Fe-doped chrysotile nanotubes containing siRNAs to silence SPAG5 to treat bladder cancer

Our plain-English summary of Fe-doped chrysotile nanotubes containing siRNAs to silence SPAG5 to treat bladder cancer, by J. Liu, Y. Zhang, H. Zeng, et al (Journal of Nanobiotechnology, 2021).

The study

• Authors: J. Liu, Y. Zhang, H. Zeng, L. Wang, Q. Zhang, P. Wu, X. Liu, H. Xie, W. Xiang, B. Liu, J. Liu, X. Liu, J. Xie, J. Tang, Z. Long, L. He, M. Xiao, L. Xiang, K. Cao
• Journal: Journal of Nanobiotechnology
• Published: 2021;19(1):189
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: For certain human cancers, sperm associated antigen 5 (SPAG5) exerts important functions for their development and progression. However, whether RNA interference (RNAi) targeting SPAG5 has antitumor effects has not been determined clinically.

Results: The results indicated that Fe-doped chrysotile nanotubes (FeSiNTs) with a relatively uniform outer diameter (15-25 nm) and inner diameter (7-8 nm), and a length of several hundred nanometers, which delivered an siRNA against the SPAG5 oncogene (siSPAG5) efficiently. The nanomaterials were designed to prolong the half-life of siSPAG5 in blood, increase tumor cell-specific uptake, and maximize the efficiency of SPAG5 silencing. In vitro, FeSiNTs carrying siSPAG5 inhibited the growth, migration, and invasion of bladder cancer cells. In vivo, the FeSiNTs inhibited growth and metastasis in three models of bladder tumors (a tail vein injection lung metastatic model, an in-situ bladder cancer model, and a subcutaneous model) with no obvious toxicities. Mechanistically, we showed that FeSiNTs/siSPAG5 repressed PI3K/AKT/mTOR signaling, which suppressed the growth and progression of tumor cells.

Conclusions: The results highlight that FeSiNTs/siSPAG5 caused no activation of the innate immune response nor any systemic toxicity, indicating the possible therapeutic utility of FeSiNTs/siSPAG5 to deliver siSPAG5 to treat bladder cancer.

In plain English

The authors synthesised Fe-doped chrysotile nanotubes (FeSiNTs) by hydrothermal treatment and tested them in cells and animals as carriers for a small interfering RNA against the SPAG5 gene in bladder cancer. In their background the authors stated that long-term asbestos exposure can cause chronic pleural diseases, pulmonary fibrosis and lung cancers, depending on length-to-diameter ratio and possibly metal content, and argued that synthetic chrysotile a few hundred nanometres long has little toxic potential compared with natural chrysotile longer than 10 micrometres; no human exposure was studied. Electron microscopy showed hollow tubes with an outer diameter of 7-8 nm and inner diameter of 3-5 nm. In T24 human bladder cancer cells, FeSiNTs carrying a negative-control siRNA showed no obvious toxicity up to 200 micrograms/mL, and FeSiNTs-siRNA at 150 nM siRNA equivalent reduced SPAG5 mRNA by 95% versus untreated control. In the subcutaneous mouse model treated by weekly intratumoral injection, tumour volume was 69% lower than with PBS (19% lower with free siRNA); in a separate tail-vein lung metastasis model, lung metastatic nodules were 81.8% fewer than with PBS. The authors concluded the nanoparticles could potentially be used for siRNA delivery in bladder-directed therapy.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory nanomaterial synthesis with in vitro cell experiments and animal tumour experiments (mice and rats)
• Who was studied: T24 human bladder cancer cell line; male BALB/c nude mice bearing subcutaneous T24 xenografts and a tail-vein lung metastasis model (5 mice per group); 60 female SD rats with MNU-induced in-situ bladder cancer assigned to 4 groups of 15
• Exposure: Synthetic Fe-doped chrysotile nanotubes (FeSiNTs, Fe content up to 1.37 wt.%) loaded with siRNA against SPAG5, given to cells (150 nM siRNA) and to animals by intratumoral injection (20 micrograms siSPAG5 per injection, weekly for 5 weeks), bladder instillation, or tail vein injection (0.3 mg/kg)
• Main results:
  • The nanotubes had a hollow tubular morphology with outer diameter 7-8 nm, inner diameter 3-5 nm, and length of several hundred nanometres (note: the article's own abstract gives different diameters)
  • Cytotoxicity in T24 cells was assessed with FeSiNTs carrying the negative-control (NC) siRNA
  • No obvious toxicity of the FeSiNTs complexes was seen in T24 cells at the highest concentration tested, 200 micrograms/mL
  • In T24 cells, FeSiNTs-siRNA at 150 nM siRNA equivalent reduced SPAG5 mRNA by 95% compared with the untreated control
  • Cell-cycle proliferation index (PI) values in T24 cells: 0.52 (PBS), 0.51 (FeSiNTs), 0.50 (FeSiNTs/siNC), 0.39 (FeSiNTs/siSPAG5)
  • In the subcutaneous mouse model, in which 20 micrograms of siRNA was injected intratumorally weekly five times, tumour volume was 69% lower with FeSiNTs-siSPAG5 and 19% lower with free siRNA, compared with PBS control
  • Route and schedule in the subcutaneous model
  • In the tail-vein injection lung metastasis mouse model, pulmonary metastatic nodules were 81.8% fewer in the FeSiNTs-siSPAG5 group than in the PBS group
  • In the rat in-situ bladder cancer model, most tumours after FeSiNTs-siSPAG5 were stage pTa/T1 while most tumours in the other groups were higher than pT2
  • Organ histology showed no obvious differences between FeSiNTs-siSPAG5-treated and control-treated mice; free siRNA was associated with relatively high ALT and AST and increased IL-6 and TNF-alpha
  • In tumour tissue from the subcutaneous model, PI3K/AKT/mTOR pathway proteins were decreased after FeSiNTs-siSPAG5, but unchanged after FeSiNTs or free siSPAG5
• The authors' conclusion: The authors concluded that the Fe-doped chrysotile nanotubes could potentially serve as an siRNA delivery method for bladder-directed therapy and were well tolerated in their experiments
• Limitations the authors state:
  • The explanation offered for the longer tumour retention of the loaded nanotubes was stated as speculation
  • The authors presented the downstream signalling mechanism tentatively, saying SPAG5 might act through the PI3K/AKT/mTOR pathway

Topics

The National Library of Medicine indexes this study under subjects our site covers: Chrysotile.

Medical terms in this study, explained in our Lexicon: Chrysotile, Metastasis.

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