Paclitaxel-Loaded Cationic Fluid Lipid Nanodiscs and Liposomes with Brush-Conformation PEG Chains Penetrate Breast Tumors and Trigger Caspase‑3 Activation

• Published in: ACS applied materials & interfaces 2022-12, Vol.14 (51), p.56613-56622
• Main Authors: Simón-Gracia, Lorena, Scodeller, Pablo, Fisher, William S., Sidorenko, Valeria, Steffes, Victoria M., Ewert, Kai K., Safinya, Cyrus R., Teesalu, Tambet
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Phytogenic - chemistry; Biological and Medical Applications of Materials and Interfaces; Breast Neoplasms - drug therapy; Caspase 3; Cell Line, Tumor; Drug Carriers - chemistry; Female; Humans; Lipids; Liposomes - chemistry; Mice; Paclitaxel - chemistry; Polyethylene Glycols - chemistry; Tissue Distribution
• ISSN: 1944-8244; 1944-8252; 1944-8252
• DOI: 10.1021/acsami.2c17961

Novel approaches are required to address the urgent need to develop lipid-based carriers of paclitaxel (PTX) and other hydrophobic drugs for cancer chemotherapy. Carriers based on cationic liposomes (CLs) with fluid (i.e., chain-melted) membranes (e.g., EndoTAG-1) have shown promise in preclinical and late-stage clinical studies. Recent work found that the addition of a cone-shaped poly­(ethylene glycol)-lipid (PEG-lipid) to PTX-loaded CLs (CLsPTX) promotes a transition to sterically stabilized, higher-curvature (smaller) nanoparticles consisting of a mixture of PEGylated CLsPTX and PTX-containing fluid lipid nanodiscs (nanodiscsPTX). These CLsPTX and nanodiscsPTX show significantly improved uptake and cytotoxicity in cultured human cancer cells at PEG coverage in the brush regime (10 mol % PEG-lipid). Here, we studied the PTX loading, in vivo circulation half-life, and biodistribution of systemically administered CLsPTX and nanodiscsPTX and assessed their ability to induce apoptosis in triple-negative breast-cancer-bearing immunocompetent mice. We focused on fluid rather than solid lipid nanodiscs because of the significantly higher solubility of PTX in fluid membranes. At 5 and 10 mol % of a PEG-lipid (PEG5K-lipid, molecular weight of PEG 5000 g/mol), the mixture of PEGylated CLsPTX and nanodiscsPTX was able to incorporate up to 2.5 mol % PTX without crystallization for at least 20 h. Remarkably, compared to preparations containing 2 and 5 mol % PEG5K-lipid (with the PEG chains in the mushroom regime), the particles at 10 mol % (with PEG chains in the brush regime) showed significantly higher blood half-life, tumor penetration, and proapoptotic activity. Our study suggests that increasing the PEG coverage of CL-based drug nanoformulations can improve their pharmacokinetics and therapeutic efficacy.