External and Internal Stimuli-Responsive Metallic Nanotherapeutics for Enhanced Anticancer Therapy

Abstract

Therapeutic, diagnostic, and imaging approaches based on nanotechnology offer distinct advantages in cancer treatment. Various nanotherapeutics have been presented as potential alternatives to traditional anticancer therapies such as chemotherapy, radiotherapy, and surgical intervention. Notably, the advantage of nanotherapeutics is mainly attributable to their accumulation and targeting ability toward cancer cells, multiple drug-carrying abilities, combined therapies, and imaging approaches. To date, numerous nanoparticle formulations have been developed for anticancer therapy and among them, metallic nanotherapeutics reportedly demonstrate promising cancer therapeutic and diagnostic efficiencies owing to their dense surface functionalization ability, uniform size distribution, and shape-dependent optical responses, easy and cost-effective synthesis procedure, and multiple anti-cancer effects. Metallic nanotherapeutics can remodel the tumor microenvironment by changing unfavorable therapeutic conditions into therapeutically accessible ones with the help of different stimuli, including light, heat, ultrasound, an alternative magnetic field, redox, and reactive oxygen species. The combination of metallic nanotherapeutics with both external and internal stimuli can be used to trigger the on-demand release of therapeutic molecules, augmenting the therapeutic efficacies of anticancer therapies such as photothermal therapy, photodynamic therapy, magnetic hyperthermia, sonodynamic therapy, chemodynamic therapy, and immunotherapy. In this review, we have summarized the role of different metallic nanotherapeutics in anti-cancer therapy, as well as their combinational effects with multiple stimuli for enhanced anticancer therapy.

Keywords: clinical status; external-stimuli; immunotherapy; internal-stimuli; magnetic hyperthermia; metallic nanotherapeutics; phototherapy; sonodynamic therapy.

Figure 1

Biomedical applications of metallic nanoparticles. Metallic nanoparticles are used as potent candidates for different types of diseases due to their unique properties and imaging characteristics.

Figure 2

Metallic nanotherapeutic applications in cancer theranostics. Metallic nanotherapeutics are used for different types of anticancer therapies and multimodal imaging.

Figure 3

Mechanism of cavitation and ROS production by TiO₂ and ZnO nanoparticles. Reproduced with permission (Bogdan et al., 2017) Copyright © 2017, Springer Nature.

Figure 4

Schematic representation of self-assembled MnO₂ nanoparticles modified with photosensitizer for photodynamic therapy (PDT) (A). Application of MnO₂ nanoparticles catalyze endogenous peroxidase to oxygen and water and enhance the PDT efficacy upon laser exposure (B,C). Reproduced with permission (Lin et al., 2018) under copyright Creative Commons Attribution 4.0 International License (CC-BY license).

Figure 5

Amino acid-modified copper nanoparticles (CuNPs) induce anticancer effects. CuNPs oxidize glutathione (GSH) to glutathione disulfide (GSSG) and generate Cu⁺ ions, further reacting with endogenous peroxidase to generate hydroxyl radicals to kill cancer cells. Reproduced with permission (Ma et al., 2018) Copyright © 2019, American Chemical Society.

Figure 6

Application of external and internal stimuli-triggered metallic nanotherapeutics for cancer therapy. Different stimuli such as light, an alternative magnetic field (AMF), ultrasound (US), redox, and reactive oxygen species (ROS) trigger metallic nanotherapeutics to exert their anticancer activities. External stimuli such as light, AMF, and US induce phototherapy, magnetic hyperthermia, and sonodynamic therapy, whereas internal stimuli such as redox and ROS promote toxic radical production, resulting in tumor death. Antigens are released upon tumor death and captured by antigen-presenting cells, which further trigger cytotoxic immune cell activation against metastatic tumors.

Figure 7

Synthesis procedure of magnetic nanoparticle (A). Mechanism of Brain tumor targeted IONP application in cancer cells via the Fenton reaction (B). Reproduced with permission (Shen et al., 2018). Copyright © 2018, American Chemical Society.

Figure 8

Application of PEGylated titanium monoxide nanorods (TiO₂ NRs) in sonodynamic therapy. Oxygen-deficient TiO₂ NRs have shown higher reactive oxygen species (ROS) generation upon ultrasound irradiation. Reproduced with permission (Wang et al., 2020d) Copyright © 2020, American Chemical Society.

Figure 9

Alternative magnetic field (AMF)-induced hyperthermia and immune therapy. AMF-induced heat triggers immunogenic cell death (ICD) and antigen release in tumors, which further induces cytotoxic T lymphocyte activation, and the combination with checkpoint blockade activates antitumor immune therapy. Reproduced from Liu et al. (2019b) Copyright © 2019, American Chemical Society.

Figure 10

Gold nanostars (GNS) modified with folic acid and thiolated polyethylene glycol (PEG) for targeted cancer therapy. GNS coated with dopamine can facilitate doxycycline (DOX)-loading and are modified with targeting ligands for near-infrared (NIR)-triggered drug release and photothermal chemotherapy. Reproduced with permission from You et al. (2019) under copyright Creative Commons Attribution 4.0 International License (CC-BY license).

Figure 11

Schematic representation of Cu-PPT based synergistic anticancer effect with photothermal therapy, photodynamic therapy, and chemodynamic therapy (A). Mechanism of Synergistic therapy triggers the release of tumor-associated antigens and PD-1/PD-L1 combination induced a robust antitumor immunity (B). Reproduced with permission from Hu et al. (2020) under Copyright © 2020, American Chemical Society.

Figure 12

Mechanism of toll-like receptor (TLR)-7 agonist-based iron oxide nanoparticle (IONP) delivery with a checkpoint blockade antibody for alternative magnetic field (AMF)-induced magnetic hyperthermia and immune therapy. Reproduced from Chao et al. (2019) Copyright © 2019, American Chemical Society.