Speciation of Phenanthriplatin and Its Analogs in the Core of Tobacco Mosaic Virus

Abstract

Efficient loading of drugs in novel delivery agents has the potential to substantially improve therapy by targeting the diseased tissue while avoiding unwanted side effects. Here we report a first systematic study of the loading mechanism of phenanthriplatin and its analogs into tobacco mosaic virus (TMV), previously used by our group as an efficient carrier for anticancer drug delivery. A detailed investigation of the preferential uptake of phenanthriplatin in its aquated form (~2000 molecules per TMV particle versus ~1000 for the chlorido form) is provided. Whereas the net charge of phenanthriplatin analogs and their ionic mobilities have no effect on loading, the reactivity of aqua phenanthriplatin with the glutamates, lining the interior walls of the channel of TMV, has a pronounced effect on its loading. MALDI-MS analysis along with NMR spectroscopic studies of a model reaction of hydroxy-phenanthriplatin with acetate establish the formation of stable covalent adducts. The increased number of heteroaromatic rings on the platinum ligand appears to enhance loading, possibly by stabilizing hydrophobic stacking interactions with TMV core components, specifically Pro102 and Thr103 residues neighboring Glu97 and Glu106 in the channel. Electron transfer dissociation-MS/MS fragmentation, a technique that can prevent mass condition-vulnerable modification of proteins, reveals that Glu97 preferentially participates over Glu106 in covalent bond formation to the platinum center.

Viral nanoparticles for drug delivery, imaging, immunotherapy, and theranostic applications

“…Plant virus-based nanoparticles have been widely used for targeted delivery of platinum-based anticancer drugs, which are used in the treatment of nearly 50% of cancer patients undergoing chemotherapy [48]. TMV makes an intriguing platform for efficient delivery of platinum-based drugs such as cisplatin [49] and drug candidate phenanthriplatin (phenPt) [50] as they can be efficiently loaded into the TMV cavity via a charge-driven reaction or by forming stable covalent adducts (Fig. 4a,b).…”

“…Plant VLPs have also been used for the delivery of mRNA. In one study, CCMV was examined for the delivery of heterologous mRNA encoding enhanced yellow fluorescent protein (EYFP) to mammalian [50]) b) Graphical illustration of the phenPt docking onto the Glu97 and Glu106 residues of TMV as discovered through matrix-assisted laser desorption/ionizationmass spectrometry and nuclear magnetic resonance spectroscopy c) Graphical schematic of the assembly of TMV spherical nanoparticles using a fluorous ponytail interaction (F-TMVCP). Cisplatin was loaded into the F-TMVCP using the same glutamic residues as in b (not shown) (reproduced with permission from ref [52]).…”

Phthalocyanine–Virus Nanofibers as Heterogeneous Catalysts for Continuous‐Flow Photo‐Oxidation Processes

“…This geometry, which renders a negatively charged helix on the outer surface of the virus at pH above 4.5, can function as a well‐defined scaffold for unidimensional ensembles. TMV has been employed as drug delivery platform, as well as building block in different biohybrid arrays together with small functional molecules, or nanoparticles …”

Four-component relativistic 31P NMR calculations for trans-platinum(ii) complexes: importance of the solvent and dynamics in spectral simulations

“…[10][11] Crucial for establishing the mechanism of action of platinum complexes is their speciation in water solution, which has been studied in detail by several techniques. [12][13][14][15][16] Nuclear Magnetic Resonance (NMR) spectroscopy, in particular the multinuclear variants, is an useful tool for understanding the aquation of complexes under physiological conditions, [17][18] and very convenient to connect theory and experiment. 19 For platinum complexes containing aliphatic amines in a trans configuration, NMR studies demonstrated a direct relationship between the aquation process, the complexes' structure and their cytotoxicity.…”