Ultrasmall gold nanoparticles in cancer diagnosis and therapy

Abstract

Due to their lower systemic toxicity, faster kidney clearance and higher tumor accumulation, ultrasmall gold nanoparticles (less than 10 nm in diameter) have been proved to be promising in biomedical applications. However, their potential applications in cancer imaging and treatment have not been reviewed yet. This review summarizes the efforts to develop systems based on ultrasmall gold nanoparticles for use in cancer diagnosis and therapy. First, we describe the methods for controlling the size and surface functionalization of ultrasmall gold nanoparticles. Second, we review the research on ultrasmall gold nanoparticles in cancer imaging and treatment. Specifically, we focus on the applications of ultrasmall gold nanoparticles in tumor visualization and bioimaging in different fields such as magnetic resonance imaging, photoacoustic imaging, fluorescence imaging, and X-ray scatter imaging. We also highlight the applications of ultrasmall gold nanoparticles in tumor chemotherapy, radiotherapy, photodynamic therapy and gene therapy.

Keywords: cancer therapy; imaging; size; theranostics; ultrasmall gold nanoparticles.

Figure 1

The use of ultrasmall GNs in cancer diagnosis. (A) T2-weighted MR images of a healthy mouse (top) and a mouse bearing a liver tumor (MDA-MB-468; bottom) using superparamagnetic gold-nanoparticle clusters as a contrast agent. Adapted with permission from , copyright 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (B) Representative PAI cross-sectional images of A431 cells labeled with different concentrations of 5 nm ultrasmall GNs for 10 hours. Adapted with permission from , copyright 2019 Optical Society of America. (C) PET, CT, and PET/CT imaging of BALB/c mice injected with only radiolabeled GSH-GNs or radiolabeled GSH-GNs and cold Au. Adapted with permission from , copyright 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. (D) Representative in vivo and ex vivo NIR fluorescence images of MCF-7 tumor-bearing mice i.v.-injected with GSH-GNs and IRDye 800CW. Adapted with permission from , copyright 2013 American Chemical Society.

Figure 2

Ultrasmall GNs in cancer chemotherapy. Schematic representation of the synthesis and mechanism of action of GNs targeting the neuropilin-1 receptor. The scheme for the functionalization of GSH-GNs (Au-GSH) with the chemotherapeutic drug Pt(IV) and the targeting peptide CRGDK is shown in the top part. The fully functionalized delivery system is Au@Pt(IV)+CRGDK. The individual components are shown in the bottom part. The middle part shows the interaction between the neuropilin-1 receptor on the prostate cancer cell surface and the targeting ligand on the nanoparticles. This enhances cellular uptake of the nanoparticles by endocytosis and release of active cisplatin into the nucleus. Adapted with permission from , copyright 2014 American Chemical Society.

Figure 3

Ultrasmall GNs in cancer chemotherapy. Schematic representation of the synthesis and drug release mechanism of DOX-conjugated GNs. The upper part shows the scheme for preparing DOX-conjugated GNs. The lower part shows the release process after endocytosis of the DOX-conjugated GNs. DOX-mPEG is liberated from the GNs in the acidic lysosomes, and then free DOX is generated in the cytoplasm as a result of esterase activity. Adapted with permission from , copyright 2017 American Chemical Society.

Figure 4

Ultrasmall GNs in cancer radiotherapy. Schematic representation of the mechanism of action of nanodroplets containing ultrasmall GNs for cancer radiotherapy. The right part shows the nanodroplets efficiently accumulating at the tumor site and further triggering a rapid release of oxygen and ultrasmall GNs upon ultrasound treatment. The left part shows how the ultrasmall GNs enhance DNA damage induced by radiotherapy, while the oxygen simultaneously relieves tumor hypoxia and fixes the DNA radical intermediates, consequently preventing DNA repair and eventually causing cancer cell death. Adapted with permission from , copyright 2018 American Chemical Society.

Figure 5

Ultrasmall GNs in cancer PDT. The left part shows a schematic representation of the GN-based PDT drug delivery system, which has greatly increased water solubility and reduced drug delivery time. PEGylated GNs are conjugated to the hydrophobic PDT drug Pc 4. The right part shows the structure of Pc 4. Adapted with permission from , copyright 2008 American Chemical Society.

Figure 6

Ultrasmall GNs in PDT of prostate cancer in a mouse model. Schematic representation of ultrasmall GNs carrying the prostate-specific membrane antigen PSMA-1 for targeted delivery of the fluorescent PDT drug Pc 4 to prostate cancer cells. Pc 4 kills cancer cells when exposed to light. Adapted with permission from , copyright 2018 American Chemical Society.

Figure 7

Ultrasmall GNs in cancer gene therapy. Schematic representation of the distribution and localization behavior of smaller (2 nm) and larger (10 nm) GNs in MCF-7 cancer cells. The ultrasmall 2 nm GNs were able to enter the nucleus, and were used as a carrier to deliver a triplex-forming oligonucleotide (TFO) to regulate gene expression. Adapted with permission from , copyright 2014 American Chemical Society.

Figure 8

Ultrasmall GNs in cancer gene therapy. Schematic representation of the synthesis and mechanism of action of gold-DNA nanosunflowers for efficient gene silencing. The upper part (A) shows the reversible assembly of the large nanostructures from thiol-oligonucleotide-modified ultrasmall GNs. The lower part (B) shows that the large gold-DNA nanostructures dissociate upon NIR irradiation and release small units which enter the cell nucleus and silence the target oncogene (c-myc). Adapted with permission from , copyright 2019 The Authors.

Figure 9

Ultrasmall GNs in other treatments: amplification of mitochondrial oxidative stress. Schematic representation of the design and mechanism of triphenylphosphine- and cinnamaldehyde-modified carbon dots containing gold atoms. After the nanoparticles are taken up by endocytosis, acid-responsive cinnamaldehyde is released and then generates ROS in mitochondria. Following cinnamaldehyde release, gold atoms consume GSH by forming Au-S bonds. The changes of ROS and GSH in cells eventually lead to apoptotic cell death. Adapted with permission from , copyright 2019 The Author(s).