1951 : scintigraphe à balayage · 2016. 7. 8. · Radium-223 (Alpharadin) ©2016 Hôpitaux Universitaires de Genève Targeted Radionuclide Therapy • Phase II and phase III studies

New developments in Molecular Imaging

Osman Ratib, MD, PhD

Division of Nuclear Medicine and Molecular Imaging Department of Medical Imaging and Information Sciences University Hospital of Geneva

Applications in personalized medicine

«name» - «studyName»

Image 1

©2016 Hôpitaux Universitaires de Genève

Healthcare economicsShift of paradigm

Keynote Lecture Elias Zerhouni

International Society for Strategic Studies in Radiology

Transformation of medical paradigm

• Treat disease before it becomes symptomatic

• Four P • 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..) • Genomics, proteomics • Molecular Imaging (quantitative…) • Radiomics


Molecular ImagingEvolution of medical imaging


HISTORYEvolution of molecular imaging

Master Physique Médicale Lyon - Tomographie d’émission monophotonique - Irène Buvat – septembre 2011 - 26

•  Détecteur à scintillations

1951 : scintigraphe à balayage

spectromètre

cristal

imprimante collimateur

PM

asservissement mécanique

➩ scintigraphie 1958 Planar scintigram 2015 Hybrid PET-CT


Evolution of medical imaging

3D 4D

Multidetector scanners


Anatomy (CT) Metabolism (PET)

Molecular ImagingThe fifth dimension


Positron emission tomographyMolecular imaging


CT PET

PET vs CT

Pre treatment

Post treatment

Advantages


19941998

University of PittsburghMedical Center

Positron Emission TomographyInvention of hybrid PET-CT


Evolution of hybrid ImagingPET-CT scanners


PET-CT

T.M. 3487591

Staging in oncology

Better characterization of lesions


PET-CT

T.M. 3487591

Treatment monitoring

Follow up of treatment response

Staging

Staging

Post therapy


Mobile PET-CT


Hybrid imagingFrom PET-CT to PET-MR

CT PET

CT

PET-CT PET-MRI

PET-CT

PET

MRI

MRI

PET-MRI


Hybrid PET-MRIEvolution...

PET MRI

Separate



PET MRI

Separate ➟ Co-planar



PETMRI

Separate ➟ Co-planar ➟ Integrated


PET-MR hybrid imaging

World premier in hybrid imaging...


Hybrid whole-body PET-MRICo-planar registration of standard scanners

MRI PET

3m


Hybrid PET-MR

• Le PET-CT est un nouvel outil diagnostic pour la détection et le suivi des cancers

• 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

• 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

Clinical applications of hybrid PET-MR


Hybrid PET-MR

Head & Neck

PET$CT

Breast Prostate Sarcoma PelvisClinical applications of hybrid PET-MR


from diagnostic to Theranostic

A new paradigm in molecular imaging...


THERANOSTICS FOR PERSONALIZED MOLECULAR TARGETED THERAPYShift of paradigm

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”.

• 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

Personalized Medicine


HISTORYRadionuclide can cure cancer..

Published: May 12th 1921

© The New York Times


Targeted Radionuclide TherapyRadium-223 (Alpharadin)

1921 2015©2016 Hôpitaux Universitaires de Genève

Targeted Radionuclide Therapy

• 223Ra (Alpharadin) for treatment of bone metastases in patients with prostate cancer resistant to hormonotherapy

Radium-223 (Alpharadin)


Targeted Radionuclide TherapyRadium-223 (Alpharadin)


Targeted Radionuclide Therapy

• 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

Radium-223 (Alpharadin)

Nilsson et al. Lancet Oncol 2007


HISTORYTheranostics in nuclear medicine

EDITORIAL

Nothing new under the nuclear sun: towards 80 yearsof theranostics in nuclear medicine

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-levelbiological information in choosing the optimal therapy for thatindividual [1]. In the modern era of “personalized medicine”,theranostics is increasingly pursued in many branches ofmedicine in order to develop ever more effective treatmentregimens. There are now many studies and reviews dedicatedto theranostics, and even a journal bearing the name of thisprinciple, detailing many different concepts on how tocombine imaging and therapy using, for example, complexmolecules [2] or nanotechnology [3].

