment certainly was not without success, it has since been superseded by more effective nonradioactive chemotherapy. Shortly afterwards Pecher [6] discovered that 89 Sr accumulated in secondary bone tumours in animals, and subsequently successfully used this radioisotope to treat patients with painful bone metastases (unfortunately this work was immediately classified as secret and it took more than five decades for 89Sr to be registered as a therapeutic drug). These two studies are perhaps the earliest examples of diagnostic studies leading to targeted therapy of cancer using radionuclides. Around the same time the most prominent example of pure nuclear theranostic medicine emerged: the diagnosis and treatment of thyroid disorders using various isotopes of iodine. Hertz et al. in 1938 described the first study of thyroidal radioiodine uptake [7], and in 1942 Hertz and Roberts reported on the treatment of the first patients with Graves’ disease with radioiodine [8]. A short time later Seidlin et al. treated the first patient with metastatic thyroid cancer with radioiodine [9] – at the time this compound was so rare that radioiodine was purified from the patient’s urine and readministered. During this therapy, additional metastases were identified using a Geiger counter and the first rudimentary dosimetry was performed. It is of course only with the benefit of hindsight that we can now say that this was the first application of theranostics in targeted molecular medicine through a specific molecular target, the sodium iodine symporter, long before any of these concepts were first described as “theranostics”. Indeed, even today it is hard to think of a single combination of targeted diagnostics and therapy that is more specific than radioiodine. ©2016 Hôpitaux Universitaires de Genève Radionuclide therapy Radionuclide therapy Choice of carriers 131 F. A. Verburg : F. M. Mottaghy Department of Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands H. Hänscheid Department of Nuclear Medicine, University of Wuerzburg, Wuerzburg, Germany M. Luster Department of Nuclear Medicine, University Hospitals Giessen-Marburg, Marburg, Germany L. Giovanella Department of Nuclear Medicine, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland I/90Y labelled antibody for NHL therapy • Monoclonal antibody • Labelled with Beta emitting isotope CD20 ©2016 Hôpitaux Universitaires de Genève ©2016 Hôpitaux Universitaires de Genève Rituximab Radionuclide therapy 131 Radionuclide therapy I/90Y labelled antibody for NHL therapy Treatment of indolent lymphoma with 131 Radio-immunotherapy 90 Y-Ibritumomab (Zavalin®) I-tositumomab Cellule B antigène CD20 (cellule cancéreuse) Anticorps monoclonal (ibritumomab), associé à un radioisotope (yttrium-90) L’yttrium-90 se décompose en zirconium-90 stable, par l’émission des particules bêta riches en énergie (demi-vie: 2.67 jours). La portée des rayons bêta de l’yttrium-90 dans le tissu est de 5 mm au maximum. F. Buchegger et al British Journal of Cancer (2006) 94, 1770 – 1776 et J Nucl Med 2011; 52:896–900 ©2016 Hôpitaux Universitaires de Genève 4 ©2016 Hôpitaux Universitaires de Genève Peptide Receptor Radiotherapy (PRRT) 68 68 PET tracers without a cyclotron Ga Generators and labeling kits GA/177LU DOTATOC in Neuroendocrine tumors (NET) 177 68 LU GA • 177 LU emits intermediate energy beta particles (133 KeV) • Beneficial in small sized tumors (tissue range 2mm) • Concomitant gamma emission enables imaging with gamma cameras ©2016 Hôpitaux Universitaires de Genève ©2016 Hôpitaux Universitaires de Genève Radionuclide therapy Radionuclide therapy Peptide Receptor Radionuclide Therapy (PRRT) Peptide Receptor Radionuclide Therapy (PRRT) Lutathera® Lutathera® • Phase II results in progressive midgut carcinoid showed Progression-Free Survival of more than 44 months compared to the reported 14.6 months of Novartis' Sandostatin® LAR • Phase II results in progressive midgut carcinoid showed Progression-Free Survival of more than 44 months compared to the reported 14.6 months of Novartis' Sandostatin® LAR • Lutathera® was shown to increase overall survival by between 3.5 and 6 years in comparison to current treatments, including chemotherapy. • Lutathera® was shown to increase overall survival by between 3.5 and 6 years in comparison to current treatments, including chemotherapy. • It was also shown to significantly improve quality of life • It was also shown to significantly improve quality of life ©2015 Hôpitaux Universitaires de Genève ©2015 Hôpitaux Universitaires de Genève PSMA ligand 68 Prostate-Specific Membrane Antigen Prostate-Specific Membrane Antigen • PSMA (Prostate Specific Membrane Antigen) is a