From single DNA molecule to nanoparticle formation: mechanistic basis for monocationic aromatic drug-induced DNA...

Area of Science:

• Biochemistry and Molecular Biology
• Nanotechnology
• Drug Delivery Systems

Background:

• Small molecules can influence DNA structure and drive the formation of higher-order DNA frameworks.
• Understanding drug-DNA interactions is crucial for developing novel therapeutic agents and nanomedicines.

Purpose of the Study:

• To investigate the interaction between propranolol (PPL) and double-stranded DNA (dsDNA).
• To elucidate the mechanism by which PPL drives DNA frameworks and nanoparticle (NP) formation.
• To explore the potential of DNA as a building block for nucleic acid-based nanomedicines.

Main Methods:

• Single-molecule force spectroscopy using optical tweezers to probe PPL-dsDNA interactions.
• Atomic force microscopy (AFM) to visualize DNA compaction and condensed structures.
• Electrophoretic mobility shift assays (EMSA) to assess aggregate formation.
• UV-vis spectroscopy to confirm intercalation and determine binding affinity.
• Dynamic light scattering (DLS) and zeta potential measurements to characterize formed nanoparticles.

Main Results:

• Propranolol (PPL) interacts with dsDNA through an intercalation-like mode at lower concentrations, altering DNA's mechanical properties.
• At higher concentrations, PPL induces dsDNA compaction and aggregation.
• Stable nanoparticles (NPs) with high drug loading (59-72%) and good stability were formed at millimolar PPL/dsDNA ratios.
• Binding affinity (K_b) was determined to be 1.67 × 10⁶ M⁻¹.

Conclusions:

• Propranolol (PPL) engages dsDNA via intercalation-like behavior, compaction, and aggregation, leading to efficient nanoparticle formation.
• This study reveals a novel mechanism for a monocationic aromatic drug interacting with DNA.
• DNA can serve as a versatile building block for developing nucleic acid-based nanomedicines with potential applications in drug delivery.