Indrajit Roy

Sunil Krishnan

Andrei V Kabashin

Irina N Zavestovskaya

Paras N Prasad

Transforming Nuclear Medicine with Nanoradiopharmaceuticals

Keywords: nuclear medicine, nanomedicine, nanoradiopharmaceuticals, multimodality, theranostics, radiation therapy, ion-beam therapy, neutron capture therapy, laser ablation

Nuclear medicine is expected to make major advances in cancer diagnosis and therapy; tumor-targeted radiopharmaceuticals preferentially eradicate tumors, while causing minimal damage to healthy tissues. The current scope of nuclear medicine can be significantly expanded by integration with nanomedicine, which utilizes nanoparticles for cancer diagnosis and therapy by capitalizing on the increased surface area-to-volume ratio, the passive/active targeting ability and high loading capacity, the greater interaction cross-section with biological tissues, the rich surface properties of nanomaterials, the facile decoration of nanomaterials with a plethora of functionalities, and the potential for multiplexing several functionalities within one construct. This review provides a comprehensive coverage of nuclear nanomedicine using tumor-targeted nanoparticles for cancer radiation therapy with either pre-embedded radionuclides or non-radioactive materials which can be extrinsically triggered using various external nuclear particle sources to produce in-situ radioactivity. In addition, it describes the prospect of combining nuclear nanomedicine with other modalities to enable synergistically enhanced combination therapies. The review also discusses advances in the fabrication of radionuclides as well as describes laser ablation technologies for producing nanoradiopharmaceuticals, which combine the ease of production with exceptional purity and rapid biodegradability, along with additional imaging or therapeutic functionalities. From a practical standpoint, these attributes of nanoradiopharmaceuticals may provide distinct advantages in diagnostic/therapeutic sensitivity and specificity, imaging resolution, and scalability of turnkey platforms. Coupling image-guided targeted radiation therapy with the possibility of in-situ activation of nanomaterials as well as combining with other therapeutic modalities using a multifunctional nanoplatform could herald an era of exciting technological and therapeutic advances to radically transform the landscape of nuclear medicine. The review concludes with a discussion of current challenges and presents the authors' views on future opportunities to stimulate further research in this rewarding field of high societal impact.

Introduction

Continuing advances in nuclear technologies have led to the emergence of exciting drugs and radiopharmaceuticals, which demonstrate high efficiency in imaging and therapy of cancer and other diseases. In the traditional approach, radiopharmaceuticals accumulate in tumors and preferentially eradicate them by spontaneous radioactive emission, while causing minimal damage to healthy tissues. [START_REF]Handbook of Radiotherapy Physics: Theory and Practice[END_REF] In such cases, they are already prepared in a radioactive state and then administered to the patient. An emerging paradigm of nuclear medicine is irradiation of tumors with nuclear particles such as neutrons and protons to directly destroy the tumor by inducing in-situ radioactivity. [START_REF] Luderer | Advancements in Tumor Targeting Strategies for Boron Neutron Capture Therapy[END_REF][START_REF] Farr | New horizons in particle therapy systems[END_REF] Although radiotherapy using x-rays, γ-rays, or charged particles do not involve interaction with the atomic nucleus to produce radioactivity, they can also be included in a broader definition of nuclear medicine. Indeed, the interaction of radiation beams with high atomic number elements such as hafnium, gold, and gadolinium leads to increased localized ionizations around these elements, which can also be used in imaging and therapy. [START_REF] Farr | New horizons in particle therapy systems[END_REF] Thus, for this review, we define and cover nuclear medicine as a field of medicine, which employs particle radiation (α, β, neutrons, protons, etc) and electromagnetic waves such as x-rays and γ-rays from external sources (accelerator, reactor, etc.), as well as internal radioactivity generated by tumor-localizing radionuclides, for diagnosis and treatment. In particular, the imaging functionality implies the use of x-rays for large-view imaging of organs and tissues, while γ and β + (positron) emission from radionuclides can be used to precisely locate the distribution of radionuclides in the whole organism. On the other hand, the therapeutic functionality implies either the focusing of external radiation sources (e.g. high energy x-rays, ion beams) directly on tumors to cause cancer cell death, or the injection of internal therapeutic radionuclides (e.g. α, β -, auger electron emitters) through a direct catheter or via suitable carriers (e.g. peptides, antibodies) to deliver the radionuclide to the tumor and initiate radiation-induced DNA damage of actively proliferating cancer cells leading to their selective elimination. [START_REF] Volkert | Therapeutic Radiopharmaceuticals[END_REF] Methods of nuclear medicine have demonstrated spectacular progress over the last few decades and become one of the key tools for the diagnosis and treatment of tumors, with Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) being the main methods to diagnose tumors and metastases, [START_REF] Fass | Imaging and cancer: a review[END_REF] and radiation therapy (or radiotherapy) being employed for cancer treatment. [START_REF]Handbook of Radiotherapy Physics: Theory and Practice[END_REF][START_REF] Kwatra | Nanoparticles in radiation therapy: a summary of various approaches to enhance radiosensitization in cancer[END_REF] Until recently molecular delivery vehicles such as peptides, antibodies, and antibody fragments and their therapeutic payload had been primarily used to target radionuclides to the tumor. [START_REF] Peltek | Current outlook on radionuclide delivery systems: from design consideration to translation into clinics[END_REF][START_REF] Filippi | Theranostic approaches in nuclear medicine: current status and future prospects[END_REF] Despite significant progress being made in this field, the clinical adoption of such agents has been limited due to a lack of robust overall survival data and logistical/financial challenges. However, their application prospects have recently been re-energized by the appearance of promising radiopharmaceuticals, including radium-223 chloride (Alpharadin/Xofigo) for treatment of bone metastases from hormone-refractory prostate cancer, [START_REF] Den | Ra-223 Treatment for Bone Metastases in Castrate-Resistant Prostate Cancer: Practical Management Issues for Patient Selection[END_REF] and lutetium Lu-177 dotatate (Lutathera) for treatment of gastroenteropancreatic neuroendocrine tumors. [START_REF] Van Der Zwan | Salvage peptide receptor radionuclide therapy with [ 177 Lu-DOTA,Tyr 3]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours[END_REF] Overall, there are a series of problems and challenges which complicate the widespread application of radiopharmaceuticals based on molecular delivery vehicles in clinical practice. Such vehicles are relatively small (typically, less than 60-65 kDa) and can carry only a few linked radionuclides. [START_REF] Peltek | Current outlook on radionuclide delivery systems: from design consideration to translation into clinics[END_REF][START_REF] Filippi | Theranostic approaches in nuclear medicine: current status and future prospects[END_REF] Therefore, high concentrations of radionuclide-carrying molecules are required to achieve a substantial therapeutic outcome, but this can lead to severe side effects, taking into account relatively low efficiency of molecular targeting (typically, less than 10-12%). As another problem, the size of molecular targeting agents is within the renal glomerular filtration range (< 7-8 nm), which leads to immediate accumulation of radionuclides in the kidneys. Since the radionuclides are in a highly radioactive state at the time of infusion, they typically cause severe kidney damage, including interstitial nephritis or complete renal failure. [START_REF] Van Der Zwan | Salvage peptide receptor radionuclide therapy with [ 177 Lu-DOTA,Tyr 3]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours[END_REF] Other problems include altered biodistribution and pharmacodynamics profile upon radionuclide incorporation, potential immunogenic effects, inability to co-incorporate additional active agents for multiple biological effect, etc.

Paralleling recent advances in the development of radiopharmaceuticals, there has been a burgeoning interest in combining nuclear medicine with nanomedicine to produce nanopradioharmaceuticals.

Nanomedicine employs functional nanoscale objects (nanoparticles) in the diagnosis and therapy of cancer and other diseases. [START_REF] Nie | Nanotechnology applications in cancer[END_REF][START_REF] Farokhzad | Impact of nanotechnology on drug delivery[END_REF][START_REF] Prasad | Introduction to Nanomedicine and Nanobioengineering[END_REF][START_REF] Chen | Nanochemistry and Nanomedicine for Nanoparticle-based Diagnostics and Therapy[END_REF] Depending on physico-chemical properties of nanomaterials, they can be employed in different tasks of nuclear medicine. As an example, exhibiting strong absorption of x-rays, nanoparticles of nonradioactive elements with high atomic numbers (Au, Bi, etc.) can be used as contrast agents in radioimaging, [START_REF] Popovtzer | Targeted Gold Nanoparticles Enable Molecular CT Imaging of Cancer[END_REF] and as sensitizers of radiotherapies. [START_REF] Kwatra | Nanoparticles in radiation therapy: a summary of various approaches to enhance radiosensitization in cancer[END_REF] Additionally, a large surface area-tovolume ratio and high loading capacity enable nanoparticles as efficient transport vehicles of radionuclides in order to enhance image contrast and maximize therapeutic outcome. [START_REF] Petriev | Nuclear nanomedicine using Si nanoparticles as safe and effective carriers of 188Re radionuclide for cancer therapy[END_REF] Furthermore, many inorganic nanoparticles can provide additional imaging and therapeutic functionalities (optical, magnetic, etc.) or combine several functionalities within one construct, thus producing multi-modal theranostics. Several review articles already exist highlighting this rapidly developing research field; but they have considered only particular aspects of nuclear nanomedicine, such as the development of nanoparticle-based carriers for radionuclides, [START_REF] Hamoudeh | Radionuclides delivery systems for nuclear imaging and radiotherapy of cancer[END_REF][START_REF] Peltek | Current outlook on radionuclide delivery systems: from design consideration to translation into clinics[END_REF][START_REF] Smith | Nanomaterials for in Vivo Imaging[END_REF][START_REF] Polyak | Nanoparticles for SPECT and PET Imaging: Towards Personalized Medicine and Theranostics[END_REF][START_REF] Mitra | Nanocarriers for nuclear imaging and radiotherapy of cancer[END_REF] nanoparticles as contrast agents for Computed Tomography (CT) imaging, [START_REF] Lee | Nano-Sized CT Contrast Agents[END_REF] or nanotechnologies for radiotherapy. [START_REF] Song | Emerging Nanotechnology and Advanced Materials for Cancer Radiation Therap[END_REF] This review article is an attempt to describe a broder perspective of nuclear medicine, from nanoparticles as contrast agents and sensitizers of therapies using external radiation or particle beams, to nanomaterials as carriers of diagnostic and/or therapeutic radionuclides. Given the vastness of the already existing literature, we have selectively highlighted those we felt served as prototypes for conveying our central message. A special focus of this review is the use of external radiation modalities to activate non-radioactive materials that home on to tumors. This is particularly exciting because of the explosion of interest in nuclear particle therapy worldwide with installation of dozens of proton therapy centers and increasing numbers of carbon ion therapy centers for treatment of cancer with greater precision and efficacy. [START_REF] Luderer | Advancements in Tumor Targeting Strategies for Boron Neutron Capture Therapy[END_REF][START_REF] Farr | New horizons in particle therapy systems[END_REF] In addition, we highlight multimodal imaging as well as combination therapy for dramatically enhanced image guided therapy, labelled as theranostics, [START_REF] Prasad | Introduction to Nanomedicine and Nanobioengineering[END_REF] which may provide distinct advantages in diagnostic/therapeutic sensitivity and specificity, and imaging resolution. Another important feature of this review is describing coupling of image-guided precision radiotherapy options with the possibility of internal activation of nanomaterials. The entire scope of this review is provided in Figure 1. The review ends with a critical assessment of current challenges and our subjective view of future opportunities, with a vision to engage global multidisciplinary research efforts for rapidly advancing this emerging frontier.