membrane glycoprotein which is overexpressed on prostate cancers • PSMA expression increases with tumor aggressiveness, androgenindependence, metastatic disease, and disease recurrence. Ga labelled PSMA ligand • • • • Type II membrane bound glycoprotein Expressed in all forms of prostate tissue Over-expressed in carcinoma Also found in the neovasculature of most solid tumors • Ga-68 PSMA PET/CT Imaging identifies tumor cells expressing PSMA antigen with excellent sensitivity & specificity. ©2015 Hôpitaux Universitaires de Genève ©2016 Hôpitaux Universitaires de Genève 68 68 Ga labelled PSMA ligand 68 Ga(HBED-CC) 18 F-Fluorocholine Ga labelled PSMA ligand Glu-NH-CO-NH-Lys-(Ahx)[68Ga(HBED-CC)] Compared to 18F-Fluorocholine ©2016 Hôpitaux Universitaires de Genève Ga labelled PSMA ligand ©2016 Hôpitaux Universitaires de Genève 177Lu-labeled F-Fluorocholine PSMA-Targeted Radionuclide Therapy of Prostate Cancer PSMA-Targeted Radionuclide Therapy of Prostate Cancer Anti-PSMA Antibody ©2016 Hôpitaux Universitaires de Genève PSMA-Targeted Radionuclide Therapy of Prostate Cancer ©2016 Hôpitaux Universitaires de Genève 18 ©2016 Hôpitaux Universitaires de Genève PSMA-Targeted Radionuclide Therapy of Prostate Cancer Bone scan Ga(HBED-CC) ©2016 Hôpitaux Universitaires de Genève 68 99mTC 68 99mTC Bone scan 177Lu-labeled Anti-PSMA Antibody ©2016 Hôpitaux Universitaires de Genève PSMA-Targeted Radionuclide Therapy of Prostate Cancer ©2016 Hôpitaux Universitaires de Genève Future of theranostics Future of theranostics 18 18 F-Galacto-RGD (Integrin ∝Vß3 receptors) F-Galacto-RGD (Integrin ∝Vß3 receptors) 18 • Neoangiogenesis markers ( F-Galacto RGD) • The ∝Vß3 integrin is up-regulated during wound healing and cancer • Imaging with 18F-galacto-RGD PET has been used for antiangiogenic therapy planning and monitoring ∝ ∝ ©2016 Hôpitaux Universitaires de Genève ©2016 Hôpitaux Universitaires de Genève Future of theranostics Future of theranostics 18 68 F-Galacto-RGD (Integrin ∝Vß3 receptors) GA-Bombesin receptor antagonist LEENAARDS((award((2014 A theranostic approach towards targeted chemotherapy delivery by RGD-conjugated cytotoxic compounds • 68 • GRPr proteins are highly overexpressed in several human tumors, including prostate cancer Dr Anita Wolfer (CHUV), Pr. Elena Dubikovskaya (EPFL), Pr. Yann Seimbille (UniGE-HUG) ©2016 Hôpitaux Universitaires de Genève ©2016 Hôpitaux Universitaires de Genève Future of theranostics Evolution of medical imaging 68 Fluorescence imaging GA-Bombesin receptor antagonist • • • Ga-labeled Bombesin analog is a synthetic bombesin receptor antagonist, which targets gastrinreleasing peptide receptors (GRPr) 149Tb-DOTA-bombésine 161Tb-DOTA-bombésine 152Tb-DOTA-bombésine (beta+ emitter) ©2016 Hôpitaux Universitaires de Genève ©2015 Hôpitaux Universitaires de Genève Evolution of medical imaging Evolution of medical imaging Fluorescence imaging PET & Fluorescence imaging Synthesis of fluorescent-PET probes Pre-op PET/MR MRI PET Intra-op Fluorescent Neuroonkologisches Zentrum Clemenshospital GmbH Courtesy Prof. Van Dam UMCG (Nat. Med. 2011 17:1315-9) ©2015 Hôpitaux Universitaires de Genève ©2015 Hôpitaux Universitaires de Genève orb light in the visible spectral region epth penetration of light is limited to s, thereby only allowing the treatment al lesions. However, advances in optienabled the development of optical corporated into endoscopes, bronchoopes to allow for the delivery of light ities, thereby extending the scope of DT is being explored in the treatment luding skin,104 bladder,105 prostate,106 08 pancreatic,109 stomach,110 and head name a few. d in PDT can functionally be classified active (Fig. 3). Passive PDT nanofor photosensitizers and can be made dable material or non–polymer-based ceramic and metallic nanoparticles. particle carriers, made from PLGA or wn to provide an alternative solution to eir ability to encapsulate photosensirrier capacity. This is important as highly hydrophobic with inherent poor ulting in aggregation in solution that o be parentally administered. In addigy and composition of the polymer ized for the controlled degradation of ce release of the photosensitizer moleer-loaded nanoparticles have been r photoactivity than “free” photosensismaller nanoparticle carriers have a fect compared with larger carriers due of intracellular uptake via endocytosis, ease of photosensitizers within the extracellular environment. In addition, oparticle size, the larger the surface o, which increases the surface area rounding medium, thus resulting in er release rates.112 Nonbiodegradable loaded with photosensitizers and have nic polymeric nanoparticles, including ontrol over size, shape, and