A Stereochemically Driven Supramolecular Polymerisation

Area of Science:

• Supramolecular chemistry
• Materials science
• Biophysical chemistry

Background:

• Anthracyclines, including doxorubicin, are known for their self-assembly properties in aqueous solutions.
• The influence of salt concentration on the self-assembly behavior of anthracyclines is not fully understood.
• Doxorubicin exhibits distinct gelation properties compared to closely related compounds like daunomycin and epirubicin.

Purpose of the Study:

• To elucidate the self-assembly mechanism underlying doxorubicin gelation in high salt concentrations.
• To investigate the structural and dynamic characteristics of doxorubicin aggregates.
• To determine the role of specific chemical groups and stereochemistry in the self-assembly process.

Main Methods:

• Spectroscopic techniques (fluorescence)
• Scattering methods (small-angle X-ray scattering)
• Imaging techniques
• Computational modeling (molecular dynamics)
• Gelation studies

Main Results:

• Doxorubicin forms long, highly chiral, supramolecular aggregates composed of hundreds of units.
• These aggregates exhibit redshifted fluorescence spectra, short fluorescence lifetimes, and scattering profiles consistent with long cylinders.
• Gelation is triggered by high salt (NaCl) concentrations and involves a nucleation-elongation polymerization mechanism.
• Molecular dynamics calculations support the involvement of specific chemical groups and stereochemistry in stabilizing the aggregates via hydrogen bonding.

Conclusions:

• Doxorubicin undergoes salt-induced, temperature-dependent supramolecular polymerization.
• The formation of stable, chiral, cylindrical aggregates is crucial for doxorubicin gelation.
• The findings provide insights into the rational design of drug delivery systems based on self-assembling molecules.