Novel Implications of Nanoparticle-Enhanced Radiotherapy and Brachytherapy: Z-Effect and Tumor Hypoxia

Abstract

Radiotherapy and internal radioisotope therapy (brachytherapy) induce tumor cell death through different molecular signaling pathways. However, these therapies in cancer patients are constrained by dose-related adverse effects and local discomfort due to the prolonged exposure to the surrounding tissues. Technological advancements in nanotechnology have resulted in synthesis of high atomic elements such as nanomaterials, which can be used as radiosensitizers due to their photoelectric characteristics. The aim of this review is to elucidate the effects of novel nanomaterials in the field of radiation oncology to ameliorate dose-related toxicity through the application of ideal nanoparticle-based radiosensitizers such as Au (gold), Bi (bismuth), and Lu (Lutetium-177) for enhancing cytotoxic effects of radiotherapy via the high-Z effect. In addition, we discuss the role of nanoparticle-enhanced radiotherapy in alleviating tumor hypoxia through the nanodelivery of genes/drugs and other functional anticancer molecules. The implications of engineered nanoparticles in preclinical and clinical studies still need to be studied in order to explore potential mechanisms for radiosensitization by minimizing tumor hypoxia, operational/logistic complications and by overcoming tumor heterogeneity in radiotherapy/brachytherapy.

Gold‐Enhanced Brachytherapy by a Nanoparticle‐Releasing Hydrogel and 3D‐Printed Subcutaneous Radioactive Implant Approach

“…[48,54] The low-energy emissions activate the production of ROS, which are toxic to cancer cells, making this one of the most important mechanisms of action of these radiosensitizers. [51,55,56] The optimal size for AuNPs as radiosensitizers is estimated to be around 5 nm to maximize cellular uptake, facilitate diffusion in tumors, and enhance renal clearance. [51] Catalytic reactions, which occur at the electronically active surfaces of AuNPs, are one of the well-documented chemical contributions to radiosensitization.…”

“…[48] In turn, the ROS can damage DNA, proteins, and lipid mem-branes via oxidation. [51,55,56] Moreover, the cellular internalization and radiosensitization effect of spherical AuNPs is known to be greater than rod, cubic, prismatic, and star-shaped ones of similar size. [58][59][60] The administration route of AuNPs as radiosensitizers is an essential factor for their application.…”

“…[ 48,54 ] The low‐energy emissions activate the production of ROS, which are toxic to cancer cells, making this one of the most important mechanisms of action of these radiosensitizers. [ 51,55,56 ]…”

Hypoxia-Responsive Aggregation of Gold Nanoparticles for Near-Infrared-II Photoacoustic Imaging-Guided Enhanced Radiotherapy

“…In clinical practice, RT is used in different phases of treatment for 60–70% of patients with malignant tumors . Unfortunately, the therapeutic use of RT in cancer treatment is severely constrained by radioresistance brought on by intratumoral hypoxia and the toxicity of high-dose radiation for surrounding healthy tissues. − It is well known that hypoxia is one of the defining characteristics of most solid tumors and an important cause of cancer progression and poor prognosis. − During RT, the hypoxic environment reduces the production of ROS and cytotoxic substances. , In addition, reducing substances, including sulfhydryl-containing molecules within the tumor, can significantly reduce the ionizing damage to the genomic DNA of cancer cells caused by ionizing radiation. − To address these issues, a variety of radiosensitizers that attempt to increase the radiation sensitivity of cancer cells have been developed and used in clinical settings, including sodium glycidazole and nimozole. − However, due to the low bioavailability in the body, large doses of sensitizers are required to achieve satisfactory radiosensitization effects, leading to serious negative impacts on healthy tissues, organs, and the central nervous system. High-atomic-number (high-Z) metals have received a lot of interest in the field of radiosensitization because they can greatly enhance the attenuation of X-rays and facilitate the deposition of radiation energy within the tumor. − To date, many nanoplatforms containing high-Z elements for radiosensitization have been successfully developed. − However, most of the current nanomedicines are unable to penetrate tumors and cannot reach cancer cells located far from the tumor-associated blood vessels, especially in the hypoxic area.…”

“…16−18 During RT, the hypoxic environment reduces the production of ROS and cytotoxic substances. 19,20 In addition, reducing substances, including sulfhydryl-containing molecules within the tumor, can significantly reduce the ionizing damage to the genomic DNA of cancer cells caused by ionizing radiation. 21−23 To address these issues, a variety of radiosensitizers that attempt to increase the radiation sensitivity of cancer cells have been developed and used in clinical settings, including sodium glycidazole and nimozole.…”