porosity; anges in pH and microbial attack. In easily functionalized for selective tarue, which will allow for the selective tosensitizers at the site of cancer while lation of photosensitizers in nontarget will therefore lower the concentration used to generate the same phototoxic sing the phototherapeutic index. Two yes can convert low-energy radiation missions, which can be directly transxygen to generate singlet oxygen. The tem is that it can be activated in deep Future of theranostics Future of theranostics Optical imaging Nanotheranostics Figure 2: WL, NIR and overlay images of catheter-based upper GI endoscopy from OE-33 (panel A, B and C), OE-19 (panel D, E and F) and control (panel G, H and I) groups. Upper GI endoscopy demonstrates significant elevated NIR signal at the tumor foci while in the control animals the signal is absent in this region. ©2015 Hôpitaux Universitaires de Genève ©2015 Hôpitaux Universitaires de Genève Future of theranostics Future of theranostics Nanotheranostics Nanotheranostics Nanooncology: The Future of Cancer Diagnosis and Therapy Nanooncology: The Future of Cancer Diagnosis and Therapy TABLE 2. Examples of Nanoparticles Used in Cancer Imaging IMAGING MODALITY DESCRIPTION OF NANOPARTICLE CANCER IMAGED BY THE NANOPARTICLE MRI Liver tumors (ie, hepatocellular carcinoma, liver metastases) Superparamagnetic iron oxide nanoparticles High-grade glioma Ultrasmall superparamagnetic iron oxide nanoparticle Preoperative staging of pancreatic cancer STAGE OF DEVELOPMENT/CLINICAL TRIAL NO. Currently used in clinical practice142 NCT00769093 NCT00920023 Pelvic lymph node metastases from prostate, NCT00147238 bladder, or other GU cancers CT Heavy metal (ie, gold, lanthanide, and tantalum) nanoparticles Solid organ tumors Preclinical stage of development143 SPECT TC-99m sulfur colloid nanoparticles Sentinel lymph node mapping in invasive breast cancer NCT00438477 124 PET Melanoma and malignant brain tumors NCT01266096 Optical Surface-enhanced Raman scattering nanoparticles I-labeled cRGDY silica nanoparticles Colorectal cancer Preclinical stage of development57 Photoacoustic Single-walled carbon nanotubes Solid organ tumors Preclinical stage of development144 FIGURE 2. The Criteria Nanoparticles Need to Fulfill to Be Effective Carriers for Chemotherapeutic Drugs. (A) The nanoparticle carrier must bind or contain the desired chemotherapeutic drug(s). (B) The nanoparticle-drug complex must remain stable in the serum to allow for the systemic delivery of the drug. (C) The nanoparticle-drug complex must be delivered only to tumor cells. (D) The nanoparticle must be able to release the drug once at the site of the tumor. (E) After drug delivery, the residual nanoparticle carrier must be safely degraded. MRI indicates magnetic resonance imaging; NCT, National Clinical Trial; GU, genitourinary; CT, computed tomography; SPECT, single-photon emission computed tomography; TC-99m, technetium-99m; PET, positron emission tomography; 124I, iodine-124; cRGDY, cyclic Arg-Gly-Asp-Tyr. FIGURE 2. The Criteria Nanoparticles Need to Fulfill to Be Effective Carriers for Chemotherapeutic Drugs. (A) The nanoparticle carrier must bind or contain the desired chemotherapeutic drug(s). (B) The nanoparticle-drug complex must remain stable in the serum to allow for the systemic delivery of the ©2015 Hôpitaux de Genève drug. (C) The nanoparticle-drug complexUniversitaires must be delivered only to tumor cells. (D) The nanoparticle must be able to release the drug once at the site ©2015 Hôpitaux Universitaires de Genève at the target site. Examples include gadolinium-containing monomers that assemble in cells via thiol-sensitive reduction of 1,2-aminothiol and 2-cyanobenzothiazole and probes with a motif sensitive to proteases such as furin and caspase-3, which are overexpressed in tumor cells.153 Although a lot of work is currently being undertaken preclinically to develop new nanoparticle agents, superparamagnetic iron oxide nanoparticles (SPIONs) are already being used in clinical practice for hepatic, cardiovascular, cellular, and lymphatic imaging. Iron oxide (magnetite, Fe3O4; maghemite, Fe2O3) nanoparticles become superparamagnetic at room temperature if their core diameter is 20 nm or less,154 which allows for susceptibility effects at micromolar concentrations that modify the T2 and T2* relaxation times of water protons for enhanced MRI contrast.155 SPIONs are also considered to have low toxicity in vivo as they are thought to be biodegradable, Nanotheranostics with the iron from the nanoparticles released upon CA CANCER J CLIN 2013;63:395–418 degradation into the normal plasma iron pool, where it can subsequently be