Nanoparticle‐Mediated Radiotherapy Remodels the Tumor Microenvironment to Enhance Antitumor Efficacy

Abstract

or intra-arterial administration of therapeutic radionuclides or by direct implantation of radioisotope-embedded beads into tumors. [3] In external RT, therapeutic doses of ionizing radiation are delivered to tumors using external beams of photo ns, electrons, and protons. [4] Both types of RT can directly induce local apoptosis, autophagy, necrosis, or replicative senescence of cancer cells [5] by producing reactive oxygen species (ROS) [6] to cause DNA damage. [7] Advances in hardware and software technologies have provided conformal radiation techniques, [8] which are aided by advanced imaging systems to deliver a desired dose of radiation to the precise location of a tumor, thus maximizing therapeutic effects while minimizing radiation damage to normal organs. [9] Radiosensitizers can be introduced during RT to enhance the radiotherapeutic effects of ionizing radiation. The radiosensitizers can be classified as: 1) chemotherapies such as cisplatin, 5-fluorouracil, and taxanes; 2) gaseous molecules such as O 2 , NO, and H 2 S; and 3) high-Z elements such as Au, Ba, Bi, Pt, Hf, and W. Chemotherapies presumably enhance RT by arresting cancer cells in the most radiation-sensitive phases of the cell cycle and eliminating radioresistant cells in late S phase but often cause debilitating side effects to cancer patients. Gaseous radiosensitizers enhance RT by increasing ROS production and/or reducing the expression of hypoxia-inducible factor-1α (HIF-1α). It is, however, challenging to ensure therapeutic efficacy due to the difficulty in controlling their concentrations, diffusion rates, and tumor retention. High-Z elements enhance RT by increasing biological reactions and depositing more radiation energy in tumors, via their stronger interactions with secondary photons and electrons, than in normal tissues. [10] In addition to increasing local antitumor effects of RT, the holy grail of radiosensitizer design is to improve the killing of tumor cells outside of the irradiated fields (abscopal effect). An ideal radiosensitizer would enhance RT to produce systemic antitumor effects by inducing immunogenic cell death (ICD), enhancing the presentation of tumor-associated antigens (TAAs), and activating cytotoxic T cells to mount host immune responses.Although RT is widely used to treat many different types of tumors, it has several limitations. First, radio-resistance is a key impediment to both curative and palliative RT. Previous research on enhancing the effectiveness of RT has mainly focused on cancer cells while neglecting the complicated Radiotherapy (RT) uses ionizing radiation to eradicate localized tumors and, in rare cases, control tumors outside of the irradiated fields via stimulating an antitumor immune response (abscopal effect). However, the therapeutic effect of RT is often limited by inherent physiological barriers of the tumor microenvironment (TME), such as hypoxia, abnormal vasculature, dense extracellular matrix (ECM), and an immunosuppressive TME. Thus, it is critical to develop new RT strategies tha...

Albumin-Modified Gold Nanoparticles as Novel Radiosensitizers for Enhancing Lung Cancer Radiotherapy

“…However, the therapeutic efficacy could not be ensured due to the difficulty in controlling the concentration, diffusion rate, and retention time of gas molecules at the tumor site. 39 …”

“…However, the therapeutic efficacy could not be ensured due to the difficulty in controlling the concentration, diffusion rate, and retention time of gas molecules at the tumor site. 39 As an alternative option, metal-based nanomaterials, especially high-Z materials (eg, Au, bismuth, platinum, gadolinium), have been used in experimental and clinical applications as common radiosensitizers. [40][41][42] Owing to the emission of low-energy photoelectrons and the interaction of Auger electrons, high-Z nanomaterials can absorb, scatter, and eradicate radiation energy.…”

Oxygen-generating biocatalytic nanomaterials for tumor hypoxia relief in cancer radiotherapy

“…120 This is because radiobiology plays an essential role in the immunostimulatory effects that can synergize with other immune-tumor agents for combating tumors. 53,121,122 In a recent study, Yue et al developed a small molecule PI3-kinase γ (PI3kγ) inhibitor (IPI549) loaded PEGylated HMnO 2 (HMP) bridged radioimmunotherapy nanoplatform (Fig. 7c).…”

Bi2–xMnxO3 Nanospheres Engaged Radiotherapy with Amplifying DNA Damage

“…RT induced tumor cell apoptosis or necrosis by directly or indirectly damaging DNA to achieve the goal of eliminating tumors. − However, the radiation resistance effect formed by the complex physiological environment and metabolic mode of solid tumors limited its long-term application. − To overcome the radiation tolerance and resistance, a radiosensitization strategy was proposed to improve local radiation deposition and reactive oxygen species (ROS) accumulation by employing high atomic number (high- Z ) nanomaterials . Many high- Z metal element nanomaterials were developed for the purpose of enhancing radiosensitivity to improve the efficiency of radiotherapy, hafnium (Hf), tantalum (Ta), tungsten (W), gadolinium (Gd), gold (Au), platinum (Pt), and bismuth (Bi). ,, Among them, Bi-based nanostructures were widely developed for computed tomography-guided radiosensitization due to their high atomic number and X-ray attenuation coefficient. − Nevertheless, the hypoxia and antioxidant microenvironment not only incalculably improved the reparation of incomplete DNA induced by irradiation, but also maintained the immunosuppressive microenvironment, causing the failure of tumor elimination. − Despite that, many strategies were attempted to alleviate hypoxia and deplete glutathione (GSH) to enhance DNA damage, thus improving the radiotherapy efficiency, such as delivering exogenous O 2 , , increasing intratumoral blood flow, − generating O 2 in situ , − and thiol oxidants or electrophilic chemicals reacting and transition metal ions depleting GSH. , It was very important to develop new Bi-based radiosensitizers with O 2 generation and GSH consumption properties to amplify DNA damage for enhancing radiotherapy.…”

“…RT could induce the breakage of double-stranded DNA, which was sensed by cyclic GMP-AMP synthase (cGAS) in tumor cells, resulting in the activation of the stimulator of STING. Then, STING as an innate immune sensor could induce the generation of type I interferons and proinflammatory factors to activate DCs, triggering a systemic immune response. , Meanwhile, Mn 2+ was confirmed to be the most prominent agonist of the cGAS–STING pathway, which not only directly activated cGAS and STING but also increased the sensitivity of cGAS to recognize cytoplasmic DNA, thereby significantly reducing the dsDNA threshold concentration required for cGAMP synthesis. , …”