1. Academic Validation
  2. Selective Targeting of Cancer-Associated Fibroblasts by Engineered H-Ferritin Nanocages Loaded with Navitoclax

Selective Targeting of Cancer-Associated Fibroblasts by Engineered H-Ferritin Nanocages Loaded with Navitoclax

  • Cells. 2021 Feb 5;10(2):328. doi: 10.3390/cells10020328.
Leopoldo Sitia 1 Arianna Bonizzi 1 Serena Mazzucchelli 1 Sara Negri 2 Cristina Sottani 2 Elena Grignani 2 Maria Antonietta Rizzuto 3 Davide Prosperi 3 Luca Sorrentino 4 Carlo Morasso 2 Raffaele Allevi 1 Marta Sevieri 1 Filippo Silva 1 Marta Truffi 2 Fabio Corsi 1 2
Affiliations

Affiliations

  • 1 Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università di Milano, 20157 Milan, Italy.
  • 2 Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy.
  • 3 Department of Biotechnology and Biosciences, University of Milan-Bicocca, 20126 Milan, Italy.
  • 4 Colorectal Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133 Milan, Italy.
Abstract

Cancer-associated fibroblasts (CAFs) are key actors in regulating Cancer progression. They promote tumor growth, metastasis formation, and induce drug resistance. For these reasons, they are emerging as potential therapeutic targets. Here, with the aim of developing CAF-targeted drug delivery agents, we functionalized H-ferritin (HFn) nanocages with fibroblast activation protein (FAP) antibody fragments. Functionalized nanocages (HFn-FAP) have significantly higher binding with FAP+ CAFs than with FAP- Cancer cells. We loaded HFn-FAP with navitoclax (Nav), an experimental Bcl-2 Inhibitor pro-apoptotic drug, whose clinical development is limited by its strong hydrophobicity and toxicity. We showed that Nav is efficiently loaded into HFn (HNav), maintaining its mechanism of action. Incubating Nav-loaded functionalized nanocages (HNav-FAP) with FAP+ cells, we found significantly higher cytotoxicity as compared to non-functionalized HNav. This was correlated with a significantly higher drug release only in FAP+ cells, confirming the specific targeting ability of functionalized HFn. Finally, we showed that HFn-FAP is able to reach the tumor and to target CAFs in a mouse syngeneic model of triple negative breast Cancer after intravenous administration. Our data show that HNav-FAP could be a promising tool to enhance specific drug delivery into CAFs, thus opening new therapeutic possibilities focused on tumor microenvironment.

Keywords

H-ferritin; cancer-associated fibroblasts; fibroblast activation protein; navitoclax; targeted nanoparticles.

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