biostudies-literatureSimon-Gracia LEesti TeadusagentuurH2020 Marie Sklodowska-Curie ActionsEuroNanoMed IIIDivision of Materials ResearchMinisterio de Ciencia e Innovaci?nNational Institute of General Medical SciencesNIGMS NIH HHSEuropean Regional Development Fund56613-56622https://www.ebi.ac.uk/biostudies/studies/S-EPMC9879205biostudies-literatureUnknown14(51)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 (CLs_PTX) promotes a transition to sterically stabilized, higher-curvature (smaller) nanoparticles consisting of a mixture of PEGylated CLs_PTX and PTX-containing fluid lipid nanodiscs (nanodiscs_PTX). These CLs_PTX and nanodiscs_PTX 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, <i>in vivo</i> circulation half-life, and biodistribution of systemically administered CLs_PTX and nanodiscs_PTX and assessed their ability to induce apoptosis in triple-negative breast-cancer-bearing immunocompetent mice. We focused on <i>fluid</i> rather than <i>solid</i> 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 CLs_PTX and nanodiscs_PTX 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.ACS applied materials & interfacesPaclitaxel-Loaded Cationic Fluid Lipid Nanodiscs and Liposomes with Brush-Conformation PEG Chains Penetrate Breast Tumors and Trigger Caspase-3 Activation.PMC9879205R01GM130769PRG2302014-2020.4.01.15-0012DMR-1807327R01 GM130769EAG79PSG38RYC2020-028754-IMOBJD11PID2021-122364OA-I00Ewert KKSteffes VMSafinya CRSimon-Gracia LSidorenko VTeesalu TScodeller PFisher WSfalsePaclitaxel-Loaded Cationic Fluid Lipid Nanodiscs and Liposomes with Brush-Conformation PEG Chains Penetrate Breast Tumors and Trigger Caspase-3 Activation.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 (CLs_PTX) promotes a transition to sterically stabilized, higher-curvature (smaller) nanoparticles consisting of a mixture of PEGylated CLs_PTX and PTX-containing fluid lipid nanodiscs (nanodiscs_PTX). These CLs_PTX and nanodiscs_PTX 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, <i>in vivo</i> circulation half-life, and biodistribution of systemically administered CLs_PTX and nanodiscs_PTX and assessed their ability to induce apoptosis in triple-negative breast-cancer-bearing immunocompetent mice. We focused on <i>fluid</i> rather than <i>solid</i> 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 CLs_PTX and nanodiscs_PTX 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.2022-01-01T00:00:00Z2022 Dec2026-03-18T14:09:24.058Z2025-04-06T12:27:59.231ZS-EPMC98792053652123310.1021/acsami.2c17961