incorporated into hemoglobin in erythrocytes or used for other metabolic processes.156,157 SPIONs have been used to characterize liver lesions since they are phagocytosed by cells of the RES. As normal liver parenchyma contains RES, they will accumulate SPIONs, resulting in a decrease in signal intensity on both T2-weighted and T1-weighted images. In contrast, most liver tumors do not contain RES and hence they will not uptake SPIONs, thereby improving contrast between the tumor (high signal) and the surrounding tissue (low signal).158 However, these signal characteristics are reversed when SPIONs are combined with ligands for active targeting.159 In these circumstances, SPIONs will now of the tumor. (E) After drug delivery, the residual nanoparticle carrier must be safely degraded. accumulate at the site of the tumor, resulting in a low signal compared with the background liver parenchyma; however, this relies on SPIONs avoiding the RES. To avoid the RES and improve colloidal stability and bioAlternatively, if a nonbiodegradable material is used, it primarily composed of amphipathic phospholipids encloscompatibility, SPIONs used for active targeting are usually must be proven to be safe at the doses needed or clear ing an interior aqueous space. They are able to contain coated with a polymer (ie, dextran, starch, or PEG).159 hydrophilic drugs, which can remain encapsulated in the from the subject. Ligands such as folate are then conjugated to SPIONs via central aqueous interior, and can be designed to adhere to 160,161 162 or PEG. their polymer coatings of either dextran The Nanoparticle-Drug Complex cell membranes and release drugs after endocytosis. Studies Folate has been used as a ligand since folate receptors are Nanoparticles that are used as carriers will either bind the have shown improved pharmacokinetics and pharmacodyexpressed in limited quantities on the apical surfaces of drug on their surface or entrap and encapsulate the drug to namics of drugs associated with liposomes.15 Over the normal epithelial cells but are generally overexpressed in protect it from degradation or denaturation. Nanoparticle years, liposomes have been surface modified with glycocarriers also offer the potential to codeliver 2 or more drugs lipids and/or polyethylene glycol (PEG) to prevent their cancerous tissues due to the vital role that folate plays in simultaneously for combination therapy. Newer rapid clearance from the circulation system by mononuclear cellular proliferation. Transferrin has also been covalently applications also include the delivery of noncytotoxic phagocytic cells from the reticuloendothelial system coupled to SPIONs163 as it will bind to the transferrin prodrugs that can be activated once they are delivered to (RES).16 The addition of PEG or other hydrophilic conjureceptor (also known as CD71), which is a type II cancer cells (ie, platinum [Pt]-based chemotherapeutic gates to the surface of all types of nanoparticle carriers, transmembrane glycoprotein that is overexpressed on the agents can be photoreduced using visible light from their Pt including liposomes, provides increased stability of the surfaces of proliferating cancer cells because of their Nanotheranostics [IV] prodrug state to the active Pt [II] anticancer drug once nanoparticle in biological fluids while also creating a increased iron requirements.164 SPIONs have also been delivered inside cells using nanoparticle carriers).14 There dynamic cloud of hydrophilic and neutral chains at the surNanooncology: The Future of Cancer Diagnosis and Therapy combined with peptide sequences such as arginylare several types of nanoparticle systems that have been face that reduces protein opsonization thereby enabling glycyl-aspartic acid (RGD),165 which can combine with used as carriers including liposomal, solid lipid, polymeric, nanoparticles to partially evade the macrophages of the living subjects. exciting results surface of Nevertheless, thesemesoporous integrins such as avb3 that are expressed oninthe silica, and inorganic nanoparticles. RES.2 This will increase nanoparticle half-life in blood, provide great promise for the future. proliferating endothelial cells such as those undergoing Liposomes are a biologically based nanoparticle system which combined with their ability to conjugate targeting Carbon nanotubes (CNTs) have been studied for photofrom optia self-assembling concentric lipid bilayer that is moieties, will allow them to preferentially accumulate at with angiogenesis.166 Initially, SPIONs conjugated acoustic andmonooptical imaging since they made have a strong cal absorbance in the high-near infrared region of the clonal antibodies