Conventional radionuclide delivery systems

Currently, there are more than 80 known radionuclides used to produce radiopharmaceuticals in more than 75 nuclear reactors and 200 cyclotrons operated worldwide. Most of them are produced in research reactors. [START_REF]Application of Research Reactors[END_REF] Accelerators offer several advantages over nuclear reactors for medical isotope production. "Baby cyclotrons" with energy E ≤ 20 MeV are convenient for direct placement in medical centers, where they can readily be operated on site for production of ultrashort-lived radionuclides for PET diagnostics. [START_REF] Synowiecki | Production of novel diagnostic radionuclides in small medical cyclotrons[END_REF] Another emerging technology utilizes isotope generators having much smaller sizes. The use of generators permits multiple injections of nuclides in patients to produce long term cumulative effects. [START_REF] Zhernosekov | Processing of Generator-Produced 68Ga for Medical Application[END_REF] The requirements for a diagnostic or therapeutic radionuclide include both physical and biochemical characteristics. [START_REF] Troutner | Chemical and physical properties of radionuclides[END_REF][START_REF] Hoefnagel | Radionuclide therapy revisited[END_REF] The physical characteristics of the radionuclides include their half-life, decay mode, and the emission properties. [START_REF] Volkert | Therapeutic radionuclides: production and decay property considerations[END_REF] Biochemical characteristics include in vivo stability and toxicity of radionuclides. Additional biomedical factors to be considered are the type and size of the targeted cancer, density of the target and its heterogeneity.

The type of emission of a specific radiopharmaceutical gives its diagnostic and/or therapeutic character. [START_REF] Mitra | Nanocarriers for nuclear imaging and radiotherapy of cancer[END_REF] The major emissive species and their tissue penetration range are depicted in Figure 2. The emissions of α, β -and Auger electrons have variable energy, penetrating range, and linear energy transfer (LET). The α particles can cause irreversible damage to DNA within a core cross-section of 2-3 tracks, whereas the β -particles require nearly a hundred tracks to cause similar damage. [START_REF] Ward | DNA Damage Produced by Ionizing Radiation in Mammalian Cells: Identities, Mechanisms of Formation, and Reparability[END_REF][START_REF] Kassis | Therapeutic radionuclides: biophysical and radiobiologic principles[END_REF][START_REF] Yong | Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from 177Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts[END_REF] High-and low-energy (between 0.1 and 2.2 MeV) β -emitters are ideal radioisotopes for the treatment of small to large clusters of tumor cells. [START_REF] Kassis | Radiobiologic principles in radionuclide therapy[END_REF] The high tissue penetration range (1-10mm) of β -particles allows them to be used for relatively large tumors. The tissue penetration range of α emitters is about 50-100 μm; thus α emitters hold great promise as therapeutics for small cancer lesions and micrometastatic cancers. Auger electrons have an energy of <30 keV and very small subcellular path lengths of 2 nm-12 μm. [START_REF] Dash | Targeted radionuclide therapy--an overview[END_REF] Radionuclides that emit Auger electrons are usually effective only when their carrier molecules can penetrate the cell membrane to act intracellularly. [START_REF] Dash | Targeted radionuclide therapy--an overview[END_REF] The ultra-selective localized irradiation of DNA in the cell nucleus through Auger electron-carrying metabolic substrates offers an extremely effective strategy for inducing cell death and breaking resistance to more conventional types of chemo-radiation therapies. 35 of DNA repair mechanisms. [START_REF] Ward | DNA Damage Produced by Ionizing Radiation in Mammalian Cells: Identities, Mechanisms of Formation, and Reparability[END_REF][START_REF] Kassis | Therapeutic radionuclides: biophysical and radiobiologic principles[END_REF][START_REF] Yong | Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from 177Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts[END_REF][START_REF] Kassis | Radiobiologic principles in radionuclide therapy[END_REF][START_REF] Dash | Targeted radionuclide therapy--an overview[END_REF][START_REF] Rosenkranz | Delivery systems exploiting natural cell transport processes of macromolecules for intracellular targeting of Auger electron emitters[END_REF] A snapshot of the various biomedical applications of radionuclides in diagnostics, therapeutics and theranostics is provided in Figure 3. Gamma-emitters with an energy range between 100 and 370 keV and half-lives of a few minutes to several days are the ideal radionuclides for SPECT imaging. [START_REF] Coleman | Radionuclide Imaging in Cancer Medicine[END_REF] Ultrashort-lived high-energy β + emitters with half-lives from a few seconds to several hours and annihilation energy of 511 keV are used for PET imaging. 17 β -emitters account for the largest share of the global therapeutic radionuclide market. The main demand is for preparations based on iodine-131 ( 131 I), samarium-153 ( 153 Sm), rhenium-186 ( 186 Re), yttrium-90 ( 90 Y) and lutetium-177 ( 177 Lu). [START_REF]Proceedings of an International Symposium Organized by the IAEA[END_REF] In 90% of cases of targeted radionuclide therapy in the clinic, 131 I and 90 Y isotopes are used. [START_REF] Larson | Radioimmunotherapy of human tumours[END_REF] The 188 Re radionuclide is one of most promising generator-type therapeutic β -emitters, with the energy of β -emission of 1.96 MeV (25.6%) and 2.12 MeV (71.1%), and a half-life of 17 hours. [START_REF] Volkert | Therapeutic radiopharmaceuticals[END_REF] In clinical practice, radiopharmaceuticals based on 188 Re are used for the treatment of prostate and breast cancers. With the development of radiopharmaceuticals based on the generatortype 188 Re, a rapid expansion of its usage can be expected. Recently, several α-emitters ( 225 Ac, 213 Bi, 223 Ra, etc.) have emerged as promising radionuclides for targeted therapy. [START_REF] Seidl | Radioimmunotherapy with α-particle-emitting radionuclides[END_REF] For example, 223 Ra is used for the treatment of bone cancer (osteosarcoma).

Figure 3: Snapshot of various biomedical applications of radionuclides. Radionuclides for nuclear imaging/diagnostics. [START_REF] Mitra | Nanocarriers for nuclear imaging and radiotherapy of cancer[END_REF][START_REF] Lee | Nano-Sized CT Contrast Agents[END_REF][START_REF] Coleman | Radionuclide Imaging in Cancer Medicine[END_REF][START_REF] Velikyan | Prospective of 68 Ga Radionuclide Contribution to the Development of Imaging Agents for Infection and Inflammation[END_REF][START_REF] Tishchenko | Boneseeking radiopharmaceuticals based on phosphonic acids and 68Ga (review)[END_REF][START_REF] Rösch | Nuclear and Radiochemistry[END_REF][START_REF] Kuntic | Radioisotopes Used as Radiotracers for in Vitro and in Vivo Diagnostics[END_REF][45][START_REF] Yoshinaga | Generator-produced rubidium-82 positron emission tomography myocardial perfusion imaging-From basic aspects to clinical applications[END_REF] The grey color stands for the targeted radionuclides used for tumor imaging, while the blue color stands for the radionuclides used in PET and SPECT diagnostics, but are not used yet as nanotargeted radionuclides; yellow -in vitro diagnostics. Radionuclides for therapy: 47- 58 *Blue color stands for the radionuclides used in therapy with nanocarriers, grey color represents radionuclides used in traditional radiotherapy, and green color denotes brachytherapy radionuclides.

Radionuclides for theranostics either use radionuclides that exhibit diagnostic and therapeutic species (examples are highlighted by Orange color), or combine diagnostic and therapeutic radionuclides in one construct (some examples are highlighted by blue). [START_REF]Proceedings of an International Symposium Organized by the IAEA[END_REF][START_REF] Eds | Theranostics, Gallium-68 and Other Radionuclides -A Pathway to Personalized Diagnosis and Treatment[END_REF][START_REF] Oh | Effect of Peptide Receptor Radionuclide Therapy on Somatostatin Receptor Status and Glucose Metabolism in Neuroendocrine Tumors: Intraindividual Comparison of Ga-68 DOTANOC PET/CT and F-18 FDG PET/CT[END_REF][START_REF] Rösch | The Beginning and Development of the Theranostic Approach in Nuclear Medicine, as Exemplified by the Radionuclide Pair 86Y and 90[END_REF][START_REF] Yordanova | Theranostics in nuclear medicine practice[END_REF][START_REF] Müller | A Unique Matched Quadruplet of Terbium Radioisotopes for PET and SPECT and for α-and β--Radionuclide Therapy: An in Vivo Proof-of-Concept Study with a New Receptor-Targeted Folate Derivative[END_REF][START_REF] Argyrou | Rhenium-188 Production in Hospitals, by W-188/Re-188 Generator, for Easy Use in Radionuclide Therapy[END_REF][START_REF] Pillai | Rhenium-188: availability from the (188)W/(188)Re generator and status of current applications[END_REF] More than 80% of medical radionuclides produced are used for imaging-based diagnostics. SPECT with gamma detection and PET based on positron (β + ) detection are used to produce in vivo images. [START_REF] Man | Nuclear imaging of liposomal drug delivery systems: A critical review of radiolabelling methods and applications in nanomedicine[END_REF] PET offers high spatial resolution, sensitivity, and accurate signal quantification with the potential for providing accurate metabolic information about tumors. [START_REF] Hamoudeh | Radionuclides delivery systems for nuclear imaging and radiotherapy of cancer[END_REF] The image resolution and sensitivity advantages of PET are crucial, especially in the case of small lesions.

Radionuclides for therapy must cause significant damage to the tumor cell during radioactive decay or radiation exposure. The half-life should be longer than the time required for preparation of the radiopharmaceutical and its introduction and localization in the tumor, but not significantly larger than that. The ideal half-life range for isotopes used in radionuclide therapy is typically from 6 hours to 7 days. [START_REF] Qaim | Therapeutic radionuclides and nuclear data[END_REF] The isotopes must be produced with utmost chemical purity and be free of trace impurities of accompanying elements and metals and must be stable, both in short-term storage and in contact with biological fluids.

