The transferrin receptor (TfR) is a promising target in cancer therapy owing to its overexpression in most solid tumors and on the blood-brain barrier. Nanostructures chemically derivatized with transferrin are employed in TfR targeting but often lose their functionality upon injection in the bloodstream. As an alternative strategy, we rationally designed a peptide coating able to bind transferrin on suitable pockets not involved in binding to TfR or iron by using an iterative multiscale-modeling approach coupled with quantitative structure-activity and relationship (QSAR) analysis and evolutionary algorithms. We tested that selected sequences have low aspecific protein adsorption and high binding energy toward transferrin, and one of them is efficiently internalized in cells with a transferrin-dependent pathway. Furthermore, it promotes transferrin-mediated endocytosis of gold nanoparticles by modifying their protein corona and promoting oriented adsorption of transferrin. This strategy leads to highly effective nanostructures, potentially useful in diagnostic and therapeutic applications, which exploit (and do not suffer) the protein solvation for achieving a better targeting.

Rational Design of a Transferrin-Binding Peptide Sequence Tailored to Targeted Nanoparticle Internalization

LUIN, Stefano;
2017

Abstract

The transferrin receptor (TfR) is a promising target in cancer therapy owing to its overexpression in most solid tumors and on the blood-brain barrier. Nanostructures chemically derivatized with transferrin are employed in TfR targeting but often lose their functionality upon injection in the bloodstream. As an alternative strategy, we rationally designed a peptide coating able to bind transferrin on suitable pockets not involved in binding to TfR or iron by using an iterative multiscale-modeling approach coupled with quantitative structure-activity and relationship (QSAR) analysis and evolutionary algorithms. We tested that selected sequences have low aspecific protein adsorption and high binding energy toward transferrin, and one of them is efficiently internalized in cells with a transferrin-dependent pathway. Furthermore, it promotes transferrin-mediated endocytosis of gold nanoparticles by modifying their protein corona and promoting oriented adsorption of transferrin. This strategy leads to highly effective nanostructures, potentially useful in diagnostic and therapeutic applications, which exploit (and do not suffer) the protein solvation for achieving a better targeting.
2017
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
Settore FIS/03 - Fisica della Materia
Settore CHIM/09 - Farmaceutico Tecnologico Applicativo
Settore BIO/09 - Fisiologia
Settore CHIM/06 - Chimica Organica
Metal nanoparticles; Peptides and proteins; Protein corona; Nanoparticles; Endocytosis
File in questo prodotto:
File Dimensione Formato  
Santi2017_BiocChem28_471_withSI.pdf

Accesso chiuso

Descrizione: Manuscript + SI
Tipologia: Published version
Licenza: Non pubblico
Dimensione 3.81 MB
Formato Adobe PDF
3.81 MB Adobe PDF   Richiedi una copia
Santi2017_BiocChem28_471_preprint.pdf

Open Access dal 02/12/2017

Descrizione: Accepted manuscript, pre-proof version
Tipologia: Accepted version (post-print)
Licenza: Solo Lettura
Dimensione 717.04 kB
Formato Adobe PDF
717.04 kB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11384/65376
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 73
  • ???jsp.display-item.citation.isi??? 64
social impact