Direct introduction of cationic and anionic lipids to create pH-sensitive charge-reversible liposomes with optimized pharmacokinetics and antitumor effects

Abstract

The development of pH-sensitive charge-reversing nanodrug delivery systems often requires complex chemical modifications that can be difficult to control, limiting their scalability and clinical use. We directly incorporated varying ratios of the cationic lipid 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (EPC) and the anionic lipid dioleoyl phosphatidylglycerol (DOPG) into liposomes to simplify the creation of pH-sensitive charge-reversible liposomes. Paclitaxel (PTX) was encapsulated in these liposomes as a model chemotherapeutic agent for the treatment of triple-negative breast cancer. The liposomes composed of DOPG and EPC at a ratio of 1:1.2 (1:1.2 DE) presented an extended half-life, increased area under the curve, prolonged mean residence time, and reduced clearance rate, along with a uniform distribution within tumors. These results indicated that the liposomes with 1:1.2 DE not only exhibited prolonged circulation but also enhanced tumor penetration. Moreover, the liposomes with 1:1.2 DE showed significant in vivo antitumor effects, including the highest tumor inhibition rates, largest necrotic area, highest apoptosis index, lowest proliferation index, and longest survival of mice, while maintaining excellent biosafety. This method represents a straightforward way to create pH-sensitive charge-reversible liposomes without chemical modification, providing an effective system to optimize chemotherapy drug pharmacokinetics, enhance intratumoral penetration, improve therapeutic efficacy, and reduce toxicity.