Theranostics achieved by using radionuclides that emit both diagnostic and therapeutic species mainly comprises of radionuclides that in addition to generating therapeutic  -or α particles, also emit γ radiation for imaging. Gamma radiation should be of low energy (the optimal value is 140 Kev) in order to ensure efficient operation of the gamma camera and minimize negative effects on normal tissues. [START_REF]Proceedings of an International Symposium Organized by the IAEA[END_REF] Alternatively, theranostics can be achieved by combining separate diagnostic and therapeutic radionuclides. The examples of promising theranostic radionucledes and theranostics pairs for possible personalized medicine are presented in Fig 3.

Conventionally, target specificity has been attained by tagging radionuclides with antibodies, antibody-fragments, smaller peptides, carbohydrates and other macromolecular biorecognition agents. Monoclonal antibodies (mAbs), many already approved by FDA, are used in diagnostics and therapy due to their distinct pharmacokinetics, such as highly specific binding to the antigens and easy clearance because of relatively small size. [START_REF] Jurcic | Monoclonal Antibody Therapy of Cancer[END_REF] The mAbs can specifically bind target antigens without further modifications. Significant progress has been made in the application of mAb in radioimmuno therapy (RIT). [START_REF] Jabbour | Monoclonal antibodies in acute lymphoblastic leukemia[END_REF][START_REF] Tsai | Aligning physics and physiology: Engineering antibodies for radionuclide delivery[END_REF][START_REF] Boldyrev | Electrochemical method for producing radionuclide Lu-177 with high specific activity[END_REF] However, antibodies due to their relatively large size have limited penetration in both normal tissues and solid tumors, [START_REF] Milenic | Antibody-targeted radiation cancer therapy[END_REF] and exhibit slow pharmacokinetics as a result of which a major part of the radionuclide decays before the radiopharmaceutical is localized at the intended tumor site. Moreover, the long circulatory half-life of a blood-borne radiolabeled antibody causes prolonged high background activity levels, leading to unwanted non-specific normal organ exposure to radiation. This limitation can be overcome by using antibody fragments. However, due to the ultrasmall size of antibody fragments, it is not always possible to perform effective labeling with radiometals, since the pharmacokinetics of such small fragments is affected by incorporation of chelators.

In contrast, peptides used for tumor targeting are small and show rapid diffusion into (target) tissues resulting in rapid pharmacokinetics, while their fast blood clearance could lead to high tumor-to-background ratios, shortly after administration of the radiopeptide. Another promising targeting approach uses scaffold proteins, which are much smaller and can offer better affinity, low immunogenicity, excellent solubility, and thermodynamic stability. [START_REF] Boersma | DARPins and other repeat protein scaffolds: advances in engineering and applications[END_REF][START_REF] Löfblom | Affibody molecules: Engineered proteins for therapeutic, diagnostic and biotechnological applications[END_REF] The use of aptamers, which are synthetic, single-stranded oligomers containing ribonucleotides (RNA aptamers) or deoxyribonucleotides (DNA aptamers), presents another promising targeting strategy because of their small size, stability, ease of production, nonimmunogenicity, etc. [START_REF] Lipi | in Vitro evolution of chemically-modified nucleic acid aptamers: Pros and cons, and comprehensive selection strategies[END_REF] The tumor accumulation of molecular radionuclides with poor pharmacokinetics can be substantially improved when combined with pre-targeted nanoparticles. Herein, nanoparticles modified with specific functionalities are initially administered in tumorbearing mice, and allowed to accumulate at tumor sites with high precision owing to their inherent target specificity. This is followed by treatment with radiolabelled complementary molecules having avidity to the pre-targeted nanoparticles, which thus home-in at the nanoparticle-infiltrated tumor sites.

Nanocarriers for radionuclides

Nanoparticles have revolutionized the field of medicine owing to several advantages over molecular drug carriers. [START_REF] Farokhzad | Impact of nanotechnology on drug delivery[END_REF][START_REF] Prasad | Introduction to Nanomedicine and Nanobioengineering[END_REF][START_REF] Chen | Nanochemistry and Nanomedicine for Nanoparticle-based Diagnostics and Therapy[END_REF] Their high surface-to-volume ratio, as well as well-defined porosity in some cases, allows high radionuclide loading and thus labelling. They can be synthesized with suitable physico-chemical parameters, including uniform size and shape, which ensures a good transport and pharmacokinetics in vivo. Rich surface chemistry of nanoparticles allows them to be properly functionalized (e.g., by polymers such as PEG) to avoid immediate recognition by the immune system as well as to attach targeting moiety to ensure their delivery inside tumor cells, or even within desired subcellular compartments.

Moreover, nanoparticle-based formulations show passive tumor-targeting as a result of the EPR effect. [START_REF] Prasad | Introduction to Nanomedicine and Nanobioengineering[END_REF][START_REF] Chen | Nanochemistry and Nanomedicine for Nanoparticle-based Diagnostics and Therapy[END_REF][START_REF] Maeda | Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review[END_REF] A biorecognition agent tagged with the nanoparticles provides active targeting to further enable their internalization inside tumor cells, as well as within desired subcellular compartments. [START_REF] Prasad | Introduction to Nanomedicine and Nanobioengineering[END_REF][START_REF] Chen | Nanochemistry and Nanomedicine for Nanoparticle-based Diagnostics and Therapy[END_REF] Finally, based on their intrinsic properties, certain nanoparticles can provide per se additional imaging (e.g., fluorescence, MRI, photoacoustic, etc.) or therapeutic (e.g., photothermal, magnetothermal, PDT, etc.) functionalities, which could be enabled in parallel with the nuclear medicine modality. [START_REF] Prasad | Introduction to Nanomedicine and Nanobioengineering[END_REF][START_REF] Chen | Nanochemistry and Nanomedicine for Nanoparticle-based Diagnostics and Therapy[END_REF] Nanoparticles for biomedical applications were originally developed as simple drug carriers for disease-directed delivery of large dosages of pharmaceuticals. Initially, nanoparticles were tagged with radionuclides for studying their pharmacokinetics, pharmacodynamics, biodistribution, and in vivo excretion using non-invasive imaging modalities such as planar gamma scintigraphy, SPECT, and PET. However, over the years, nanoparticulate-carriers of radionuclides have rapidly emerged as exciting radiopharmaceuticals with vastly expanded scope and applications, including targeted, image-guided therapy and theranostics. [START_REF] Smith | Nanomaterials for in Vivo Imaging[END_REF][START_REF] Polyak | Nanoparticles for SPECT and PET Imaging: Towards Personalized Medicine and Theranostics[END_REF][START_REF] Mitra | Nanocarriers for nuclear imaging and radiotherapy of cancer[END_REF][START_REF] Lee | Nano-Sized CT Contrast Agents[END_REF][START_REF] Song | Emerging Nanotechnology and Advanced Materials for Cancer Radiation Therap[END_REF][START_REF]Application of Research Reactors[END_REF] Radionuclides may either be a major constituent of the nanoparticle, or 'encapsulated' within the nanoparticles, or incorporated on their surface by direct conjugation or via chelation with a conjugated chelating agent. [START_REF] Goldenberg | Radiolabelled monoclonal antibodies in the treatment of metastatic cancer[END_REF][START_REF] Joncour | Seek & Destroy, use of targeting peptides for cancer detection and drug delivery[END_REF][START_REF] Lingasamy | Bi-specific tenascin-C and fibronectin targeted peptide for solid tumor delivery[END_REF] Nanoparticle-containing radionuclides can target tumors by both passive and active targeting approaches (Figure 4). Described below are only selected examples of nanoparticles used as radionuclide carriers with their distinct merits. Dendrimers are a special type of hyperbranched artificial polymers which can be prepared with exquisite size control. Albumins are the most extensively used protein-based nanoparticles in biomedical applications. We shall briefly discuss some of such nanocarriers from the perspective of development of nanoradiopharmaceuticals.

Liposomes are the earliest and most well-known carriers of active agents, owing to their structural resemblance to biological membranes. [START_REF] Pattni | New Developments in Liposomal Drug Delivery[END_REF] They have a hydrophilic interior and hydrophobic bi-layered membrane, which can host both hydrophilic and hydrophobic drugs.

They can incorporate radionuclides in their interior 'core', or in their membrane bilayer, or conjugated to their external surface, as depicted in Figure 5. Radionuclides are mainly incorporated within liposomes via complexation with chelators, such as dodecane tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-triacetic acid (NOTA), conjugated on the liposome surface. [START_REF] Phillips | Strategies for nonviral nanoparticle-based delivery of CRISPR/Cas9 therapeutics[END_REF] This surface chelation approach, despite yielding high loading (up to 90%), results in poor in vivo stability. The stability of chelated radionuclides can be enhanced, when they are either encapsulated within the hydrophilic core or entrapped in the lipophilic bilayer of liposomes. Lipophilic chelators such as BMEDA and HMPAO are useful in the bilayer-encapsulation approach. [START_REF] Kleynhans | Radiopharmaceutical enhancement by drug delivery systems: A review[END_REF] Simple radionuclide-containing liposomes have been used for tracking the biodistribution, pharmacokinetics, targeting, and compartmental modeling. SPECT/CT imaging have been used for studying the in vivo fate and targeting using liposomes labelled with 99m Tc, 111 In, 188 Re, etc. [START_REF] Belhaj-Tayeb | in Vitro and in Vivo study of 99mTc-MIBI encapsulated in PEG-liposomes: a promising radiotracer for tumour imaging[END_REF][START_REF] Carmo | m)Tc-Hexamethylpropyleneamine oxime pH-sensitive liposomes[END_REF][START_REF] Aiyer | The effect of internalizing human single chain antibody fragment on liposome targeting to epithelioid and sarcomatoid mesothelioma[END_REF][START_REF] Chen | Biodistribution, pharmacokinetics and imaging of (188)Re-BMEDA-labeled pegylated liposomes after intraperitoneal injection in a C26 colon carcinoma ascites mouse model[END_REF] PET imaging was demonstrated using liposomes labelled with [START_REF] Argyrou | Rhenium-188 Production in Hospitals, by W-188/Re-188 Generator, for Easy Use in Radionuclide Therapy[END_REF] Cu, 124 I, [START_REF] Peltek | Current outlook on radionuclide delivery systems: from design consideration to translation into clinics[END_REF] F, and [START_REF] Marik | Long-circulating liposomes radiolabeled with [18F]fluorodipalmitin ([18F]FDP)[END_REF] Zr. [START_REF] Petersen | 64Cu loaded liposomes as positron emission tomography imaging agents[END_REF][START_REF] Medina | Optimizing tumor targeting of the lipophilic EGFR-binding radiotracer SKI 243 using a liposomal nanoparticle delivery system[END_REF][START_REF] Marik | Long-circulating liposomes radiolabeled with [18F]fluorodipalmitin ([18F]FDP)[END_REF][START_REF] Abou | Zr-labeled paramagnetic octreotide-liposomes for PET-MR imaging of cancer[END_REF] In a recent demonstration, cyclic RGDfK conjugated liposomes, radiolabelled with III In, were used for targeted delivery and efficient in vivo SPECT imaging of αVβ3 integrin expressing human melanoma tumors (Figure 6). [START_REF] Liu | Evaluation of Nanotargeted 111 In-Cyclic RGDfK-Liposome in a Human Melanoma Xenotransplantation Model[END_REF] In yet another recent development, tumor-targeted delivery of an EGFR-tagged and 111 In-labelled liposomal formulation was found to be substantially enhanced using ultrasound-induced cavitation following co-delivery of microbubbles. 92 Adapted from Reference [91].