However, it is rarely realized by either clinicians or scientiststhat nuclear medicine has been employing theranostics fornearly 80 years now. In fact, the very foundations of targetedtherapy in nuclear medicine are those that are only now beingadopted by other medical disciplines under the designation“theranostics”.

The cornerstones of theranostics can be traced back to someof the most illustrious names among the founding fathers ofnuclear medicine. Soon after Chiewitz and de Hevesy [4]described the uptake of radioactive 32P in the bones of rats, Erfand J.H. Lawrence (brother of the physicist Ernest O. Lawrence,who built the first cyclotron) applied this same radioisotope topatients suffering from leukaemia and polycythaemia vera [5].Although this treatment certainly was not without success, it hassince been superseded by more effective nonradioactivechemotherapy. Shortly afterwards Pecher [6] discovered that89Sr accumulated in secondary bone tumours in animals, andsubsequently successfully used this radioisotope to treat patientswith painful bone metastases (unfortunately this work wasimmediately classified as secret and it took more than fivedecades for 89Sr to be registered as a therapeutic drug). Thesetwo studies are perhaps the earliest examples of diagnosticstudies leading to targeted therapy of cancer using radionuclides.

Around the same time the most prominent example of purenuclear theranostic medicine emerged: the diagnosis andtreatment of thyroid disorders using various isotopes of iodine.Hertz et al. in 1938 described the first study of thyroidalradioiodine uptake [7], and in 1942 Hertz and Roberts reportedon the treatment of the first patients with Graves’ disease withradioiodine [8]. A short time later Seidlin et al. treated the firstpatient with metastatic thyroid cancer with radioiodine [9] – atthe time this compoundwas so rare that radioiodinewas purifiedfrom the patient’s urine and readministered. During this therapy,additional metastases were identified using a Geiger counter andthe first rudimentary dosimetry was performed. It is of courseonly with the benefit of hindsight that we can now say that thiswas the first application of theranostics in targeted molecularmedicine through a specific molecular target, the sodium iodinesymporter, long before any of these concepts were firstdescribed as “theranostics”. Indeed, even today it is hard tothink of a single combination of targeted diagnostics and therapythat is more specific than radioiodine.

F. A. Verburg (*) :A. Heinzel : F. M. MottaghyDepartment of Nuclear Medicine, RWTH University HospitalAachen, Pauwelsstraße 30, 52074 Aachen, Germanye-mail: [email protected]

F. A. Verburg : F. M. MottaghyDepartment of Nuclear Medicine, Maastricht University MedicalCenter, Maastricht, The Netherlands

H. HänscheidDepartment of Nuclear Medicine, University of Wuerzburg,Wuerzburg, Germany

M. LusterDepartment of Nuclear Medicine, University HospitalsGiessen-Marburg, Marburg, Germany

L. GiovanellaDepartment of Nuclear Medicine, Oncology Institute of SouthernSwitzerland, Bellinzona, Switzerland

Eur J Nucl Med Mol Imaging (2014) 41:199–201DOI 10.1007/s00259-013-2609-2


Radionuclide therapy

• Well established since the 1950s • Beta and gamma rays • Self-targeting

131I Therapy for thyroid cancer


Radionuclide therapyChoice of carriers



• Monoclonal antibody • Labelled with Beta emitting isotope

131I/90Y labelled antibody for NHL therapy

CD20 Rituximab



Treatment of indolent lymphoma with 131I-tositumomab

British Journal of Cancer (2006) 94, 1770 – 1776 et J Nucl Med 2011; 52:896–900F. Buchegger et al

131I/90Y labelled antibody for NHL therapy


Radionuclide therapyRadio-immunotherapy 90Y-Ibritumomab (Zavalin®)

4

Anticorps monoclonal (ibritumomab), associé à un radioisotope (yttrium-90)

Cellule B (cellule cancéreuse)

antigène CD20

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.


