Addressing the polycation dilemma in drug delivery: charge-converting liposomes

Area of Science:

• Nanotechnology in Drug Delivery
• Biomaterials Science
• Pharmaceutical Sciences

Background:

• The polycation dilemma poses a significant challenge in drug delivery, hindering the efficacy of positively charged carriers due to interactions with biological barriers.
• Developing advanced delivery systems that can navigate mucus layers and enhance cellular interaction is crucial for improving therapeutic outcomes.
• Liposomes represent a versatile platform for drug delivery, but their application is often limited by issues such as poor mucus penetration and cellular uptake.

Purpose of the Study:

• To engineer charge-converting liposomes that can effectively permeate mucus gel layers.
• To enhance cellular uptake of drug delivery systems by addressing the limitations of polycationic carriers.
• To develop a novel liposomal formulation that resolves the polycation dilemma for improved drug delivery applications.

Main Methods:

• Formulation of positively charged liposomes using dioleoylphosphatidylethanolamine (DOPE), cholesterol, and oleyl-oligolysine via the thin-film method.
• Coating of liposomes with polyphosphate to create negatively charged phosphorylated liposomes (pp-liposomes) with tunable charge properties.
• Characterization of liposomes for size, zeta potential, stability, cytotoxicity, and hemolytic activity; assessment of mucus permeation and cellular uptake in Caco-2 cells.

Main Results:

• Formulated liposomes exhibited optimal size (138.7 ± 2.9 nm) and positive zeta potential (+35.4 ± 1.5 mV), while pp-liposomes showed increased size (168.4 ± 1.2 nm) and negative zeta potential (-24.2 ± 2.5 mV), remaining stable for 24 hours.
• pp-liposomes demonstrated reduced toxicity and hemolytic activity compared to uncoated liposomes, with significant phosphate release and charge conversion to positive (+12.9 ± 5.19 mV) within 24 hours upon incubation with intestinal alkaline phosphatase (AP).
• pp-liposomes showed a 12-fold increase in mucus permeability in the absence of AP and comparable cellular uptake levels in Caco-2 cells to uncoated liposomes, indicating effective mucus traversal and internalization.

Conclusions:

• Charge-converting liposomes effectively overcome the mucus barrier, demonstrating significantly enhanced permeability.
• The developed pp-liposomes exhibit improved safety profiles and comparable cellular uptake, addressing the limitations of traditional polycationic drug delivery systems.
• This charge-converting liposomal approach presents a promising strategy for resolving the polycation dilemma and advancing drug delivery technologies.