Cisplatin encapsulation within a ferritin nanocage: a high-resolution crystallographic study

Abstract

Cisplatin (CDDP) can be encapsulated within the central cavity of reconstituted (apo)ferritin, (A)Ft, to form a drug-loaded protein of potential great interest for targeted cancer treatments. In this study, the interactions occurring between cisplatin and native horse spleen Ft in CDDP-encapsulated AFt are investigated by high-resolution X-ray crystallography. A protein bound Pt center is unambiguously identified in AFt subunits by comparative analysis of difference Fourier electron density maps and of anomalous dispersion data. Indeed, a [Pt(NH3)2H2O](2+) fragment is found coordinated to the His132 residue located on the inner surface of the large AFt spherical cage. Remarkably, Pt binding does not alter the overall physicochemical features (shape, volume, polarity/hydrophobicity and electrostatic potential) of the outer surface of the AFt nanocage. CDDP-encapsulated AFt appears to be an ideal nanocarrier for CDDP delivery to target sites, as it possesses high biocompatibility and can be internalized by receptor mediated endocytosis, thus carrying the drug to tumor tissue with higher selectivity than free CDDP.

Encapsulation of the Dinuclear Trithiolato‐Bridged Arene Ruthenium Complex Diruthenium‐1 in an Apoferritin Nanocage: Structure and Cytotoxicity

“…Data frames were indexed and scaled using HKL2000 or AutoProc . The structure was solved by molecular replacement method with Phaser, using the coordinates of the protein extracted from PDB ID: 5ERK as starting model. Atomic positions and individual B‐factors were refined using Refmac 5.7 and autoBuster .…”

“…Comparison of the relative B‐factors (B relative ) of DiRu‐1‐encapsulated AFt and AFt was performed by calculating B relative as the ratio between B‐factor of the α carbon atom of each residue and the average B‐factor of the α carbon atoms of the whole molecule. The structure of AFt deposited in the RCSB Protein Data Bank (PDB ID: 5ERK) was used as control …”

Protein Metalation by Anticancer Metallodrugs: A Joint ESI MS and XRD Investigative Strategy

“…Given the success commonly achieved in describing the metalation of small model proteins (<15–20 KDa), it is tempting to extend the above investigative strategy to bigger protein systems. In this respect, recently, we and others were successful in obtaining good crystals for the adducts formed in the reaction between cisplatin and human serum albumin (HSA), KP1019, and HSA and for the cisplatin‐ (Figure ), Rh‐, Pd‐, Ru‐, and Au‐encapsulated apoFerritin (AFt) nanocages …”

“…In a), cisplatin fragments are shown as spheres; residues that coordinate the Pt centres (His105, His288, Met298, Met329 and Met548) are indicated . In b) Pt centres and its ligands are reported as spheres; the only Pt binding site is His132 …”

“…For example, the interaction between KP1019 and HSA has been studied by means of X‐ray crystallography in combination with ICP MS . Similarly, the amount of Pt‐, Au‐, and Rh‐ encapsulated within AFt nanocages was determined by ICP MS and the structures of the adducts solved by XRD.…”