Peptide Receptor Radiotherapy (PRRT)

• 177LU emits intermediate energy beta particles (133 KeV)

• Beneficial in small sized tumors (tissue range 2mm)

• Concomitant gamma emission enables imaging with gamma cameras

68GA/177LU DOTATOC in Neuroendocrine tumors (NET)

68GA177LU


68Ga Generators and labeling kitsPET tracers without a cyclotron



• 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.

• It was also shown to significantly improve quality of life

Peptide Receptor Radionuclide Therapy (PRRT)

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

• 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

Peptide Receptor Radionuclide Therapy (PRRT)

Lutathera®


PSMA ligand

• PSMA (Prostate Specific Membrane Antigen) is a membrane glycoprotein which is overexpressed on prostate cancers

• PSMA expression increases with tumor aggressiveness, androgen-independence, metastatic disease, and disease recurrence.

• Ga-68 PSMA PET/CT Imaging identifies tumor cells expressing PSMA antigen with excellent sensitivity & specificity.

Prostate-Specific Membrane Antigen


68Ga 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

Prostate-Specific Membrane Antigen



Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)] Compared to 18F-Fluorocholine

68Ga(HBED-CC)

18F-Fluorocholine



68Ga(HBED-CC)

18F-Fluorocholine




PSMA-Targeted Radionuclide Therapy of Prostate Cancer



177Lu-labeled Anti-PSMA Antibody99mTC Bone scan



177Lu-labeled Anti-PSMA Antibody99mTC Bone scan






Future of theranostics

• Neoangiogenesis markers (18F-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

∝

18F-Galacto-RGD (Integrin ∝Vß3 receptors)


Future of theranostics18F-Galacto-RGD (Integrin ∝Vß3 receptors)

∝



A theranostic approach towards targeted chemotherapy delivery by RGD-conjugated cytotoxic compounds

Dr Anita Wolfer (CHUV), Pr. Elena Dubikovskaya (EPFL), Pr. Yann Seimbille (UniGE-HUG)

LEENAARDS((award((2014

18F-Galacto-RGD (Integrin ∝Vß3 receptors)



• 68Ga-labeled Bombesin analog is a synthetic bombesin receptor antagonist, which targets gastrin-releasing peptide receptors (GRPr)

• GRPr proteins are highly overexpressed in several human tumors, including prostate cancer

68GA-Bombesin receptor antagonist



• 149Tb-DOTA-bombésine • 161Tb-DOTA-bombésine • 152Tb-DOTA-bombésine

(beta+ emitter)

68GA-Bombesin receptor antagonist


Evolution of medical imagingFluorescence imaging



Courtesy Prof. Van Dam UMCG

(Nat. Med. 2011 17:1315-9)

Fluorescence imaging



Synthesis of fluorescent-PET probes

PET & Fluorescence imaging

Neuroonkologisches Zentrum Clemenshospital GmbH

Pre-op PET/MR

Intra-op Fluorescent

PETMRI


Future of theranosticsOptical imaging

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.


Future of theranosticsNanotheranostics



at the target site. Examples include gadolinium-containingmonomers that assemble in cells via thiol-sensitive reductionof 1,2-aminothiol and 2-cyanobenzothiazole and probes witha 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 undertakenpreclinically to develop new nanoparticle agents, superpara-magnetic iron oxide nanoparticles (SPIONs) are alreadybeing used in clinical practice for hepatic, cardiovascular,cellular, and lymphatic imaging. Iron oxide (magnetite,Fe3O4; maghemite, Fe2O3) nanoparticles become super-paramagnetic at room temperature if their core diameter is20 nm or less,154 which allows for susceptibility effects atmicromolar concentrations that modify the T2 and T2*relaxation times of water protons for enhanced MRIcontrast.155 SPIONs are also considered to have lowtoxicity in vivo as they are thought to be biodegradable,with the iron from the nanoparticles released upondegradation into the normal plasma iron pool, where it cansubsequently be incorporated into hemoglobin in erythro-cytes or used for other metabolic processes.156,157 SPIONshave been used to characterize liver lesions since theyare phagocytosed by cells of the RES. As normal liverparenchyma contains RES, they will accumulate SPIONs,resulting in a decrease in signal intensity on bothT2-weighted and T1-weighted images. In contrast, mostliver tumors do not contain RES and hence they will notuptake SPIONs, thereby improving contrast between thetumor (high signal) and the surrounding tissue (lowsignal).158 However, these signal characteristics are reversedwhen SPIONs are combined with ligands for activetargeting.159 In these circumstances, SPIONs will now