The  -emitting radionuclide 188 Re has been incorporated with PEGylated liposomes for radiotherapeutic applications. A recently concluded multicenter phase-0 low-radioactivity clinical trial of the 188 Re-liposome in patients with metastatic cancer found that favorable tumor accumulation and clinically acceptable pharmacokinetics, biodistribution, and dosimetry results could be achieved. [START_REF] Wang | A phase 0 study of the pharmacokinetics, biodistribution, and dosimetry of 188 Re-liposome in patients with metastatic tumors[END_REF] Solid lipid nanoparticles (SLNs), on the other hand, are mainly composed of lipids (e.g. triglycerides), which are solids at room temperature. [START_REF] Mu | Solid lipid nanocarriers in drug delivery: characterization and design[END_REF] Videira et al. demonstrated that SLNs labelled with 99m Tc can be used as efficient probes for lymphoscintigraphy in adult male

Wistar rats following delivery via the inhalation route. [START_REF] Videira | Lymphatic uptake of pulmonary delivered radiolabelled solid lipid nanoparticles[END_REF] In an example of active-targeted delivery using SLNs, Ucar et al. surface-modified paclitaxel loaded with a folate derivative and 99m Tc tricarbonyl complex. In vivo studies conducted on female Wistar albino rats revealed a higher uptake of the targeted SLNs in folate receptor positive organs using gamma scintigraphy. [START_REF] Ucar | Synthesis, characterization and radiolabeling of folic acid modified nanostructured lipid carriers as a contrast agent and drug delivery system[END_REF] Andreaozzi et al. showed that intravenous injection of [START_REF] Argyrou | Rhenium-188 Production in Hospitals, by W-188/Re-188 Generator, for Easy Use in Radionuclide Therapy[END_REF] Cu labelled SLNs in mice facilitates their biodistribution analysis using PET imaging. [START_REF] Andreaozzi | Novel method to label solid lipid nanoparticles with 64cu for positron emission tomography imaging[END_REF] Polymeric nanoparticles include nanoparticles of natural polymers (e.g. chitosan), synthetic polymers (e.g. PLGA, PLA, polycaprolactone), hyperbranched polymers (e.g dendrimers), polymeric micelles, etc. Such polymeric nanoparticles have also been labelled/loaded with radiopharmaceuticals for imaging and theranostic purposes. 'Hard' or 'inorganic' nanocarriers 'Hard' nanoparticles are mainly composed of inorganic components, which have some advantages over their organic counterparts. Specialized synthetic methods (e.g. hot-colloidal synthesis, laser-ablation) allow precise control of their physical parameters, such as size, shape, porosity, and crystallinity, which in turn facilitates their reproducible in vivo behavior, such as prolonged circulation, desirable biodistribution, targeted delivery, facile excretion, etc. 109,110 From the point of view of radionuclide delivery, their size characteristics make possible a time-delayed clearance to exclude the accumulation of radionuclides in kidneys at their early highly radioactive stage, which could have otherwise caused a series of renal damages. [START_REF] Farokhzad | Impact of nanotechnology on drug delivery[END_REF] Several such nanoparticles are known to have special physical properties at the nanoscale, such as plasmonic properties of noble metal nanoparticles allowing for tandem photothermal therapy, superparamagnetic property of iron-oxide nanoparticles as MRI contrast agents, etc. [110][111][112] Most of these nanoparticles are known to be non-immunogenic and biocompatible.

Gold nanoparticles, owing to their plasmonic properties, are used as probes for optical imaging, photoacoustic imaging, photothermal therapy, etc. [START_REF] Prasad | Introduction to Nanomedicine and Nanobioengineering[END_REF][START_REF] Chen | Nanochemistry and Nanomedicine for Nanoparticle-based Diagnostics and Therapy[END_REF] Combining radiopharmaceuticals with gold nanoparticles facilitates the fabrication of multifunctional and theranostic nanoparticles. [START_REF] Argyrou | Rhenium-188 Production in Hospitals, by W-188/Re-188 Generator, for Easy Use in Radionuclide Therapy[END_REF] Cu labelled gold nanoparticles have been used for dual optical and PET imaging in prostate cancer. 113 Gold nanoparticles labelled with 131 I have been used for targeted tumor SPECT/CT imaging and radionuclide therapy of MMP-2 overexpressing tumors, 114 and EGFR-expressing lung tumors. 115 177 Lu labelled gold nanoparticles, conjugated with the cyclic RGD peptide, were used to effectively target and suppress v3-integrin-positive C6 gliomas in athymic mice, with no discernible sign of systemic or organ toxicity. 116 Magnetic nanoparticles have magnetic properties that make them attractive probes for magnetic resonance imaging (MRI), magnetic hyperthermia therapy (MHT), magnetic targeting, etc. The core size and shell compositions of radiolabelled core-shell nanoparticles containing magnetite (Fe3O4) or cobalt ferrite (CoFe2O4) nanocores hybridized with polymeric shells were found to dictate their radiolabeling ability and in vivo fate. 118 Magnetic melanin nanoparticles (MMNs) labelled with [START_REF] Argyrou | Rhenium-188 Production in Hospitals, by W-188/Re-188 Generator, for Easy Use in Radionuclide Therapy[END_REF] Cu were developed as a multimodal, versatile, biomimetic theranostic system for combined PET, photoacoustic (PA) and MR imaging in vivo in mouse bearing U87MG tumors [Figure 8], along with image-guided cancer photothermal therapy. 119 Carbon-based nanoparticles such as single-wall carbon nanotubes (CNTs) radiolabelled with 125 I were used for bio distribution studies in mice using SPECT imaging. 121 In an early report of CNTs for radiotherapy, ultrashort carbon nanotubes (US-tubes, length 20-50 nm) were loaded with the α-emitting radionuclide, 211 At, as a mixed halogen ( 211 AtCl@US-tube) for targeted radiotherapy. 122 Silica-based nanoparticles, have been extensively used for drug delivery studies. We synthesized 124 I labelled-ormosil nanoparticles (diameter 20-25 nm), conjugated with a near infra-red (NIR) fluorophore, for biodistribution, clearance and toxicity analysis in vivo.

Radioactivity counting from harvested organs, revealed higher nanoparticle accumulation in liver, spleen and stomach, than in kidney, heart and lungs, following their intravenous injection in healthy mice, with no indication of toxic side effects. 125 Upconversion nanophosphors (UCNPs) are inorganic crystalline matrices such as NaYF4, doped with small amounts of specific rare-earth ions that allows the multiphoton nonlinear optical phenomenon of energy upconversion, whereby absorption of lower energy (higher wavelength) radiation leads to higher energy (shorter wavelength) emission. [START_REF] Prasad | Introduction to Nanomedicine and Nanobioengineering[END_REF]129 UCNPs not only have emerged as attractive optical imaging probes spanning the visible and NIR regions, but also provide a platform for co-incorporation of additional probes, such as radionuclides, for multimodal image-guided therapy applications. (e.g. Hf, Bi, Gd, etc.) have been found to efficiently absorb x-rays and subsequently emit lowenergy species such as Auger electrons, thereby, escalating the local radiation dose to produce localized therapy. [START_REF] Kwatra | Nanoparticles in radiation therapy: a summary of various approaches to enhance radiosensitization in cancer[END_REF]132 In addition, nanoparticle can enhance nuclear particle irradiation therapies using charged particles (ion beam), as well as neutrons. [START_REF] Luderer | Advancements in Tumor Targeting Strategies for Boron Neutron Capture Therapy[END_REF][START_REF] Farr | New horizons in particle therapy systems[END_REF] These nanoparticles, after being localized at target sites through carefully-crafted delivery methods in vivo, locally escalate the dosage of externally applied radiation and enhance site-specific damage. Such localized radiation dose-escalation promises to treat deep-seated lesions, with minimal collateral damage. Even though such therapies do not involve interaction with nuclear particles, we include these in this review for reasons already described in the introduction.

X-ray radiosensitization:

Radiation therapy (RT) involving externally applied x-rays is routinely used in clinics for the treatment of cancer and some other diseases. Since X-rays have unlimited penetration through soft-tissues, as a result of which a single beam will irradiate all tissues (normal or diseased) in its path, a series of low-intensity beams from various angles are converged on the target site for achieving better target specificity. A recent development in this area involves in situ generation of cytotoxic photoelectrons and/or Auger electrons upon sensitizing non-radioactive nanoparticles (radiosensitizers) with x-rays, which leads to higher localized dose-escalation and reduced requirement of administered dose. [START_REF] Kwatra | Nanoparticles in radiation therapy: a summary of various approaches to enhance radiosensitization in cancer[END_REF]132 Radiosensitizers or radiation enhancers consist of primarily non-radioactive high atomic number (high Z) elements (metals), which have high x-ray absorption cross-section. 132 Gold nanoparticles are potent radiosensitizers owing to their high photoelectric absorption coefficient, along with optical properties for facilitating additional modalities. The

Ion beam particle therapy

Another significant development is the use of charged particles, such as protons, ions, etc. as irradiation sources. Unlike x-ray photons, which are uncharged, charged particles are characterized by a 'Bragg Peak', whereby the maximum radiation dose (peak) occurs at a particular depth which relies on the incident beam energy. Thus, by tuning the beam energy, the tissue depth of maximum dose can be made to coincide with the tumor volume, with reduced effect on the skin and normal tissues. High-Z metal nanoparticles can absorb ion beams and locally generate secondary electrons (from small angle scattering of outer electrons), and x-rays, leading to further dose enhancement. Therefore, ion beam therapy of solid tumor pre-loaded with nanoparticles benefits from the dual effects of (a) maximum dose deposition at the tumor volume ('Bragg Peak'), and (b) localized dose enhancement by nanoparticle-ion beam interaction. proton therapy) application. The nanoparticles were targeted to folate-positive C6 brain cancer cells in vitro. Following proton beam irradiation, the highest radiosensitization enhancement factor was observed for the dual-therapeutic nanoparticles, as compared to other controls (paclitaxel only, SPION only). This data shows the possibility of combining other therapies with proton therapy using a single nanoparticle system. 148

In addition to experimental evidence, a number of simulation studies were also done to investigate the radiosensitization of proton beams using metallic nanoparticles. Both the  particles and the lithium nuclei produce closely spaced ionizations in the immediate vicinity of the reaction, with a range of 5-9 µm, which is approximately the diameter of the target cell. The lethality of the capture reaction is limited to 10 B-infiltrated cells. Therefore, for effective NCT, it is critical to deliver the 10 B-containing probe inside the target cells, prior to irradiation with neutron beam (Figure 10A). 156 On the other hand, gamma rays, internal conversion and Auger electrons are products of the 157 Gd (n,γ) 158 Gd capture reaction: 157 157 Gd + nth (0.025eV) → [ 158 Gd]* → 158 Gd + γ + 7.94 MeV.

