Human ferritin H-chain (HFt) nanoparticles represent one of the most appropriate vectors for cellular delivery of molecules thanks to their specific cell internalization by human Transferrin Receptor 1 (CD71), a transmembrane receptor overexpressed in most cancer cell types. In this PhD thesis I report the determination of the structure of HFt and CD71 in the form of complex, by using cryo electron microscopy (cryo-EM) technique. The two proteins have been shown to interact very tightly with nanomolar affinity, as assessed by Surface Plasmon Resonance (SPR) experiments. Our cryo-EM data unveil the residues involved in this contact and provide a sound structural basis to elaborate on the possibility of developing alternative ferritin-like anti-viral or anti-parasite therapeutic ligand, be it an antibody or a peptidomimetic capable of blocking the “common contacts” epitope on CD71 residue, and to further engineering ferritins as theranostic agents. In this thesis I also report the development and characterization, in vitro and in vivo, of two HFt-based nanovectors containing Mitoxantrone (MIT) or Genz-644282 as cancer drug payload, named HFt-MP-PASE-MIT or The-0504, respectively. The results reported here are very promising and pave the way for an effective cancer-targeted chemotherapy using our HFt-based nanovector platforms.

Engineered human nanoferritin for cancer therapy: development and biophysical characterization / Pitea, Martina. - (2021 Dec 13).

Engineered human nanoferritin for cancer therapy: development and biophysical characterization

PITEA, MARTINA
2021

Abstract

Human ferritin H-chain (HFt) nanoparticles represent one of the most appropriate vectors for cellular delivery of molecules thanks to their specific cell internalization by human Transferrin Receptor 1 (CD71), a transmembrane receptor overexpressed in most cancer cell types. In this PhD thesis I report the determination of the structure of HFt and CD71 in the form of complex, by using cryo electron microscopy (cryo-EM) technique. The two proteins have been shown to interact very tightly with nanomolar affinity, as assessed by Surface Plasmon Resonance (SPR) experiments. Our cryo-EM data unveil the residues involved in this contact and provide a sound structural basis to elaborate on the possibility of developing alternative ferritin-like anti-viral or anti-parasite therapeutic ligand, be it an antibody or a peptidomimetic capable of blocking the “common contacts” epitope on CD71 residue, and to further engineering ferritins as theranostic agents. In this thesis I also report the development and characterization, in vitro and in vivo, of two HFt-based nanovectors containing Mitoxantrone (MIT) or Genz-644282 as cancer drug payload, named HFt-MP-PASE-MIT or The-0504, respectively. The results reported here are very promising and pave the way for an effective cancer-targeted chemotherapy using our HFt-based nanovector platforms.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1596739
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