were not considered practical for in vivo electromagnetic spectrum (ie, 700-1100 398 nm), where CA: A biologCancer Journal for Clinicians diagnostics due to the large particle size, which facilitated ical systems have a transparent window.207 This therefore makes them for near-infrared photothermal ablation thisidealhas their rapid clearance by the RES.159 However, therapy, with the temperature within tumors shown to proved not to be the case, with several studies showing increase in a light-dependent and CNT dose-dependent monoclonal antibody-conjugated SPIONs manner having (Fig.strong 8).196,208 In addition, CNTs are being investigated for against their use in gene and drug delivery, since they specificity for antigen-expressing tissues. Antibodies can readily cross biological barriers.207 Although the mechEGFR have been conjugated with SPIONsanism for by thewhich detecCNTs are internalized by cells is not fully 209 tion of colorectal, small cell lung, and esophageal squamous they can enter cells independently of cell understood, 167-169 and surface functional groups. Due to the capacity of cell carcinomas in experimental type models. Future of theranostics 408 CA: A Cancer Journal for Clinicians FIGURE 3. Nanoparticles in Photodynamic Therapy. Nanoparticles can deliver light-activatable chemicals, known as photosensitizer molecules, to tumor cells for use in photodynamic therapy. After the absorption of light, photosensitizer molecules can generate cytotoxic oxygen-based reactive species, which can subsequently cause cellular damage and cell FIGURE 3. Nanoparticles death via oxidative stress. in Photodynamic Therapy. Nanoparticles can deliver light-activatable chemicals, known as photosensitizer molecules, to tumor cells for useby in photodynamic the absorption of light,(750-1000 photosensitizer tissues light in thetherapy. tissue After transparent window molecules can generate cytotoxic oxygen-based reactive species, which can nm), which has deeper tissue depth penetration. Neverthesubsequently cause cellular damage and cell death via oxidative stress. their backbone to form supramolecular complexes, CNTs have been conjugated with chemotherapeutic drugs such as doxorubicin,210 methotrexate,211 paclitaxel,212 cisplatin,213 and gemcitabine.214 Several groups have also used CNTs for antitumor immunotherapy, whereby CNTs act as antigen-presenting carriers to improve weakly immunogenic tumor-based peptides/antigens to trigger a humeral 215 FIGURE 8. Theranostic Nanoparticles. Nanoparticles can be designed to immune response within the patient against the tumor. be simultaneously used 8. for Theranostic diagnosis and treatment. Using near-infrared FIGURE Nanoparticles. Nanoparticles can be designed Cationic CNTs have also been used as molecular transportlaser light, carbon nanotubes can be detected using photoacoustic imagers Using applicable to be simultaneously used for diagnosis and treatment. near- for siRNA therapeutics to silence ing in addition to causing tumor cell thermal ablation via photothermal therapy. geneusing expression in both cell culture and in xenograft infrared laser light, carbon nanotubes can be detected 216 micecell models. photoacoustic imag- ing in addition to causing tumor thermal targeting,ablation which via coencapsulates Gold nanoparticles that are used for optical and photothermalSPIONs therapy. for imaging and doxorubicin for controlled drug release.204 Other photoacoustic imaging can also be used in PTT. Following platforms include using SPION cores with a polycationic irradiation, the high electron density within the metallic surface coating (ie, poly(hexamethylene biguanide) or lattice of gold nanoparticles results in absorption of photon polyethyleneimine), which can bind siRNA through energy that, in turn, causes the lattice and hence the electrostatic interactions to form magnetic vectors that can nanoparticle to heat up. The small size and the rapid be rapidly drawn to and concentrated on the surface of the heating ability of gold nanoparticles are attractive for the target cells using the attractive force of an externally selective heating and killing of cancer cells with an applied magnetic field. This facilitates the uptake of the appropriate light source without the destruction of the magnetic vector into the cell endosomes, thereby improving surrounding normal and healthy tissue. Although NIRsiRNA transfection efficiency.205 SPIONs have also been mediated ablation has shown promise, its efficacy is radiolabeled with 64Cu (for combined imaging PET/MRI), limited by its depth of penetration, which only allows the conjugated with doxorubicin (for chemotherapy), and treatment of