accumulate at the site of the tumor, resulting in a lowsignal compared with the background liver parenchyma;however, this relies on SPIONs avoiding the RES. Toavoid the RES and improve colloidal stability and bio-compatibility, SPIONs used for active targeting are usuallycoated with a polymer (ie, dextran, starch, or PEG).159

Ligands such as folate are then conjugated to SPIONs viatheir polymer coatings of either dextran160,161 or PEG.162

Folate has been used as a ligand since folate receptors areexpressed in limited quantities on the apical surfaces ofnormal epithelial cells but are generally overexpressed incancerous tissues due to the vital role that folate plays incellular proliferation. Transferrin has also been covalentlycoupled to SPIONs163 as it will bind to the transferrinreceptor (also known as CD71), which is a type IItransmembrane glycoprotein that is overexpressed on thesurfaces of proliferating cancer cells because of theirincreased iron requirements.164 SPIONs have also beencombined with peptide sequences such as arginyl-glycyl-aspartic acid (RGD),165 which can combine withintegrins such as avb3 that are expressed on the surface ofproliferating endothelial cells such as those undergoingangiogenesis.166 Initially, SPIONs conjugated with mono-clonal antibodies were not considered practical for in vivodiagnostics due to the large particle size, which facilitatedtheir rapid clearance by the RES.159 However, this hasproved not to be the case, with several studies showingmonoclonal antibody-conjugated SPIONs having strongspecificity for antigen-expressing tissues. Antibodies againstEGFR have been conjugated with SPIONs for the detec-tion of colorectal, small cell lung, and esophageal squamouscell carcinomas in experimental models.167-169

TABLE 2. Examples of Nanoparticles Used in Cancer Imaging

IMAGING MODALITY DESCRIPTION OF NANOPARTICLE CANCER IMAGED BY THE NANOPARTICLESTAGE OF DEVELOPMENT/CLINICALTRIAL NO.

MRI Superparamagnetic iron oxide nanoparticles Liver tumors (ie, hepatocellular carcinoma,liver metastases)

Currently used in clinical practice142

High-grade glioma NCT00769093

Ultrasmall superparamagnetic iron oxide nanoparticle Preoperative staging of pancreatic cancer NCT00920023

Pelvic lymph node metastases from prostate,bladder, or other GU cancers

NCT00147238

CT Heavy metal (ie, gold, lanthanide, andtantalum) nanoparticles

Solid organ tumors Preclinical stage of development143

SPECT TC-99m sulfur colloid nanoparticles Sentinel lymph node mapping in invasivebreast cancer

NCT00438477

PET 124I-labeled cRGDY silica nanoparticles Melanoma and malignant brain tumors NCT01266096

Optical Surface-enhanced Raman scattering nanoparticles Colorectal cancer Preclinical stage of development57

Photoacoustic Single-walled carbon nanotubes Solid organ tumors Preclinical stage of development144

MRI indicates magnetic resonance imaging; NCT, National Clinical Trial; GU, genitourinary; CT, computed tomography; SPECT, single-photon emission computedtomography; TC-99m, technetium-99m; PET, positron emission tomography; 124I, iodine-124; cRGDY, cyclic Arg-Gly-Asp-Tyr.

Nanooncology: The Future of Cancer Diagnosis and Therapy

408 CA: A Cancer Journal for Clinicians



Alternatively, if a nonbiodegradable material is used, itmust be proven to be safe at the doses needed or clearfrom the subject.

