Review
Radiolabeled carbon-based nanostructures: New radiopharmaceuticals for cancer therapy?

https://doi.org/10.1016/j.ccr.2021.213974Get rights and content

Highlights

  • Nanotechnology promotes the efficacy of cancer diagnosis and treatment.

  • Carbon-based nanomaterials are promising in cancer nanotechnology.

  • Carbon-based nanomaterials can be radiolabeled with different methods.

  • Radiolabeled carbon-based nanomaterials are efficient cancer treatment agents.

Abstract

Nanomaterials are sophisticated multifunctional structures, with the potential to improve the efficacy of conventional cancer treatment modalities. The combination of nanomaterials with nuclear medicine isotopes, provides an opportunity to produce more precise and effective radiopharmaceuticals. Carbon-based nanomaterials (CNMs) have attracted unprecedented attention due to their remarkable physicochemical properties. CNMs can function as carriers to deliver substantial amounts of radionuclides, and can also be targeted by attachment of molecular recognition ligands. Various types of CNMs, including carbon nanotubes, graphene, fullerenes, nanodiamonds, or carbon quantum dots have been exploited to improve the delivery of radionuclides. In the current review, we summarize the principles and pitfalls of radionuclide therapy, and suggest that CNMs could be a potential solution. Studies have shown that CNMs can be effective not only as nanocarriers of radiopharmaceuticals, but also as theranostic systems.

Introduction

Cancer remains the second leading cause of death, despite an enormous research effort conducted over the last decades. The European Federation of Pharmaceutical Industries and Associations and the World Health Organization (WHO) report about 14 million new cancer cases per year worldwide, with an overall mortality of 13% [1]. Moreover, the current prevalence of cancer is increasing year-by-year due to various factors, such as modern unhealthy lifestyles and exposure to hazardous and carcinogenic substances. Unfortunately, it has been estimated that cancer-related mortality will reach 13.1 million by 2030 [2]. Despite significant advances in therapeutic and diagnostic approaches, successful treatment for cancer still remains challenging. Cancer heterogeneity, tumor hypoxia, and drug resistance are the critical hindrances preventing effective cancer treatment. Some significant breakthroughs in molecular and tumor biology have improved the cancer treatment paradigm in recent years. The current options for cancer therapy are surgery, chemotherapy, immunotherapy, hormone therapy, hyperthermia, photodynamic therapy, ionizing radiation therapy, and combinatorial therapy. Despite some considerable efficacy, they all suffer from critical issues, such as low efficiency, non-specificity, major side-effects, toxicity to healthy cells/tissues, unfavorable pharmacokinetics, and poor bioavailability [3], [4].

The overall recaltricance of cancer has motivated researchers from various fields of science and technology to develop more effective diagnostic and treatment methods [5]. Radiopharmaceuticals, also known as medicinal radioisotopes, are a class of compounds containing radioactive isotopes of several specific chemical elements used for the diagnosis or treatment of diseases [6]. When used for diagnosis, these compounds are able to emit high-energy electrons (β-particles), positrons, or gamma rays that can be detected using a dedicated piece of equipment. This could be a gamma camera for scintigraphy, SPECT (single photon emission tomography) or PET (positron emission tomography).

Radionuclides, also known as radioactive isotopes, radioactive nuclides, or radioisotopes, are unstable atoms with excess energy that can be released by changes occurring in the nucleus. These atoms radioactively decay at their own specific rate and produce electromagnetic radiation and/or elementary particles. Radionuclide imaging is a relatively noninvasive method, and allows the spatial–temporal recording of molecular, sub-cellular, or cellular processes, and imaging of organs or tissue functions [7], [8]. On the other hand, radioisotope therapy involves the application of various radiopharmaceuticals to target the cancerous cells and destroy them by emitting ionizing radiation with ideally only minimal damage to healthy cells/tissues. Although this method is usually not used as a first-line treatment, it is often used as an adjuvant or concomitant therapy in combination with other types of cancer therapy. The efficacy of radioisotopes in the treatment of cancers, such as bone metastases, thyroid cancer, liver cancer, brain cancer, neuroblastoma, neuroendocrine tumors, non-Hodgkin’s lymphoma, and bile duct cancer has been reported [9], [10]. One of the most significant drawbacks of the radiopharmaceuticals used in the past, was their nonspecific activity, however advances in nanotechnology, material science, biochemistry, and molecular biology, have allowed the development of more specific targeted compounds, to lessen the damage to healthy cells. Many research groups and pharmaceutical companies have been working on improved target-specific radiopharmaceuticals against different cancers or other diseases [11].

Nanomaterials have been widely studied in the search to develop more specific formulations, not only for radioisotopes, but also for chemotherapy drugs, genes, and proteins. Nanotechnology describes the study, design, and application of particles and systems at the nanometer scale, and has been widely exploited in drug development, discovery, and delivery [12], [13]. Nanomaterials can be used to develop more potent, active, and specific radiopharmaceuticals with fewer side effects and off-target activity. Hence, significant attention has been devoted to combinations of nuclear-medicine and nanomaterials to revolutionize the current diagnosis and treatment methods of cancer. Nanomaterials have the potential to be loaded with, transport, and deliver a large number of radioactive atoms using a single nanomaterial. Nanomaterials can deliver the highest amount of radioactivity around or inside the tumor tissue compared to small molecule radiopharmaceuticals [14], [15].

