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Fusion-proteins based on human ferritin and protease-cleavable peptides and their use as chemotherapeutics carriers

A technology of fusion protein and protease, applied in the field of fusion protein, can solve problems such as decreased mineralization, osteopenia, and inhibition of human osteoblasts

Active Publication Date: 2020-06-23
THENA BIOTECH SRL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Finally, its native ferrous oxidase activity may inhibit the development and maturation of human osteoblasts and lead to decreased mineralization, osteopenia, and osteoporosis (Zarjou A, Jeney V, Arosio P, Poli M, Zavaczki E , Balla G, Balla J.Ferritin ferroxidase activity: a potent inhibitor of osteogenesis.J Bone Miner Res.2010,25:164-72)

Method used

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  • Fusion-proteins based on human ferritin and protease-cleavable peptides and their use as chemotherapeutics carriers
  • Fusion-proteins based on human ferritin and protease-cleavable peptides and their use as chemotherapeutics carriers
  • Fusion-proteins based on human ferritin and protease-cleavable peptides and their use as chemotherapeutics carriers

Examples

Experimental program
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Effect test

example 1

[0075] Example 1 is used for the construction of the expression vector of HFt-MP-PASE fusion protein

[0076] To reduce protein aggregation and increase stability, it was decided to introduce negatively charged residues in the outer shield-forming PAS sequence fused to each HFt subunit. Analysis of previously obtained HFt-MP-PAS constructs did show that the introduction of two glutamic acid residues in the 40-residue PAS sequence induces sufficient electrostatic repulsion to prevent dissimilar 24-mer assemblies from forming between each other. aggregation without affecting subunit assembly within the 24-mer. In order to distribute as much negative charge as possible on the surface of the construct, glutamic acid residues were placed at a distance of 20 residues.

[0077] The HFt-MP-PASE gene was obtained by combining three different sequences into one single sequence: HFt (SEQ ID NO: 1), MP (SEQ ID NO: 5) and PASE (SEQ ID NO: 10). This construct differs from the previously p...

example 2

[0080] Example 2 The preparation of HFt-MP-PAS and HFt-MP-PASE carrying chemotherapeutic drugs

[0081] As a chemotherapeutic agent, the inventors reported an example in which the drug mitoxantrone (MIT) or picantron (PIX) was used. According to the protocol disclosed in Falvo et al., 2016, Biomacromolecules. 17(2):514 22, these drugs were encapsulated within the protein cavity of the fusion protein by utilizing the coupling process of protein uncoupling as a function of pH. Disassembly / reassembly process such as image 3 shown.

example 3

[0082] Example 3 Test the encapsulation yield of drug mitoxantrone and picantron

[0083] The encapsulation efficiency of MIT or PIX in HFt-MP-PASE was compared with that in native HFt and HFt MP PAS ( Figure 4 ). In all experiments performed, HFt-MP-PASE outperformed both native HFt and HFt-MP-PAS proteins in terms of the amount of protein recovered at the end of the reaction. This indicates that HFt-MP-PASE is more stable and does not aggregate / precipitate out of solution during protein-drug complex formation.

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Abstract

A fusion protein, a nanoparticle composed by a plurality of monomers of said fusion protein, and uses thereof. A fusion protein based on the heavy chain of human ferritin is de- scribed, which includes at the N terminus of the protein at least one metalloproteinase cleavage sequence and a modified PAS polypeptide that acts as a masking polymer that in- creases the protein drug stability, as well as a nanoparticle composed of multiple monomers of said fusion protein, a nucleic acid encoding for said fusion protein, and diagnostic and therapeutic applications thereof.

Description

technical field [0001] The present invention relates to a fusion protein, a nanoparticle composed of multiple monomers of the fusion protein, a nucleic acid encoding the fusion protein, and diagnostic and therapeutic applications thereof. The present invention relates to a fusion protein, a nanoparticle composed of multiple monomers of the fusion protein and its use. A fusion protein based on the heavy chain of human ferritin comprising at least one metalloprotease cleavage sequence at the N-terminus of the protein and a modified PAS polypeptide that acts as a protein drug stability enhancer is described. The masking polymer of said fusion protein, as well as nanoparticles composed of multiple monomers of said fusion protein, nucleic acid encoding said fusion protein and its diagnostic and therapeutic applications. Background technique [0002] Selective release of therapeutic agents at diseased regions is one of the most important challenges to improve current therapies, e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/62B82Y5/00C07K14/47
CPCB82Y5/00C07K14/47C07K2319/31C07K2319/33C07K2319/50C07K2319/735A61K47/64A61K47/6925A61P35/00A61K9/51
Inventor 奥尔多·布拉卡
Owner THENA BIOTECH SRL
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