Transmembrane gradient driven phase transitions within vesicles: lessons for drug delivery

Area of Science:

• Biochemistry
• Materials Science
• Pharmacology

Background:

• Phase transitions in closed vesicles are crucial for various applications, including drug delivery.
• Lipid bilayer membranes control the transport of ions and molecules.
• Efficient liposomal therapeutics require high drug loading and low leakage rates.

Purpose of the Study:

• To investigate efficient drug encapsulation via intraliposomal precipitation.
• To characterize the state of encapsulated drugs within liposomes.
• To validate a theoretical model for membrane-permeable species based on chemical potential equilibration.

Main Methods:

• Intraliposomal precipitation for drug encapsulation.
• Characterization of encapsulated drug states.
• Comparison of experimental data with a theoretical model.
• High-resolution cryo-electron microscopy (cryoEM) for visualizing precipitate structures.

Main Results:

• High drug loading efficiencies were achieved through intraliposomal precipitation.
• A theoretical model based on chemical potential equilibration showed good agreement with experimental data.
• Anticancer drug doxorubicin precipitated as fibers, exhibiting low solubility and minimal leakage.
• Antibiotic ciprofloxacin precipitated as globules, showing higher solubility and significant in vitro/in vivo leakage.

Conclusions:

• Intraliposomal precipitation is an effective method for high drug loading.
• Drug retention in liposomes depends on precipitation form, solubility, and membrane permeability.
• Doxorubicin's fibrous precipitate ensures long-term retention, crucial for effective therapies.
• Ciprofloxacin's globular precipitate and membrane permeability lead to poor retention, limiting its therapeutic efficacy.