The Nanoparticle-Drug ComplexNanoparticles that are used as carriers will either bind thedrug on their surface or entrap and encapsulate the drug toprotect it from degradation or denaturation. Nanoparticlecarriers also offer the potential to codeliver 2 or more drugssimultaneously for combination therapy. Newerapplications also include the delivery of noncytotoxicprodrugs that can be activated once they are delivered tocancer cells (ie, platinum [Pt]-based chemotherapeuticagents can be photoreduced using visible light from their Pt[IV] prodrug state to the active Pt [II] anticancer drug oncedelivered inside cells using nanoparticle carriers).14 Thereare several types of nanoparticle systems that have beenused as carriers including liposomal, solid lipid, polymeric,mesoporous silica, and inorganic nanoparticles.

Liposomes are a biologically based nanoparticle systemmade from a self-assembling concentric lipid bilayer that is

primarily composed of amphipathic phospholipids enclos-ing an interior aqueous space. They are able to containhydrophilic drugs, which can remain encapsulated in thecentral aqueous interior, and can be designed to adhere tocell membranes and release drugs after endocytosis. Studieshave shown improved pharmacokinetics and pharmacody-namics of drugs associated with liposomes.15 Over theyears, liposomes have been surface modified with glyco-lipids and/or polyethylene glycol (PEG) to prevent theirrapid clearance from the circulation system by mononuclearphagocytic cells from the reticuloendothelial system(RES).16 The addition of PEG or other hydrophilic conju-gates to the surface of all types of nanoparticle carriers,including liposomes, provides increased stability of thenanoparticle in biological fluids while also creating adynamic cloud of hydrophilic and neutral chains at the sur-face that reduces protein opsonization thereby enablingnanoparticles to partially evade the macrophages of theRES.2 This will increase nanoparticle half-life in blood,which combined with their ability to conjugate targetingmoieties, will allow them to preferentially accumulate at

FIGURE 2. The Criteria Nanoparticles Need to Fulfill to Be Effective Carriers for Chemotherapeutic Drugs. (A) The nanoparticle carrier must bind or con-tain the desired chemotherapeutic drug(s). (B) The nanoparticle-drug complex must remain stable in the serum to allow for the systemic delivery of thedrug. (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 siteof the tumor. (E) After drug delivery, the residual nanoparticle carrier must be safely degraded.



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.



photosensitizers absorb light in the visible spectral regionbelow 700 nm, the depth penetration of light is limited toonly a few millimeters, thereby only allowing the treatmentof relatively superficial lesions. However, advances in opti-cal engineering have enabled the development of opticalfibers that can be incorporated into endoscopes, broncho-scopes, and colonoscopes to allow for the delivery of lightto internal body cavities, thereby extending the scope ofPDT. Currently, PDT is being explored in the treatmentof several cancers including skin,104 bladder,105 prostate,106

lung,107 esophageal,108 pancreatic,109 stomach,110 and headand neck111 cancer to name a few.

Nanoparticles used in PDT can functionally be classifiedas either passive or active (Fig. 3). Passive PDT nano-particles are carriers for photosensitizers and can be madefrom either biodegradable material or non–polymer-basedmaterials such as ceramic and metallic nanoparticles.Biodegradable nanoparticle carriers, made from PLGA orPLA, have been shown to provide an alternative solution toliposomes due to their ability to encapsulate photosensi-tizers with high carrier capacity. This is important asphotosensitizers are highly hydrophobic with inherent poorwater solubility, resulting in aggregation in solution thatlimits their ability to be parentally administered. In addi-tion, the morphology and composition of the polymermatrix can be optimized for the controlled degradation ofthe polymer and hence release of the photosensitizer mole-cules. Photosensitizer-loaded nanoparticles have beenshown to have higher photoactivity than “free” photosensi-tizers. Furthermore, smaller nanoparticle carriers have agreater phototoxic effect compared with larger carriers dueto their higher rate of intracellular uptake via endocytosis,resulting in the release of photosensitizers within thecytosol and not the extracellular environment. In addition,the smaller the nanoparticle size, the larger the surfacearea-to-volume ratio, which increases the surface areaexposed to the surrounding medium, thus resulting inhigher photosensitizer release rates.112 Nonbiodegradablematerials can also be loaded with photosensitizers and haveadvantages over organic polymeric nanoparticles, includingstability; exquisite control over size, shape, and porosity;and immunity to changes in pH and microbial attack. Inaddition, they can be easily functionalized for selective tar-geting of tumor tissue, which will allow for the selectiveaccumulation of photosensitizers at the site of cancer whilereducing the accumulation of photosensitizers in nontargetnormal tissues. This will therefore lower the concentrationof photosensitizers used to generate the same phototoxiceffect, thereby increasing the phototherapeutic index. Twophoton absorption dyes can convert low-energy radiationinto higher-energy emissions, which can be directly trans-ferred to molecular oxygen to generate singlet oxygen. Theadvantage of this system is that it can be activated in deep

