High-grade serous ovarian cancer (HGSOC) is among the deadliest human cancers and its prognosis remains extremely poor. An article published in Advanced Science explored the self-therapeutic properties of gold nanoparticles to identify a molecular axis that fosters the growth of HGSOC.
The gold nanoparticles injected intravenously or intraperitoneally in single or multiple doses over two weeks were assessed for their biodistribution and toxicity. The gold nanoparticles showed no histological or biochemical toxicity to vital organs.
Furthermore, an orthotopic patient-derived xenograft (PDX) model was used to confirm that the gold nanoparticles inhibited tumor growth in patients with HGSOC. Moreover, to validate the molecular mechanisms underlying the efficacy of gold nanoparticles, a cell line-based human xenograft tumor was treated with gold nanoparticles and PI-103 (an mTOR dual-kinase inhibitor), individually and as a combination therapy (of gold nanoparticles and PI-103).
The results revealed that the combination therapy showed similar tumor growth inhibition as gold nanoparticles alone. Thus, the present report illustrated the self-therapeutic properties of gold nanoparticles which can be explored to identify a critical signaling axis associated with poor prognosis in ovarian cancer, providing an opportunity to rectify and improve patient outcomes.
Biomedical Applications of Gold Nanoparticles
HGSOC is a unique epithelial cancer characterized by the dysfunction of p53, genomic instability rather than driver mutations, advanced stage at onset, probable fallopian tube epithelium origin, and a serous tubal in situ carcinoma precursor. Germline deleterious mutations in BRCA1 and BRCA2 genes, as well as other less prevalent genes involved in DNA repairs, such as PALB2 and RAD51c, are associated with its carcinogenesis.
Major efforts in biomedical nanotechnology have focused on drug delivery and biosensor applications. Although the size- and shape-dependent physicochemical and optoelectronic properties of inorganic nanoparticles have been studied in detail, their biological properties remain practically unexplored.
Gold nanoparticles have attracted wide attention in various biomedical applications because they are biocompatible, easy to synthesize, characterize, and modify surfaces because of the strong ability of gold nanoparticles to bind to thiol (–SH-) and amine (–NH2-) containing molecules.
Gold nanoparticles have tunable chemical, optoelectronic, and biological properties, increasing their applicability in therapeutic agents, sensory probes, drug delivery vehicles, and catalytic agents.
Previously, the self-therapeutic properties of 20-nanometer gold nanoparticles that inhibited tumor growth in two preclinical orthotopic models of ovarian cancer were demonstrated. This took place through through the inhibition of mitogen-activated protein kinase (MAPK)-activation and reversal of epithelial-mesenchymal transition (EMT) via downregulation of several heparin-binding growth factors.
Furthermore, exploiting the self-therapeutic property of gold nanoparticles, the disruption of bidirectional crosstalk between pancreatic cancer cells and pancreatic cancer-associated fibroblasts (CAFs) that reprogrammed tumor microenvironment (TME) in pancreatic cancer led to the inhibition of tumor growth in an orthotopic model was reported.
Gold Nanoparticles Towards Inhibition of Ovarian Cancer Growth
Previously, gold nanoparticles were utilized as a tool to capture proteins of interest. Once administered into a biological system, gold nanoparticles interact with various molecules and form a protein corona on the surface, impacting the biological properties of the particle.
Exploring the modulation of the protein corona around gold nanoparticles helped identify various new targets, including hepatoma-derived growth factor (HDGF), survival motor neuron domain containing 1 (SMNDC1), inorganic pyrophosphatase (PPA1), peptidase inhibitor 15 (PI15), gasdermin B, and insulin-like growth factors (IGFs) in ovarian cancer.
Based on the bioaccumulated gold nanoparticles, the non-toxic dose of the nanoparticles was determined to demonstrate the suppression of tumor growth in an orthotopic PDX model mouse. The antitumor activity was mediated via an autoregulatory feedback loop of IGFBP2/PTEN interaction through the deactivation of the PI3K/Akt/mTOR growth signaling pathway and activating the survival protein PTEN. Moreover, the combination therapy of gold nanoparticles and PI-103 showed similar tumor growth inhibition as gold nanoparticles alone.
Thus, the present study demonstrated that the gold nanoparticles could serve as an important tool to investigate and identify the critical molecular axes responsible for the progression of ovarian cancer.
Conclusion
In conclusion, a new regulatory protein, IGFBP2, was identified that facilitated the gold nanoparticles to impair the development and progression of ovarian cancer. Based on the non-toxic dose of gold nanoparticles, the suppression of tumor growth in an orthotopic PDX model mouse was demonstrated.
A novel application of self-therapeutic nanoparticles was demonstrated in the present study. Additionally, the key signaling axis responsible for tumor growth was identified. These nanoparticles were used to validate their IGFBP2 targeting capacity to study the feasibility of this concept. The results revealed that the reduction of IGFBP2 levels partially mediated the antitumor efficacy of gold nanoparticles.
Thus, self-therapeutic gold nanoparticles were presented as a promising therapy for ovarian cancer either as an individual or combination therapy (with PI-103), adding value to the current treatment, which is limited by options and poor outcomes. These nanoparticles can also be quickly translated into the clinic.
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