Here, the effective path length of the ionizing radiations is even shorter (in the range of 5-40 nm). Therefore, for effective NCT, the 157 Gd-containing probe is needed to be delivered not only inside the target cells, but also within sub-cellular organelles such as the mitochondria, or even better inside DNA strands of such organelles (Figure 10B). 156 Boron-containing nanocarriers usually have long circulation time in vivo, which leads to high tumor accumulation. Unfortunately, prolonged circulation also leads to high accumulation in non-target organs, such as liver and spleen, which poses a major drawback.

Using smaller boron-containing nanoparticles with lesser circulation time, the uptake in nontarget organs can be avoided. Yet, in such cases, the tumor accumulation can be enhanced using a pre-targeting approach. In one example, Feiner et al. have pre-targeted HER-2 positive tumors using targeting antibody Trastuzumab, modified with trans-cyclooctane (TCO). This was followed up by administration of tetrazine-functionalized smaller boron-containing carbon nanodots, which homed-in at the tumor sites with high precision owing to the specific TCO-tatrazine interaction, while avoiding off-target accumulation [10.1039/d0tb01880e].

As mentioned previously, the use of integrated nanoplatforms facilitate multimodal imaging, combination therapy, theranostics, etc. were injected with the nanoparticles, followed by irradiation with average neutron fluence of 1.8 × 10 12 n/cm 2 . A substantial reduction in the tumor burden was observed in the nanoparticle-injected animals, as compared to non-treated animals. The tumor-regression results were supported by histopathological analysis on tumor slices post-mortem. 163 Beyond boron and gadolinium, some other elements have shown potential in NCT, although their biological activity is yet to be reported. The non-radioactive Samarium-152 ( 152 Sm), doped in boron nitride nanotubes (BNNTs), was shown to be activated by thermal neutrons to generate the radioactive, beta-emitting 153 Sm. 164 We have reported that 152 Smenriched samarium oxide nanoparticles (NPs), synthesized by laser ablation described below, could be converted into a highly efficient therapeutic  -emitter ( 153 Sm) for nuclear therapy under neutron beam irradiation. 165

Recent approaches and concepts

Examples of some recently emerging approaches and concepts that can bring substantial advancements in nuclear nanomedicine are listed below.

Laser ablation for synthesis of nanomaterials for nuclear nanomedicine

For efficient in vivo pharmacokinetics, biodistribution, target specificity, clearance, biocompatibility, and reproducibility, nanoparticles should ideally have uniform size, shape, surface properties, and be devoid of unwanted contaminants. Conventional chemical synthesis cannot satisfy many of these requirements as it involves complex reactants with strictly defined quasi-equilibrium system parameters, as well as toxic by-products. [166][167] Pulsed laser ablation in liquids, which profits from a natural generation of nanoclusters under the action of laser radiation on a target, followed by their release into the liquid to form nanoparticle solutions, is free of these limitations opening up access to the synthesis of a variety of appealing nanomaterials for nuclear nanomedicine. 168,169 Laser ablation can be performed under ultrapure conditions (deionized water, etc.) to exclude any toxic contamination and be adapted for the fabrication of virtually any type of nanomaterial.

including isotope-enriched nanoparticles such as 10 B for NCT, whose chemical synthesis is unacceptably expensive due to a high cost of starting materials. Furthermore, dealing with non-equilibrium nanosynthesis conditions, laser ablation gives access to formation of complex alloys and core-shells, allowing a combination of different functionalities (nuclear, plasmonic, magnetic, etc.) in one construct. This approach is particularly efficient in the case of ultrashort laser ablation, [168][169][170] which requires a very small pulse energy to ablate a material unity and thus can form nearly monodispersed nanoparticles. This approach can be easily scaled up using multi-beam laser systems, which allow one to synthesize nanoparticles with a rate of 4 gh -1 and higher. 171,172 Furthermore, if the productivity exceeds a breakeven value of 550 mg•hour -1 , laser-based synthesis becomes more economical than traditional chemical synthesis routes 172 , which promises the less costly synthesis of many important materials for nuclear nanomedicine.

Profiting from the flexibility and cleanness of laser-ablative synthesis, a variety of nanomaterials having a great potential for nuclear medicine have been fabricated, including single element Si, 170 Au, 168,169,173 Pt, 174 Bi nanoparticles, 175 high Z-elements-containing nanostructures of gadolinium oxide, 176 tantalum oxide , 177 hafnium oxide, 178 yttrium oxide, 179 samarium oxide, 165 etc., complex alloys/core-shells, including AuFe, 180 PtAu, 181 BiAu, 182 Au-Si core shells, 183 or Gd5(Si1-xGex)4 nanocomposites. 184 Depending on an intended application, these nanomaterials could be employed as sensitizers of therapies, contrast agents in imaging or carriers of radionuclides. In addition, they can be used as therapy agents after their radiative activation, as it was proposed in our recent study. Here, laser-synthesized 152 Smenriched samarium oxide nanoparticles could be converted into a highly efficient therapeutic 153 Sm beta-emitter for nuclear therapy under neutron beam irradiation. 165 Several studies have already explored the use of laser-synthesised nanomaterials in nuclear medicine tasks. Torrisi et al. explored laser-produced Au nanoparticles as x-ray contrast agents for diagnostic imaging and confirmed their efficiency and safety in the treatment of breast-calcified tumors. 185 We demonstrated the possibility of fast (less than 30 minutes) conjugation of PEG-coated Si nanostructures with radioactive 188 Re, which is substantially shorter than the 188 Re half-life of 17 hours. [START_REF] Petriev | Nuclear nanomedicine using Si nanoparticles as safe and effective carriers of 188Re radionuclide for cancer therapy[END_REF] Upon intravenous administration in a small animal model, the conjugates circulated freely in the blood stream to reach several organs, with high accumulation in target tumors. The observed biodistribution was dramatically different from that of a 188 Re salt, mostly accumulates in the thyroid gland.

The nanoparticle-based delivery also ensured excellent retention of 188 Re in the tumor, again in contrast to the salt, thus maximizing the therapeutic effect. Ultimately, the radionuclide nanocarrier exhibited complete time-delayed bioelimination. Tests of rat survival showed excellent therapeutic effect, with 72% of treated rats surviving, while none of the untreated (control) animals survived (Figure 12). [START_REF] Petriev | Nuclear nanomedicine using Si nanoparticles as safe and effective carriers of 188Re radionuclide for cancer therapy[END_REF] In a separate work, we studied conjugation of Si nanoparticles with radioactive [START_REF] Jurcic | Monoclonal Antibody Therapy of Cancer[END_REF] Ga for PRT imaging. Adapted from reference [16]. Printed with permission from 'Springer Nature', under 'Creative Commons Attribution 4.0 International License'.

Other nuclear and combination therapies:

Recent evidence suggests that radiation can be contextually linked not only to adaptive immune system activation, but also to innate immune system activation as well. 189 This is postulated to be the driver for high linear energy transfer radiation leading to more immune activation with the putative link being the formation of micronuclei during mitosis of cells with unrepaired DNA damage, and their defective nuclear laminar envelopes allowing access to cytosolic oligonucleotide sensor proteins. 190,191 In terms of nanoparticles that can trigger such a response, a number of approaches have been advanced in recent years. 192 An abstract from the Nanobiotix group reports that patients with soft tissue sarcomas treated with hafnium oxide nanoparticles (NBTRX3) and radiation, have increased expression levels of cytokines, interleukins and immune checkpoints, and of several T cell lymphocyte activation markers compared to those treated with radiation alone. 193 In a preclinical analysis of colorectal cancer cells treated with hafnium oxide nanoparticles and radiation, there was greater cell death, DNA double strand breaks, micronuclei formation and cGAS-STING pathway activation, than when cells were treated with radiotherapy alone. 194 Recently, the group demonstrated abscopal therapeutic effect in the same colorectal cancer mouse model using combination effect of NBTRX3 and radiation therapy (Figure 13). 195 The group postulates that this immune activation could synergize with immunotherapy for even greater tumor eradication efficacy not just at the irradiated site but also at distant sites of metastatic disease. 198,199 In one early demonstration of CRET, Dothager et al. combined excreted from the body with the urine. On the other hand, for radiation-or particle beam-activated nanoparticles, the size may not be so important and can be selected depending on the clearance and toxicity prospects of each nanomaterial (for example, it can be selected to be within the glomerular filtration range).

C. Dosimetry: Accurate dosimetry during diagnostic use helps with treatment planning and during therapeutic use helps with prediction of biological and clinical outcomes.

By using isotope pairs or similar isotopes for imaging and therapy (e.g. 123 I and 131 I), one can eliminate the uncertainty that arises from using a surrogate (say 99m Tc-labeled macroalbumin aggregates for glass/resin 90 Y microspheres). Use of greater sensitivity techniques (say, PET over SPECT) also improves diagnostic accuracy. Notably, however, most of the dosimetry information is currently based on a whole-organ level rather than at a microscopic level. The latter may be especially critical for nanoradiopharmaceuticals because of their greater likelihood of achieving nonhomogeneous dose distributions within tumors. It is worthwhile to document the heterogeneity and use it as an input parameter in Monte Carlo models. Furthermore, radiobiological models need to be fitted to actual clinical data so that future treatment planning based on these models is accurate.

