Imidazole-Based pH-Sensitive Convertible Liposomes for Anticancer Drug Delivery

Area of Science:

• Nanomedicine
• Drug Delivery Systems
• Oncology

Background:

• Conventional liposomal drug delivery faces challenges in solid tumor treatment due to poor penetration and premature drug release.
• Developing stimuli-responsive liposomes that target the acidic tumor microenvironment is a promising strategy to improve therapeutic efficacy.
• pH-sensitive liposomes can enhance drug accumulation and activity within solid tumors.

Purpose of the Study:

• To design and synthesize novel imidazole-based lipids for creating pH-sensitive convertible liposomes (ICL).
• To evaluate the pH-triggered behavior, drug release kinetics, and anticancer activity of ICL containing doxorubicin (DOX).
• To investigate the impact of imidazole lipid basicity and cholesterol content on ICL performance against solid tumors.

Main Methods:

• Synthesis of three novel imidazole lipids with varying basicity.
• Incorporation of imidazole lipids into PEGylated liposomes containing doxorubicin (DOX) to form ICL.
• Characterization of ICL pH-sensitivity, lipid phase separation (TEM, DSC), aggregation, and DOX release.
• Assessment of ICL anticancer activity against monolayer cells and 3D multicellular spheroids (MCS).

Main Results:

• ICL demonstrated pH-dependent protonation and clustering, leading to increased positive surface charge and lipid phase separation at tumor-relevant pH (6.0).
• A specific imidazole lipid enhanced DOX release from ICL at lower pH.
• ICL exhibited superior anticancer activity compared to pH-insensitive liposomes in both monolayer and 3D MCS models.
• Cholesterol incorporation improved colloidal stability but reduced pH-sensitivity; lipid basicity influenced activity in different cellular models.

Conclusions:

• Novel imidazole lipids enable the development of effective pH-sensitive convertible liposomes (ICL) for targeted doxorubicin delivery.
• ICL show enhanced anticancer efficacy against solid tumors by leveraging the acidic tumor microenvironment for triggered drug release.
• Optimizing ICL composition, balancing tissue penetration, cell binding, and drug release, is key for maximizing therapeutic outcomes in solid tumors.