tissues by light in the tissue transparent window (750-1000nm), which has deeper tissue depth penetration. Neverthe-less, the dye’s toxicity remains a major problem. Entrappingthe dye in a nanoparticle carrier, which is biologically inert,can therefore reduce its toxicity to normal tissue whileallowing PDT penetration in deeper tissues. Other groupsare also exploring the use of exciting photosensitizers(energy acceptors) indirectly through fluorescence reso-nance energy transfer from photon absorbing dyes (energydonors).113 By physically encapsulating the dye and thephotosensitizer in the same nanoparticle, this approachallows for the efficient transfer of energy between thedye, which acts as an intermediary, and the activecoencapsulated photosensitizer. For efficient photon excita-tion using this concept, the loading density of the energy-donating photon absorption dye needs to be much higherthan that of the energy-accepting photosensitizer. Hence,modified silica nanoparticles have been used as they are bio-compatible, stable without releasing encapsulated hydro-phobic molecules, and suitable for PDT because theirporous matrix is permeable to oxygen molecules.114

Active PDT nanoparticles can themselves generatereactive species without the presence of a photosensitizer.This was first appreciated by Samia et al, who found that inaddition to sensitizing photosensitizer molecules through afluorescence resonance energy transfer, semiconductor QDscould themselves generate singlet oxygen alone via a tripletenergy transfer without the need for photosensitizers,albeit with a lower efficiency.115 Other groups have alsoinvestigated the ability of nanoparticles to play anadditional active intermediary role in the process of PDT,in addition to encapsulating photosensitizers and targetingthem to cancer cells.101 These nanoparticles will emitluminance of an appropriate wavelength to active

FIGURE 3. Nanoparticles in Photodynamic Therapy. Nanoparticles candeliver light-activatable chemicals, known as photosensitizer molecules,to tumor cells for use in photodynamic therapy. After the absorption oflight, photosensitizer molecules can generate cytotoxic oxygen-basedreactive species, which can subsequently cause cellular damage and celldeath via oxidative stress.

CA CANCER J CLIN 2013;63:395–418

VOLUME 63 _ NUMBER 6 _ NOVEMBER/DECEMBER 2013 403

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 death via oxidative stress. targeting, which coencapsulates SPIONs for imaging

and doxorubicin for controlled drug release.204 Otherplatforms include using SPION cores with a polycationicsurface coating (ie, poly(hexamethylene biguanide) orpolyethyleneimine), which can bind siRNA throughelectrostatic interactions to form magnetic vectors that canbe rapidly drawn to and concentrated on the surface of thetarget cells using the attractive force of an externallyapplied magnetic field. This facilitates the uptake of themagnetic vector into the cell endosomes, thereby improvingsiRNA transfection efficiency.205 SPIONs have also beenradiolabeled with 64Cu (for combined imaging PET/MRI),conjugated with doxorubicin (for chemotherapy), andfunctionalized with RGD (for tumor vasculaturetargeting).206 As PET has excellent sensitivity but relativelypoor spatial resolution, its combination with MRI willprovide excellent spatial resolution and soft-tissue contrastthat is superior to CT while also not delivering any ofionizing radiation associated with CT to the patient.Furthermore, the conjugation of doxorubicin ontoPEGylated SPIONS was performed via pH-sensitivehydrazone bonds, thereby allowing controlled drug releasewithin the acidic microenvironment of tumors. Althoughthese and many other elegant nanoplatform designs havebeen tested within cell culture, they have yet to be validated

in living subjects. Nevertheless, these exciting resultsprovide great promise for the future.