D. Decay product selection: Whenever radioisotopes are used in clinical practice, there is little ability to alter the decay products and/or kinetics; these follow first principles of physics and chemistry. However, there may be an opportunity to modulate what the target structure (the tumor) or non-target tissue (adjacent normal tissue) sees. For instance, core-shell nanoparticles with a core comprised of a radiopharmaceutical and a shell that selectively blocks a specific component of the emission spectrum may have clinical utility. For example, gadolinium NCT could be enhanced by reducing the deep penetrance of gamma emissions that cause normal tissue dose accumulation. In another incarnation, the Cerenkov radiation from a radiopharmaceutical in the core of a nanoparticle can be coupled to a photosensitizer in the shell of the nanoparticle to increase the yield of oxygen free radicals and thereby augment anti-tumor activity.

This approach not only exploits an otherwise stray radiation emission from the radiopharmaceutical but also confines the additive/synergistic and cumulative effect to the irradiation zone.

E. Stability: Whenever radiopharmaceuticals are coupled to dyes or nanoparticles via chelating agents, there is always a possibility that they may be dislodged from the chelating agent in biological tissues. This challenge persists with nanoradiopharmaceutical formulations, unless the radiopharmaceutical is entrapped within a core-shell nanostructure or there is no chelating agent used (say, with endohedral metallofullerenes). Otherwise, one still has to grapple with the known toxicity of unbound metal ions like Gd 3+ . Strategies to address this, somewhat beyond the scope of this review, include use of deferiprone, deferoxamine, deferasirox that chelate free Gd 3+ ions or N-acetylcysteine to reduce oxidative stress caused by these ions in end organs like the brain and kidney. However, invoking mitigation strategies requires recognition of high levels of free unbound metal ions (in serum or urine), which is not the current practice.

F. In-situ generation of radioactivity: A suitable nanoformulation should contain the maximum concentration of the isotope harboring the highest particle (e.g. neutron)

capture cross-section. This can be ensured by isotopic enrichment of the nanoparticles. An example is boron where the 10 B isotope (only 20% in natural abundance) has the higher neutron capture cross-section, as compared to the more abundant [START_REF] Nie | Nanotechnology applications in cancer[END_REF] B and thus 10 B isotopically enriched nanoparticles will perform the NCT at a relatively lower dosage of radiation. However, the cost of such selective isotope enrichment may be very high. In such a case, a method like laser ablation, as discussed in this review, is of great value, as it requires a relatively small amount of the sample to fabricate nanoparticles of virtually any promising material. therapy. An unanswered question is whether to introduce spatial and temporal coupling of any two treatment paradigms or to decouple and administer sequentially, concurrently or contemporaneously. Decoupling offers more flexibility of control on dose, duration, sequencing and location of action. However, in some scenarios, in situ delivery using integration of dual functionalities within a single nanoconstruct may be advantageous.

J. Recent methods of producing suitable nanoplatforms: Introducing different methods of producing nanoformulations with laboratory safety, and working with small samples and cost effectiveness can also be valuable in advancing this field. A suitable method described in this review is laser ablation, which makes possible the fabrication of a variety of promising ultrapure formulations, from nanocarriers of radionuclides to nanoparticles for radiation or particle beam activation (Bi, B, etc.). Furthermore, profiting from essentially non-equilibrium growth this method also offers the possibility to produce nanoformulations (alloys, core-shells, mixed crystalline phases) enabling several functionalities for cancer imaging and therapy (nuclear, magnetic, etc.) in one entity. Another method, introduced earlier for a PDT drug nanoformulation is reprecipitation, where a solution of the active component is mixed with a nonsolvent to precipitate nanoparticles containing the active components. 209 In summary, as highlighted in the preceding sections, nanoparticles may either embed radionuclides as their diagnostic or therapeutic cargo such that they are inherently radioactive and emit radiation from within or be non-radioactive, or home specifically to tumors whereupon they are extrinsically activated by radiation (X-rays, heavy ions, or neutrons) to generate in situ radiation on-demand. Other paradigms that have seamless clinical translational potential include laser ablation, which allows straightforward and scalable synthesis of high-purity excipient-free biodegradable materials; coupling radionuclide Cerenkov radiation with photosensitizers; and combination with immunotherapy. Collectively, these advances and exciting attributes of nanoradiopharmaceuticals may provide distinct advantages in diagnostic/therapeutic sensitivity and specificity, imaging resolution, and scalability of turnkey platforms for complementary multimodal imaging or combination therapy. Coupling image-guided precision radiotherapy options with the possibility of internal activation of nanomaterials could herald an era of exciting technological and therapeutic advances.

Figure 1 :

 1 Figure 1: The scope of nanoradiopharmaceuticals covered in this review

Figure 2 :

 2 Figure 2: The major emissive species of radionuclides and their penetration range. β + and γ-emitters are the ideal radionuclides to produce in vivo imaging. Therapeutic radioisotopes emit α or β -particles, or Auger electrons. These radiations cause cytotoxic DNA damage through numerous mechanisms,

Figure 4 :

 4 Figure 4: Passive and active targeting of radiopharmaceuticals

Figure 5 :

 5 Figure 5: Different strategies for radionuclide incorporation with Liposomal nanocarriers. Liposomes have a hydrophilic interior and hydrophobic bi-layered membrane, which can incorporate radionuclides in their interior 'core', or in their membrane bilayer, or conjugated to their external surface

Figure 6 :

 6 Figure 6: Non-invasive SPECT/CT imaging of nude mice with human melanoma tumors, injected with the (a) non-targetred 111 In-liposomes, and (b) targeted 111 In-labeled-cyclic RGDfK-liposomes.

  [START_REF] Liko | Dendrimers as Innovative Radiopharmaceuticals in Cancer Radionanotherapy[END_REF] These nanocarriers, owing to their synthetic diversity, are ideal systems for developing multifunctional, theranostic nanoplatforms. Sun et al. have synthesized a dual therapeutic paclitaxel-encapsulated triblock-copolymeric nanocarrier (diameter about 100 nm), containing farnesyl thiosalicylate (FTS), which inhibits the cancer causing Ras oncogene as the hydrophobic block, poly-oligo(ethylene glycol) methacrylate (POEG) as hydrophilic block, and poly-4-vinylbenzyl azide (PVBA) as middle block. Furthermore, an attached PET imaging probe ( 89 Zr or[START_REF] Argyrou | Rhenium-188 Production in Hospitals, by W-188/Re-188 Generator, for Easy Use in Radionuclide Therapy[END_REF] Cu) showed rapid tumor uptake and slow clearance of this nanoformulation following their intravenous administration in 4T1.2 tumor bearing mice (Figure7) and revealed effective inhibition of tumor growth.[START_REF] Sun | A multifunctional polymeric carrier for simultaneous positron emission tomography imaging and combination therapy[END_REF]

Figure 7 :

 7 Figure 7: Real-time PET imaging showing time-dependent tumor uptake of radiolabeled PTX/POVF nanomicelles in a mice bearing 4T1.2 tumors. Imaging of (A) early time points (1-8 hours) post injection using Cu-64 labeled nanocarriers, and (B) late time points (24 -96 hours) using 89 Zr labeled nanocarriers. Adapted from reference [99]. Printed with permission from 'Elsevier'.

  In a recent demonstration, Ince et al. combined magnetic nanoparticles with 131 I and the drug Thymoquinone for multimodal theranostic application in lung cancer in vivo. While the radioisotope was used for SPECT imaging and radionuclide therapy, the magnetic nanoparticles provided MR imaging and magnetic hyperthermia therapy. In a xenograft model of lung cancer, significant reduction in tumor volume was observed owing to combination therapy, as observed using in vivo imaging. Complete tumor elimination could be observed after two weeks of treatment with the nanoformulation. 120

Figure 8 :

 8 Figure 8: In vivo multi-modality PET, MR and PA imaging, in U87MG tumor-bearing mice intravenously injected with 64 Cu-MMNs. (a) PET images at different times post-injection, with tumors indicated by white dotted circles. (b) Tumor uptake of 64 Cu-MMNs, presented as %ID/g. (c) MR images pre-and post-injection, with tumors indicated by white dotted circles. (d) Quantitative MR signal from U87MG

  Miller et al. showed multiple incorporation of the positron emitting radionuclide[START_REF] Marik | Long-circulating liposomes radiolabeled with [18F]fluorodipalmitin ([18F]FDP)[END_REF] Zr within mesoporous silica nanoparticles (MSNs) for PET imaging with enhanced signal strength.126 In a demonstration of dynamic multimodal imaging, Cheng et al. loaded isolated neural stem cells (NSCs) with 111 In-labelled MSNs, which were then administered intracranially as well as systemically in mice bearing orthotopically xenografted glioblastoma. Dynamic in vivo SPECT imaging allowed real-time tracking of NSC migration towards glioblastoma. Additionally, the radionuclide-decay was associated with strong fluorescence, which allowed concurrent optical imaging of NSC migration (Figure 9). 127 Hortelao et al. have reported another example of dynamic radioimaging using 124 I labelled nanomotors comprised of mesoporous silicananoparticles, co-loaded with the enzyme urease and gold nanoparticles. Following direct administration into the bladder of mice, dynamic PET imaging was used to demonstrate the urea-powered swarming behavior of the radiolabelled nanomotors in vivo [doi: 10.1126/scirobotics.abd2823]. In a recent report involving theranostic silica-based nanoformulation, Rainone et al. demonstrated the targeted SPECT imaging and therapy of HER2 overexpressing breast cancer in vivo using trastuzumab half-chain conjugated, doxorubicin encapsulated and 99m Tc radiolabelled silica nanoparticles. Analysis of treatment efficacy in vivo using PET imaging revealed significant reduction in tumor volume using the theranostic silica-based nanoformulation, with higher efficacy than that shown by liposomal Doxorubicin (Caelyx). 128

Figure 9 :

 9 Figure 9: Tracking of NSCs in mouse brain after systemic injection. (A) SPECT imaging of 111 In-MSN-NSCs after systemic injection in tumor-bearing (top) and control (bottom) animals. (B) Hematoxylin and eosin staining confirms orthotopic tumor growth (dashed white line) in experimental animals and normal structure of brain tissue in naïve control (lower). Confocal microscopy (yellow boxes) of adjacent tissue areas reveal strong homing behaviors of NSCs labeled with 111 In-MSN (green; yellow arrows) near border of tumor mass (red), with occasional indications of intratumoral penetration by

4 .

