Ag/Au Bimetallic Nanoparticles Inhibit Tumor Growth and Prevent Metastasis in a Mouse Model

Int J Nanomedicine. 2020 Aug 12:15:6019-6032. doi: 10.2147/IJN.S251760. eCollection 2020.

Abstract

Purpose: To evaluate the antitumor efficacy of Ag3Au1Trp1:2NPs in a SCID mouse cancer model, with respect to their effect on tumor growth, on tumor's metastatic potential and the underlying molecular mechanism.

Subjects and methods: Ag3Au1Trp1:2NPs were radiolabeled with Gallium-68 and the biodistribution was studied in Swiss mice without tumors and in SCID mice bearing tumors. SCID mice received intratumoral Ag3Au1Trp1:2NPs and tumor size was measured using calipers. Lung and liver tissues were extracted and studied microscopically for the detection of any metastatic sites. Changes in the Caspase-3 and TNF-related apoptosis-inducing ligand (TRAIL) were also investigated using real-time PCR and Western blot techniques, respectively.

Results: In the 4T1 tumor-bearing SCID mice, Ag3Au1Trp1:2NPs showed quick passive accumulation at tumor sites at 30 mins post-injection. Mice that received the highest dose of NPs (5.6mg/mL) demonstrated a 1.9-fold lower tumor volume compared to that of the control group at 11 days post-injection, while mice that did not receive NPs showed metastatic sites in liver and lung. Extracted tumor tissue of treated mice revealed increased Casp-3 mRNA levels as well as elevated TRAIL protein levels.

Conclusion: Based on our results, Ag3Au1Trp1:2NPs express anti-tumor and anti-metastatic effects in vivo. Ag3Au1Trp1:2NPs also reach tumor site via the enhancement and retention effect which results in the apoptotic death of cancerous cells selectively via the extrinsic TRAIL-dependent pathway.

Keywords: Casp-3; SCID mice; TRAIL; cancer; nanoparticles.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Female
  • Gallium Radioisotopes / chemistry
  • Gold / chemistry
  • Gold / pharmacology
  • Liver Neoplasms / prevention & control
  • Liver Neoplasms / secondary
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Metal Nanoparticles / chemistry
  • Metal Nanoparticles / therapeutic use*
  • Mice, SCID
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / pathology*
  • Silver / chemistry
  • Silver / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Tissue Distribution
  • Tumor Burden

Substances

  • Antineoplastic Agents
  • Gallium Radioisotopes
  • TNF-Related Apoptosis-Inducing Ligand
  • Tnfsf10 protein, mouse
  • Silver
  • Gold
  • Gallium-68
  • Casp3 protein, mouse
  • Caspase 3

Grants and funding

This research is co-financed by Greece and the European Union (European Social Fund – ESF) through the Operational Programme Human Resources Development, Education and Lifelong Learning in the context of the project “Strengthening Human Resources Research Potential via Doctorate Research −2nd Cycle” (MIS-5000432), implemented by the State Scholarships Foundation (ΙΚΥ).