Carbon nanotubes (CNTs) have been studied for photo-acoustic and optical imaging since they have a strong opti-cal absorbance in the high-near infrared region of theelectromagnetic spectrum (ie, 700-1100 nm), where biolog-ical systems have a transparent window.207 This thereforemakes them ideal for near-infrared photothermal ablationtherapy, with the temperature within tumors shown toincrease in a light-dependent and CNT dose-dependentmanner (Fig. 8).196,208 In addition, CNTs are being inves-tigated for their use in gene and drug delivery, since theycan readily cross biological barriers.207 Although the mech-anism by which CNTs are internalized by cells is not fullyunderstood,209 they can enter cells independently of celltype and surface functional groups. Due to the capacity oftheir backbone to form supramolecular complexes, CNTshave been conjugated with chemotherapeutic drugs such asdoxorubicin,210 methotrexate,211 paclitaxel,212 cisplatin,213

and gemcitabine.214 Several groups have also used CNTsfor antitumor immunotherapy, whereby CNTs act as anti-gen-presenting carriers to improve weakly immunogenictumor-based peptides/antigens to trigger a humeralimmune response within the patient against the tumor.215

Cationic CNTs have also been used as molecular transport-ers applicable for siRNA therapeutics to silencegene expression in both cell culture and in xenograftmice models.216

Gold nanoparticles that are used for optical andphotoacoustic imaging can also be used in PTT. Followingirradiation, the high electron density within the metalliclattice of gold nanoparticles results in absorption of photonenergy that, in turn, causes the lattice and hence thenanoparticle to heat up. The small size and the rapidheating ability of gold nanoparticles are attractive for theselective heating and killing of cancer cells with anappropriate light source without the destruction of thesurrounding normal and healthy tissue. Although NIR-mediated ablation has shown promise, its efficacy islimited by its depth of penetration, which only allows thetreatment of superficial tumors up to 2 to 3 cm. However,RF ablation may be able to overcome this obstacle andallow the treatment of deep-seated tumors since goldnanoparticles have been shown to interact with shortwaveRF waves to produce heat.217 Currently, RF treatments usemacroscopic electrodes to induce ablation, which is painfuland can cause damage to surrounding tissues. However, theuse of microelectrodes could make this technique lessinvasive and more effective provided that nanoparticles canbe concentrated above a threshold level at the site of thetumor.100 Multimodal nanoparticles have also been createdsuch as those that have a superparamagnetic core to allowimaging with MRI, and a gold shell to allow PTT.218

FIGURE 8. Theranostic Nanoparticles. Nanoparticles can be designed tobe simultaneously used for diagnosis and treatment. Using near-infraredlaser light, carbon nanotubes can be detected using photoacoustic imag-ing in addition to causing tumor cell thermal ablation via photothermaltherapy.



FIGURE 8. Theranostic Nanoparticles. Nanoparticles can be designed to be simultaneously used for diagnosis and treatment. Using near-infrared laser light, carbon nanotubes can be detected using photoacoustic imaging in addition to causing tumor cell thermal ablation via photothermal therapy.



Gold nanoparticles (GNPs) are readily synthesized structures that absorb light strongly to generate thermal energy which induces photothermal destruction of malignant tissue.


Conclusions

• The role of therapy in nuclear medicine was one of its earliest applications

• As our diagnostic capability increased exponentially, we moved from an emphasis on diagnosis to an emphasis on therapy

• We are now approaching the ideal combination of extraordinary capability in both the diagnostic and therapeutic aspects of the field

• Molecular imaging has become a vital part of personalized medicine

Molecular imaging


Conclusions

• 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.

Theranostics


Conclusions

« Moving from standard treatment

of a disease to specific treatment

of individual patients »

Shift of paradigm

1951 : scintigraphe à balayage · 2016. 7. 8. · Radium-223 (Alpharadin) ©2016 Hôpitaux Universitaires de Genève Targeted Radionuclide Therapy • Phase II and phase III studies

Documents