 4 Lee et al. have used a targeted, multimodal nanoformulation for imaging of tumor angiogenesis using Er 3+ /Yb 3+ codoped NaGdF4 UCNPs radiolabeled with 124 I. The conjugated RGD peptide allowed tumor targeting in a mouse model bearing U87MG tumor xenografts, visualized using tri-modal imaging (small-animal PET, clinical 3-T T1-weighted MRI, and NIR optical imaging).130 In an example of targeted theranostics, an UCNP nanoformulation radiolabelled with the betaemitter[START_REF] Abou | Zr-labeled paramagnetic octreotide-liposomes for PET-MR imaging of cancer[END_REF] Y and tagged with the tumor-targeting protein DARPin, modified with therapeutic exotoxin-A fragment, was fabricated. Synergetic therapy effect due to a combined action of the targeted toxin and radioisotope[START_REF] Abou | Zr-labeled paramagnetic octreotide-liposomes for PET-MR imaging of cancer[END_REF] Y was observed in mice bearing HER2-positive SK-BR-3 human xenograft tumors, which could also be observed non-invasively using NIR optical imaging.131 In situ activation via external trigger One major shortcoming of radionuclide labelling of molecules or nanoparticles is the lack of external control on the radiation emission properties. This can lead to undesirable radiation damage to non-target regions, along with potentially long-term persistence of radioactivity in the body. To overcome this limitation, over the past few decades external activation of tumor-localized targets has been investigated. Here, external sources of ionizing radiations (e.g. x-rays, ion-beams) are focussed on the target tissues thereby providing better spatio-temporal control of therapy. Nanoparticles containing high atomic number elements

  effective dose enhancement of x-ray activated therapy in tumor-bearing mice treated with gold nanoparticles was first reported byHainfeld et al. 133 Since then, several reports have emerged highlighting targeted radiation therapy enhancement, combination therapy, theranostics, etc., in cultured cells and tumor-bearing animals treated with gold nanoparticles. A roadmap to clinical use of gold nanoparticles for radiation sensitization has been published by a number of groups now, underscoring the popularity of gold as a radiosensitizer and the need for meticulous documentation of the optimal operating parameters for maximal radiosensitization.134 Antosh et al. prepared ultrasmall (1.4 nm) gold nanoparticles, conjugated with the tumor-targeting pH Low-Insertion Peptide (pHLIP). In vivo studies in tumor-bearing mice revealed efficient tumor targeted delivery of the gold-pHLIP nanosensitizers, and significant reduction in tumor volume at a low administered dosage (10 mg/kg) of the nanosensitizers exposed to 20 Gy of radiation. Biodistribution measurements also demonstrated the enhanced tumor-retention of the targeted nanoparticles. 135 Recently, Ding et al. demonstrated advanced tumor targeting of ultrasmall gold nanoparticles (Au NPs) by conjugating a multifunctional peptide Tat-R-EK, consisting of the cell-penetrating peptide Tat, a tumor-microenvironment responsive cathepsin B cleavable linker, and a zwitterionic antifouling block. Once targeted within the tumor microenvironment, the locally overexpressed cathepsin B cleaves the peptide linker to expose the cell penetrating Tat peptide on the Au NP surface, leading to enhanced internalization within the tumor cells. This multi-targeted nanoformulation led to enhanced tumor cell uptake in vitro and in vivo, resulting in superior x-ray sensitized toxicity, along with rapid renal clearance in mice bearing orthotopic LM3 liver tumors. 136In addition to acting as x-ray radioenhancers, gold-nanostructures also can carry additional therapeutic agents that can sensitize cancer cells to therapy. We have demonstrated that silencing of the sphingosine kinase (SphK1) gene using specific shortinterfering RNA (siRNA) conjugated with gold nanorods can sensitize head-and-neck squamous cell carcinoma (HNSCC) cells to radiation therapy. Here, the GNRs perform the dual function of carrying the siRNA against SphK1 gene to target cells, and further radiosensitization upon x-ray exposure of the targeted cells. In a mouse model of subcutaneously implanted HNSCC cells, a significant reduction in tumor volume was observed upon sequential GNR-mediated SphK1 gene silencing and subsequent low-dose (1.0 Gy twice a week) x-ray irradiation.137 Recently,Yang et al. showed that incorporation of an siRNA targeting the hypoxia-inducible factor-1α (HIF-1α) protein with zwitterionic polyamidoamine dendrimer-entrapped gold nanoparticles can lead to both endogenous and exogeneous sensitization of radiation therapy in the treatment of both primary and metastatic tumors in mice.138 Bismuth is another high-Z metal that has shown promise in CT contrast enhancement and radiosensitization. Researchers at Jiangsu University demonstrated tumor-targeted CT imaging and radiosensitization using hyaluronic acid (HA)-functionalized bismuth oxide nanoparticles (HA-Bi2O3 NPs).139 Deng et al. synthesized biodegradable, red-blood cell (RBC) coated and folate-conjugated bismuth (F-RBC bismuth) nanoparticles. Favorable blood circulation and tumor-targeting efficiency were rendered by RBC and folate, respectively. In a mouse model of breast cancer, significant tumor suppression and improved survival ratio were observed upon treatment with F-RBC bismuth nanoparticles and x-ray radiation.140 We have recently shown that laser ablation can be used to produce stable pure elemental Bi nanoparticles which provide the highest local concentration of Bi atoms for significantly enhanced CT contrast and radiotherapy at a much lower x-ray dosage.141 Gadolinium oxide/fluoride nanoparticles can combine their MR contrast enhancement capability with radiosensitization potential for image-guided therapy. Rajaee et al. have combined the benefits of bismuth and gadolinium by synthesizing multifunctional, theranostic bismuth gadolinium oxide nanoparticles (BiGdO3), for combined radiosensitized therapy, computed tomography (CT) and magnetic resonance imaging (MRI). In vivo studies using BALB/c mice bearing 4T1 breast tumors revealed potent radiosensitizing effect of the PEG-coated BiGdO3 nanoparticles. 142 Nanobiotix, Inc., France (https://www.nanobiotix.com/) has developed hafnium oxide nanoparticles with an average diameter of 50 nm (NBTXR3) as a potent radiosensitizer for locally advanced soft tissue sarcomas (STS).143,144 Radiosensitization can also be induced by certain polymer-based nanoparticles, with the added provision of concurrent delivery of chemotherapeutic drugs. For example, Yin et al. have prepared amphiphilic block-copolymer consisting of poly(ethylene glycol)-blockpoly(L-glutamic acid) (PEG-b-PLG) and the small-molecule radiosensitizer metronidazole (MN). The obtained MN-grafted PEG-b-PLG (PEG-b-P(LG-g-MN)) nanoassemblies were further loaded with the anticancer drug doxorubicin. Upon irradiation with electron beams, these polymeric nanoassemblies showed a high sensitization enhancement ratio (SER) of 2.18. Upon combination with doxorubicin delivery in mice bearing 4T1 tumors, robust chemoradiosensitized ablation of bulky hypoxic solid tumors (~ 500 mm 3 ) could be obtained at a low radiation dose (4 Gy) [DOI: 10.1016/j.biomaterials.2018.08.014]. Synergistic chemo and radiosensitization for the treatment of cancer by combining activable prodrugs with radiation is an emerging concept. Recently, Geng et al. have demonstrated the site-specific uncaging of chemotherapy drugs or imaging probes via localized radiation treatment of corresponding azide-caged prodrugs. Such target-specific liberation of prodrugs with external radiosensitization provides potent combination of chemo-and radiation therapy at tumor sites, while avoiding chemotherapy-associated systemic toxicity [Nature Chemistry, 13, 805-810].

Figure 10 .Figure 11 .

 1011 Figure 10. While intercellular localization is required for effective NCT using 10 B (A), localization within subcellular organelles is necessary for effective NCT using 157 Gd (B).

Figure 12 .

 12 Figure 12. (a) Schematic of functionalization procedure describing the coating of laser-synthesized Si nanoparticles by PEG and their subsequent decoration by radioactive 188 Re atoms. (b) Survival curves for the rats administered intratumorally with PEGylated silicon nanoparticle-188 Re conjugate having

Figure 13 :

 13 Figure 13: Distribution and persistence of NBTXR3 after intratumoral injection was imaging by μCT performed 1 day (left panel) and 7 days (right panel) after NBTXR3 injection. Pink, NBTXR3; brown, tumor (A). For abscopal experiments (B) tumor growth curves of treated (left panel) and distant untreated (right panel) tumors (C) survival curves and (D) median survival were obtained from two independent experiments (n=2), with 12-15 mice per group. Arrows indicate radiotherapy sessions (4 Gy). Statistical analysis: two-way ANOVA test (B) or Log-rank (Mantel-Cox) test (C). **p<0.01; ***p<0.001 Adapted from reference [195]. Printed with permission from 'Dove Press'.

Figure 14 : 6 .

 146 Figure 14: (a) Representative SPECT/CT images of 4T1 tumor bearing mice intratumoral injected with 100 µCi Na 131 I, 100 µCi Na 131 I + 20 µg ZnPcC4, and 131 I-ZGCs-ZnPcC4 (100 µCi, 200 µg) at various time points. (b) Tumor growth curves, and (c) body weight curves of 4T1 tumor bearing mice following various treatments. Adapted from reference [204].

G.

  photodynamic therapy, photothermal therapy, gene therapy and immuno therapy. A particularly appealing concept is synergistic enhancement produced by combination

Table of Contents

 of

	1. Introduction
	2. Conventional radionuclide delivery systems
	3. Nanocarriers for radionuclides
	Soft' or 'organic' nanocarriers

  Ruggiero et al. incorporated radionuclides such as the -emitter 225 Ac or the PET tracer[START_REF] Marik | Long-circulating liposomes radiolabeled with [18F]fluorodipalmitin ([18F]FDP)[END_REF] Zr with single walled CNTs via chelation. These radiolabeled CNTs, tagged with the tumor neovascular-targeting antibody E4G10, were used for both targeted radioimmunotherapy (using 225 Ac) and PET imaging (using[START_REF] Marik | Long-circulating liposomes radiolabeled with [18F]fluorodipalmitin ([18F]FDP)[END_REF] Zr) in a murine xenograft model of human colon adenocarcinoma (LS174T).

123

Nanographene oxide (NGO) was radiolabeled with

111

In and conjugated with anti-HER2 antibody (trastuzumab) for targeted SPECT imaging of breast cancer, with better pharmacokinetics and clearance from circulation, as compared to radiolabeled antibody only.