Moreover, the high specific surface area to volume ratio of nanomaterials is ideal for integrating a combination of targeting and reporter agents. In this regard, metallic, polymeric, lipid-based, or carbon-based nanomaterials (CNMs) have been exploited to formulate effective radiopharmaceuticals [16]. There are several review papers in the literature which discuss different radiolabeled nanomaterial compositions for cancer diagnosis, treatment, and biodistribution studies, but there is still room for a comprehensive review paper discussing radiolabeled CNMs. Jeon [17] discussed therapeutic applications of radiolabeled nanomaterials with a few mentions of single-walled carbon nanotubes (SWCNTs). In another study, Farzin et al. [18] reviewed the nanoscale radionuclides and radiolabeled nanomaterials commonly used for imaging and therapy. They described the structure and properties of various nanomaterials, the available radiolabeling methods, and discussed the findings. They highlighted the importance of the concept of early cancer detection, and the advantages of developing multimodal cancer imaging agents using magnetic, plasmonic, or fluorescent nanomaterials. Ge et al. [19] summarized radiolabeled nanomaterials for multimodality cancer imaging. They discussed the recent progress of radiotracers in nuclear medicine imaging, and the application of nanomaterials in radiotracer development. They concluded that the fascinating properties of nanomaterials are promising to develop sophisticated multimodality imaging tracers.

Although some papers have reviewed different radiolabeled nanomaterials used in imaging and therapeutic applications, to the best of our knowledge, there is no comprehensive paper specifically discussing radiolabeled CNMs. Accordingly, in the current study we aimed to highlight the advances in the field of CNMs-mediated nuclear medicine for cancer treatment applications. In the present review, we provide a brief description of radionuclide therapy for cancer, cancer nanotechnology, and CNMs in medicine. We cover the progress made on the use of CNMs in the area of radiopharmaceutical cancer therapy over the last decades [20], [21].

Section snippets

Radionuclides used in cancer therapy

Radiation therapy is a practical treatment choice widely used in combination with other cancer treatment methods, such as surgery and chemotherapy. Tumors and cancer cells are exposed to ionizing radiation, which damages the DNA of the cells and hinders their growth and proliferation. Broadly speaking, there are two ways to expose the tumors to ionizing radiation as shown in Fig. 1. Firstly the tumor can be exposed to a beam of radiation using an external source such as an orthovoltage X-ray

Cancer nanotechnology

Structures and devices at the nanoscale have provided a revolution in biomedicine, especially for the diagnosis, detection, and treatment of cancer. Nanomaterials offer the possibility to detect cancers at an early stage, when treatment is much more successful. Moreover, nanomaterials are able to increase the precision and specificity of conventional diagnostic approaches such as magnetic resonance imaging (MRI), PET, SPECT, as well as optical and electrochemical biosensors. Using

Radiolabeling of carbon nanomaterials

A critical step in the design of radiopharmaceuticals is the stability of the conjugated radionuclide with the final compound. The radionuclide must remain firmly attached to the CNM during storage, administration into the patient's body, and on the way to reaching the target site within the body. Otherwise, the detached radionuclide may induce adverse effects and off-target side effects affecting healthy tissues. Broadly speaking, four different methods are available for the radiolabeling of

Radiolabeled carbon-based nanostructures for cancer therapy

Nanomaterials can be designed to allow precise targeting of disease sites. They can be used to report biological information from that specific site (e.g., radioisotopes for molecular imaging), and for the specific delivery of therapeutic cargoes that can destroy cells within that site [51]. Nanomaterials with bifunctional or multifunctional properties could be a better choice for medical or industrial purposes. Radiolabeling of nanoparticles (NPs) is carried out by the attachment or

Conclusion and future outlook

Despite unprecedented advances in medicine, molecular biology, and medical physics, the diagnosis and treatment of cancer remains a critical challenge. Due to its heterogeneity, complexity, and continuously evolving features, cancer treatment requires highly sophisticated, precise, combinatorial, and multifunctional treatment modality. External radiation therapy is a treatment widely used in combination with surgery and/or chemotherapy. Despite its efficacy in killing cancer cells, it also

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

This work was funded by Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran. MRH was supported by US NIH Grants R01AI050875 and R21AI121700.

Conflict of Interest

MRH declares the following potential conflicts of interest. Scientific Advisory Boards: Transdermal Cap Inc, Cleveland, OH; BeWell Global Inc, Wan Chai, Hong Kong; Hologenix Inc. Santa Monica, CA; LumiThera Inc, Poulsbo, WA; Vielight, Toronto, Canada; Bright Photomedicine, Sao Paulo, Brazil; Quantum Dynamics LLC, Cambridge, MA; Global Photon Inc, Bee Cave, TX; Medical Coherence, Boston MA; NeuroThera, Newark DE; JOOVV Inc, Minneapolis-St. Paul MN; AIRx Medical, Pleasanton CA; FIR Industries,

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