The self-association equilibria of doxorubicin at high concentration and ionic strength characterized by fluorescence spectroscopy and molecular dynamics simulations

Abstract

Graphical abstract ABSTRACTThe self-association equilibria of doxorubicin hydrochloride (DX), at high drug and NaCl concentrations, are studied by temperature scan fluorescence spectroscopy, with the support of molecular dynamics (MD) calculations. Even though all anthracyclines show dimerization equilibria, DX only can further associate into long polymeric chains according to DXmon ⇄ DXdim ⇄ DXpol. This is reflected not only in the mechanical properties of DXpol solutions (behaving as thixotropic gels) but also in their spectroscopic behaviour. Fluorescence, in particular, is the technique of election to study this complex set of equilibria. Upon increasing the temperature, DXpol melts into DXdim, which in turn is in equilibrium with DXmon. Since DXdim is non fluorescent, with a fluorescence temperature scan experiment the DXpol⇄ DXmon equilibrium is probed. However, also information on the DX dimerization equilibrium can be derived together with the relevant thermodynamic parameters ruling the dimerization process (ΔH dim°= −56 kJ mol −1 ; ΔS dim°= −97 J mol −1 K −1 ). The residence time of DX molecules in the dimer (74.7 μs), as well as the monomers mutual orientation in the dimer, are characterized by means of theoretical and computational modelling.

Encapsulation and Release of Doxorubicin from TiO2Nanotubes: Experiment, Density Functional Theory Calculations, and Molecular Dynamics Simulation

“…Moreover, the DOX molecules show some tendency to aggregate. This is in line with experimental findings and MD simulations on such aggregation.…”

“…45 MD simulations were applied to examine the structure and configuration of diverse concentrations of DOX loading in single-walled carbon nanotubes, 48 and the self-association equilibrium of DOX at high drug and NaCl concentration was studied using MD simulations. 49 In contrast to this, the molecular details of the loading and release of DOX from TiO 2 nanotubes have not yet been investigated using MD simulations. Recently, we have studied pH-sensitive drug loading and release using vitamin C as a model drug from Al 2 O 3 and TiO 2 nanotubes in a combined experimental and MD simulation approach.…”

“…A number of MD simulations have been previously performed to provide insights into the molecular levels in the drug release of DOX from TiO 2 nanoparticles and from diverse carbon-based nanotubes. − For example, MD simulations were carried out on the release, interactions, and encapsulation of DOX molecules and chitosan, on the loading of DOX PEGylated graphene oxide nanocarriers, pH-dependent diffusion, loading, and the release of DOX in graphene and graphene oxide . MD simulations were applied to examine the structure and configuration of diverse concentrations of DOX loading in single-walled carbon nanotubes, and the self-association equilibrium of DOX at high drug and NaCl concentration was studied using MD simulations . In contrast to this, the molecular details of the loading and release of DOX from TiO 2 nanotubes have not yet been investigated using MD simulations.…”

Impact of Citrate and Lipid-Functionalized Magnetic Nanoparticles in Dehydropeptide Supramolecular Magnetogels: Properties, Design and Drug Release

“…Thus, the decreasing fluorescence emission ratio of doxorubicin between the peaks at λ = 560 nm and λ = 600 nm upon addition of citrate-stabilized nanoparticles might be associated with an increasingly acidic region and its location in cavities, which are destabilized by the increasing concentration of nanoparticles (see Figure S10 in Supplementary Materials ) [ 69 ]. Nonetheless, the possibility of aggregation is not excluded, considering that at 10 µM, a fraction of 47% is dimerized [ 70 , 71 ], and the obtained spectra in gels resemble the fluorescence emission spectrum of a doxorubicin concentrated solution (0.1 mM) at pH = 7 (see Figure S11 in Supplementary Materials ). The lipid-coated nanoparticles do not show the same effects, as the wavelength and emission ratio remain mostly unchanged, i.e., no major changes are induced in the doxorubicin location microenvironment.…”

Ionizable Drug Self-Associations and the Solubility Dependence on pH: Detection of Aggregates in Saturated Solutions Using Mass Spectrometry (ESI-Q-TOF-MS/MS)

“…It is possible that aggregates were present but at a concentration under the limit of detection of the technique. Alternative techniques such as fluorescence spectroscopy 33 or proton nuclear magnetic resonance spec-troscopy 34 could be tried in these instances to confirm aggregation phenomena. Haloperidol (the negative control) does not present aggregation at low pH values (<pK a ), where the ionic form exists.…”