superficial tumors up to 2 to 3 cm. However, functionalized with RGD (for tumor vasculature RF ablation may be able to overcome this obstacle and targeting).206 As PET has excellent sensitivity but relatively allow the treatment of deep-seated tumors since gold poor spatial resolution, its combination with MRI will nanoparticles have been shown to interact with shortwave provide excellent spatial resolution and soft-tissue contrast RF waves to produce heat.217 Currently, RF treatments use that is superior to CT while also not delivering any of macroscopic electrodes to induce ablation, which is painful ionizing radiation associated with CT to the patient. and can cause damage to surrounding tissues. However, the Furthermore, the conjugation of doxorubicin onto use of microelectrodes could make this technique less PEGylated SPIONS was performed via pH-sensitive invasive and more effective provided that nanoparticles can hydrazone bonds, thereby allowing controlled drug release be concentrated above a threshold level at the site of the within the acidic microenvironment of tumors. Although tumor.100 Multimodal nanoparticles have also been created these and many other elegant nanoplatform designs have such as those that have a superparamagnetic core to allow been tested within cell culture, they have yet to be validated imaging with MRI, and a gold shell to allow PTT.218 less, the dye’s toxicity remains a major problem. Entrapping the dye in a nanoparticle carrier, which is biologically inert, can therefore reduce its toxicity to normal tissue while allowing PDT penetration in deeper tissues. Other groups are also exploring the use of exciting photosensitizers (energy acceptors) indirectly through fluorescence resonance energy transfer from photon absorbing dyes (energy donors).113 By physically encapsulating the dye and the photosensitizer in the same nanoparticle, this approach allows for the efficient transfer of energy between the dye, which acts Molecular as an intermediary, and the active imaging coencapsulated photosensitizer. For efficient photon excitation using this concept, the loading density of the energydonating photon absorption dye needs to be much higher than that of the energy-accepting photosensitizer. Hence, • silica The role of therapy inbionuclear medicine was one of its modified nanoparticles have been used as they are compatible, stable without releasing encapsulated hydroearliest applications phobic molecules, and suitable for PDT because their 114 412 CA: A Cancer Journal for Clinicians porous matrix is permeable to oxygen molecules. • As diagnostic increased exponentially, Active PDT our nanoparticles can themselvescapability generate reactive species the presence of a photosensitizer. we without moved from an emphasis on diagnosis to an This was first appreciated by Samia et al, who found that in emphasis on therapy addition to sensitizing photosensitizer molecules through a fluorescence resonance energy transfer, semiconductor QDs We generate are now approaching the ideal combination of could•themselves singlet oxygen alone via a triplet energy transfer without the need forcapability photosensitizers, in both the diagnostic and extraordinary albeit with a lower efficiency.115 Other groups have also therapeutic aspects ofanthe field investigated the ability of nanoparticles to play additional active intermediary role in the process of PDT, in addition to encapsulating photosensitizers and has targetingbecome a vital part of • Molecular imaging them to cancer cells.101 These nanoparticles will emit personalized medicine luminance of an appropriate wavelength to active ©2015 Hôpitaux Universitaires de Genève Conclusions VOLUME 63 _ NUMBER 6 _ NOVEMBER/DECEMBER 2013 ©2016 Hôpitaux Universitaires de Genève Future of theranostics Gold nanoparticles (GNPs) are readily synthesized structures that absorb light strongly to generate thermal energy which induces photothermal destruction of malignant tissue. ©2015 Hôpitaux Universitaires de Genève Conclusions Theranostics • The field of Theranostics is facilitating the shift from 'trial and error' medicine to personalized medicine • Theranostics helps identifying and selecting patients with a particular molecular phenotype indicative of positive response to treatment • The focus of theranostics lies on imaging biomarkers that can identify patients who will benefit from molecularly targeted therapy and are going to fail to respond to standard treatment. 403 ©2016 Hôpitaux Universitaires de Genève Conclusions Shift of paradigm « Moving from standard treatment of a disease to specific treatment of individual patients » ©2016 Hôpitaux Universitaires de Genève