124

  Monte Carlo simulations. Both observations revealed significant longitudinal shift(2.2-4.7 mm) of the distal edge of the Bragg peak with gold nanoparticles.Neutron capture therapy (NCT), which is conceptually different from x-ray or ionbeam therapies, forms another prime example of externally-applied radiative dose-escalation therapeutic strategy. Here, a non-radioactive isotope is converted to a radioactive one following bombardment with epithermal neutrons (energy higher than thermal neutrons, i.e. 0.025eV) from either a nuclear reactor or an accelerator. The radioisotope then undergoes nuclear reaction by capturing the incident neutron in the nucleus to emit localized toxic radiation.[START_REF] Luderer | Advancements in Tumor Targeting Strategies for Boron Neutron Capture Therapy[END_REF] If this procedure is carried out around cancer cells, it leads to potent therapy of cancer by in situ action of the emitted radiation. So far, primarily compounds based on Boron-10 ( 10 B) and Gadolinium-157 ( 157 Gd) have been used as the target isotopes for NCT owing to their high neutron capture cross sections(3,837 and 254,000 barns, respectively). 156 While 10 B has been used in both experimental and clinical NCTs (termed as boron neutron capture therapy, or BNCT),157 Gd has only been used in experimental applications.

	Of the three metals, platinum caused the greatest concentration-dependent shift. At the
	same time, dose-enhancement (6-21%) with varying nanoparticle concentrations and proton
	energies were observed. 149
	Carbon ion beam therapy is also gaining popularity in clinics for nano-radiosensitized
	therapies. Nanoparticle radiosensitization in this case also works on the ejection of electrons.
	By studying DNA damage, Lacombe and coworkers reported that platinum nanoparticles
	irradiated with carbon-ion beams facilitate potent DNA damage. Auto-amplified electronic
	cascades inside the nanoparticles were found to form a key mechanism in radiosensitization
	close to the nanoparticles. theranostic nanoformulation was reported by Li et al, who demonstrated enhanced cytotoxic
	effect on non-small cell lung cancer (NSCLC) cells treated with gadolinium oxide nanocrystals
	and fast carbon ions. A concentration-dependent increase in the production of hydroxyl
	radicals and reactive oxygen species in treated cells was observed, leading to cell death via
	several mechanisms, such as DNA damage, cell cycle arrest, apoptosis, and cytostatic
	autophagy. 155
	Neutron capture therapy

Ahmad et al.

investigated the impact of proton energy and nanoparticle concentration on the radiosensitization behavior of gold, silver and platinum nanoparticles, using tissue phantom experiments and in silico 150 Later on, Kaur et al. demonstrated that the cytotoxicity and relative biological effectiveness (RBE) values of carbon-ion irradiated human cervix cancer (HeLa) cells was enhanced when cells were pre-treated with glucose-capped gold nanoparticles. The radiation dose required for killing 90% of cells was reduced by 30% following nanoparticle treatment.

151

Li and coworkers studied hydroxyl-ion production as a plausible mechanism for gold-nanoparticle-mediated radiosensitization of carbon ion therapy. Enhancement in hydroxyl radical production could be directly correlated with the increased lethality of gold nanoparticle-sensitized carbon-ions.

152,153

Porcel et al. have shown that gadolinium-chelating polysiloxane nanoparticles (AGiuX), which were already shown to sensitize photon beam (x-rays) therapy, can also sensitize carbon ion radiation therapy and amplify cell death. The excellent MRI contrast enhancement properties of chelated gadolinium also allows these nanoparticles to serve as theranostic agents for image-guided therapy.

154

Another gadolinium-based radiosensitized 157

The Boron-10 isotope which makes up approximately 20% of natural elemental boron undergoes the following instantaneous nuclear fission. 2,156 : 10 B + nth → [ 11 B]* → α + 7 Li + 2.31 MeV

  These multifunctionalized AuNRs were robustly uptaken by gastrointestinal tumor xenografts in mice following systemic administration, without any noticeable side effect. PET-imaging mediated tumor detection, followed by both light-activated photothermal therapy (PTT) and neutron-irradiated BNCT of the tumor could be achieved, thus demonstrating image-guided combination therapy using the single nanoplatform in vivo [DOI: 10.1021/acsami.0c17575].

	Gadolinium NCT nanoformulations have been reported with nanoparticles containing
	chelated gadolinium ions, entrapped gadolinium compounds, as well as gadolinium as an
	intrinsic part of the nanoparticles. Tokumitsu et al. compared the NCT abilities of the
	commercial gadopentetate (complex of gadolinium and DTPA) solutions to that of
	gadopentetic acid-chitosan complex nanoparticles. Intratumoral injection of these
	formulations in mice bearing subcutaneous B16F10 melanoma tumors, followed by
	irradiation with thermal neutrons, resulted in significant suppression of tumor growth in the
	nanoparticle-administered group as compared to that in the gadopentetate solution-
	administered group.

In an example, Pulagam et al. have functionalized 64 Cu-labelled gold nanorods (AuNRs) with the boron-rich water-soluble complex cobalt bis(dicarbollide) ([3,3′-Co(1,2-C2B9H11)2] -). 162 Dewi et al. incorporated Gd-DTPA, a common MRI contrast agent, on the surface of calcium phosphate nanoparticles. Mice bearing colon carcinoma Col-26 tumors

  com/) has synthesized gadolinium nanoparticles that are intravenously administered to serve as both MRI agents) and therapeutic agents via a similar release of secondary electrons upon irradiation. Early results in the treatment of brain metastases with escalating doses of the nanoparticle, suggest that the particles could serve as a potent radiation sensitizer. Similarly, boronated compounds are used for BNCT in the clinic in Japan, Finland, Argentina, Taiwan and China. One combination of an accelerator-based neutron source and boronophenylalanine synthesized by Stella Pharma (https://stellapharma.co.jp/en) was granted Japanese FDA approval recently. Lastly,[START_REF] Abou | Zr-labeled paramagnetic octreotide-liposomes for PET-MR imaging of cancer[END_REF] Y microspheres, albeit not nanoparticles in a strict sense due to their micrometer size, are routinely used in the treatment of hepatocellular carcinoma via intraarterial administration.205 Collectively, these inroads into clinical radiation therapy practice made by nanoparticles, set a precedence and define a roadmap for future innovations in nanoradiopharmaceuticals. tumor targeting based on the EPR effect, which leads to their enhanced accumulation in the tumor area.[START_REF] Maeda | Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review[END_REF] However, the heterogeneity of the EPR effect across various organisms (e.g. mice versus humans) and tumor types pose a challenge, especially in the clinical translation of nanoformulations. Active targeting approaches that drive nanoformulations to tumor tissues/cells are more promising.[START_REF] Prasad | Introduction to Nanomedicine and Nanobioengineering[END_REF][START_REF] Chen | Nanochemistry and Nanomedicine for Nanoparticle-based Diagnostics and Therapy[END_REF] Other emerging approaches, such as co-delivery of nanoradiopharmaceuticals with microbubbles followed by ultrasound-induced cavitation, can enhance their target specificity to tumor sites.B. Easy and safe bioelimination of nanoradioformulations: Large transport vehicles carrying radionuclides can maximize the loading capacity and avoid immediate accumulation in the kidneys; however, they also may complicate clearance from the organism causing toxicity issues, as observed in the case of silica nanoparticles.207 To overcome this problem, one can use biodegradable nanostructures such as Si nanoparticles which biodegrade into orthosilicic acid Si(OH)4 , which are naturally

	nanoradiopharmaceuticals enable passive
	7. Current Challenges and Future perspectives of Nanoradiopharmaceuticals
	It is amply evident that the convergence of nanotechnology with nuclear medicine has
	advanced a plethora of cancer imaging and therapy paradigms. A few challenges intrinsic to
	nanotechnology are those of nanoparticle uniformity, biocompatibility, biodistribution, and
	pharmacokinetics. The US National Nanotechnology Initiative (NNI) recognized these
	attributes and equally exciting challenges of nanoparticle use in medicine, and created the
	Nanotechnology Characterization Laboratory in Frederick, MD (https://ncl.cancer.gov/) as a
	central facility for testing nanomaterials for standardization, physicochemical
	characterization, biocompatibility, etc., and outlined lessons learned over the course of
	analyzing nanoparticles from numerous suppliers (academia, industry, and government). 206
	Quite naturally, similar challenges await the forays of nanoradiopharmaceuticals into clinical
	realms.
	Outlined below are our subjective opinions on some of the important challenges for rapid
	advancement and clinical acceptance of nanoradiopharmaceuticals, and some thoughts on
	possible approaches to overcome them.
	A. Targeted delivery of nanoradiopharmaceuticals: Coupling a targeting moiety to a
	nanoradiopharmeceutical can be challenging, especially if the radionuclide has a short
	life time. However, using recent advances in nanochemistry, the surface of the
	nanoparticles can be functionalized with linking groups which couple within minutes
	to the complementary linking group on the targeting peptide or antibody. The use of
	active targeting strategies with nanoformulations enables high radionuclide loading
	and avoid immediate accumulation in kidneys, which are difficult with conventional
	targeting molecules alone, while the targeting group brings the
	nanoradiopharmaceutical	complex	to	the	tumor	site.	Additionally

Acknowledgements P.N.P. at the Institute for Lasers, Photonics and Biophotonics acknowledges support from the office of vice president for research and economic development at the University at Buffalo. A.V.K. and I.N.Z. acknowledge contribution of Russian Science Foundation (Project 19-72-30012) for access to some databases and travel exchange support. P.N.P, A.V.K and I.N.Z acknowledges support from the PhysBio Institute of MEPhI for research. I.R. acknowledges the Institute of Eminence, University of Delhi, India, for providing research support (grant number IOE/FRP/PCMS/2020/27). S.K. acknowledges support from the National Institutes of Health grants R01CA257241, CA155446 and R01DE028105.

Vocabulary

Nanoradiopharmaceuticals: A broad definition encompassing nanoparticles that are either composed of or tagged with radioisotopes, or can engender ionizing radiation upon irradiation with electromagnetic radiation or particle-beams, for diagnostic and/or therapeutic purposes.

Multimodal nanoparticles: Nanoparticles containing several types of active agents capable of performing multiple, usually medically relevant, tasks.

Theranostics: A single probe that can concurrently or sequentially perform at least one diagnostic and one therapeutic function.

Radiation therapy: A clinically practiced therapeutic paradigm that involves ablation of tumor cells with ionizing radiation emanating from non-radioactive nanoparticles with high atomic numbers exposed to x-ray radiation.

Ion-beam therapy: An emerging therapeutic paradigm that involves ablation of tumor cells with ionizing radiation emanating from certain non-radioactive nanoparticles exposed to ion-beams.

Neutron capture Therapy: A therapeutic paradigm that involves ablation of tumor cells with ionizing radiation emanating from 10 B or 157 Gd containing non-radioactive probes exposed to neutron beams.

Laser ablation nanoparticle synthesis: A top-down method of synthesizing monodispersed and ultrapure nanoparticles involving exposure of corresponding bulk materials with high-energy laser beams.