Cancer-associated fibroblasts specific gene silencing for anti-stromal therapy in primary liver cancer using novel anti-MFAP-5 siRNA-loaded polymeric nanoparticles

Background Cancer associated fibroblasts (CAF) support tumor growth and metastasis in the tumor microenvironment (TME) and are therefore promising target cells for anti-stromal therapy in hepatocellular carcinoma (HCC) [Kaps, Schuppan; Cells 2020].

Results Nanoparticles (NP) have been designed utilizing the triblock copolymer polysarcosine-b-poly(γ-benzyl glutamic acid)-b-polylysine, which enables co-loading of siRNA and desloratadine (DES), a small molecule to trigger endosomal release. For the HCC model, healthy B6 mice were intrasplenically injected with 500.000 HCC cells to develop macroscopic tumor lesions exclusively in their livers after 28 days For in vivo anti-stromal therapy, tumor mice (n=5) received three intravenous injections of NP loaded with anti-MFAP-5 siRNA (corresponding to 0.5 or 1 mg/kg siRNA) in week four, while controls received equal concentrations of NP loaded with non-targeting scrambled siRNA (scsiRNA). Liver weights of mice treated with anti-MFAP-5 siRNA were significantly (*p<0.05) lower compared to mice treated with encapsulated scsiRNA, indicating less hepatic tumor burden. The treatment was well tolerated by the mice and serum parameters for liver- and nephrotoxicity were in the normal range. Histological analysis of liver sections revealed that markers of tumor vascularization (CD34 and CD105) were down regulated in the TME, suggesting an anti-angiogenic effect of the siRNA treatment, which was supported by the transcriptome analysis of whole liver tissue.

Conclusions Liver targeting NP loaded with siRNA induced a gene specific knockdown of CAF derived MFAP-5 and demonstrated a convincing antitumor effect by interference with angiogenesis in the TME of HCC

Publication History

Article published online:
23 January 2024