Application of High-Z Nanoparticles to Enhance Current Radiotherapy Treatment

Abstract

Radiotherapy is an essential component of the treatment regimens for many cancer patients. Despite recent technological advancements to improve dose delivery techniques, the dose escalation required to enhance tumor control is limited due to the inevitable toxicity to the surrounding healthy tissue. Therefore, the local enhancement of dosing in tumor sites can provide the necessary means to improve the treatment modality. In recent years, the emergence of nanotechnology has facilitated a unique opportunity to increase the efficacy of radiotherapy treatment. The application of high-atomic-number (Z) nanoparticles (NPs) can augment the effects of radiotherapy by increasing the sensitivity of cells to radiation. High-Z NPs can inherently act as radiosensitizers as well as serve as targeted delivery vehicles for radiosensitizing agents. In this work, the therapeutic benefits of high-Z NPs as radiosensitizers, such as their tumor-targeting capabilities and their mechanisms of sensitization, are discussed. Preclinical data supporting their application in radiotherapy treatment as well as the status of their clinical translation will be presented.

Keywords: cancer; chemotherapy; nanoparticle; radiosensitizer; radiotherapy; therapeutics.

Figure 4

Enhanced cellular uptake of nanoparticles via targeting moieties. (A) Dark-field imaging of gold nanoparticles (yellow color) in MDA-MB-231 cells incubated with PBS (control), anti-CXCR4 functionalized GNPs (cGNP), or PEGylated GNPs (pGNP). Cell nuclei are stained in blue. (B) Cell uptake of rhodium-labeled folate functionalized AuNPs (Rho-FAx-AuNPs) by KB (overexpression of folate receptors) and MCF-7 (low expression of folate receptors) cells. AuNPs were functionalized with various surface concentrations of folate. Statistical significance was calculated versus non-targeted particles (Rho-Fa0 -AuNPs): **** p < 0.0001, ns nonsignificant. (C) Effects of PEG and RGD on the cellular accumulation of GNPs. Reproduced with permission from open access Creative Common license [16,28,30].

Figure 6

Radiosensitization due to high-Z nanoparticles. (A) Normalized tumor volumes of MDA-MB-231 xenograft tumor-bearing mice post treatment with cGNP alone, radiation (10 Gy single dose) alone, pGNP + radiation (RT), or cGNP + RT (B) Survival fraction curves of CHO-K1 cells treated with AuNPs and irradiated at various doses with a 200 MeV proton beam. (C) Kaplan–Meier survival curves for U251 tumor-bearing mice treated with AuNPs or AgNPs with or without ionizing radiation (IR). Mice were irradiated with a single dose of 8 Gy with a 6 MV X-ray beam. Mice were treated with AgNPs at the same molar concentration (mol-AgNPs) or mass concentration (mas-AgNPs) as AuNPs. (D) Apoptosis of U251 cells after treatment with AgNPs or AuNPs combined with a radiation dose of 6 Gy. * p < 0.05, *** p < 0.001 compared with the control group. ## p < 0.01, ### p < 0.001 compared with the corresponding AuNPs-treated group (E) Tumor volume growth curves after treatment with HA-Gd₂O₃ NPs and radiation (R + HA-Gd). Mice were administered 3 fractions of 3 Gy with a 6 MeV beam over a 7-day period for a total of 9 Gy. Reproduced with permission from open access Creative Common license [28,74,75,76].

Figure 7

Dual radiosensitization through docetaxel-loaded gold nanoparticles. (A) Normalized tumor growth curves of 22RV1 xenograft tumor-bearing mice after irradiation of 6 Gy with 6 MeV electron beam. (B) Concentration of Au in 22RV1 xenograft tumor post-injection with Au-DUPA NPs or Au@DTX-DUPA NPs. (C) Cell cycle analysis of 22RV1 cells after treatment with Au-DUPA NPs, free DTX, or Au@DTX-DUPA NPs. (D) Ki67 staining assay of tumors 15 days post treatment to indicate proliferative capacity. * p < 0.05, ** p < 0.01. Reproduced with permission from open access Creative Common license [90].

Figure 1

Idea for using radiosensitizing high-Z NPs in radiotherapy treatment regimens. Prior to radiotherapy, high-Z NPs can be administered to the patient and allowed to accumulate in tumor tissue. This can increase the tumor’s sensitivity to radiotherapy, leading to enhanced tumor control for patients. (Created using Biorender.com).

Figure 2

Passive targeting of NPs. (A) The poor structural integrity and lymphatic drainage of the tumor vasculature system result in the passive preferential accumulation of NPs in tumors compared with normal tissue. This is referred to as the EPR effect. (Created using Biorender.com). (B) Hyperspectral imaging demonstrating blood vessels facilitating the delivery of GNPs to the surrounding mice tumor tissue. Reproduced with permission from open access Creative Common license [16].

Figure 3

Active targeting of NPs. (A) Many cancer cells overexpress various surface receptors in comparison with normal cells. The surface of NPs can be strategically modified with corresponding ligands to specifically bind to these receptors, increasing their uptake in cancer cells. (Created using Biorender.com). (B) Accumulation of cancer targeting GNPs in cancer cells versus normal fibroblasts. Cancer cells demonstrate greater accumulation of GNPs compared with normal fibroblasts due to their overexpression of targeted receptors. Top panel: hyperspectral imaging of GNPs. Bottom panel: confocal imaging of GNPs (red) and microtubules (green). Reproduced with permission from open access Creative Common license [20].

Figure 5

Mechanisms of high-Z NP radiosensitization. NPs can increase the sensitivity to radiation of cells through physical, chemical, and biological mechanisms. NPs interact with ionizing radiation, producing a shower of secondary electrons that can exert damage upon the cell. The electronically active surface NPs also catalyze the production of DNA-damaging ROS and free radicals, damaging critical cellular components. NPs can also increase the sensitivity of cells to radiation through oxidative stress and cell cycle effects. (Created using Biorender.com).