| Autor: |
Simón-Gracia L; Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, Centre of Excellence for Translational Medicine, University of Tartu, Ravila 14b, 50411 Tartu, Estonia., Scodeller P; Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, Centre of Excellence for Translational Medicine, University of Tartu, Ravila 14b, 50411 Tartu, Estonia.; Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Calle Darwin 3, 28049 Madrid, Spain., Fisher WS; Materials Department, Molecular, Cellular, and Developmental Biology Department, Physics Department, and Biomolecular Science and Engineering Program, University of California, Santa Barbara, California 93106, United States., Sidorenko V; Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, Centre of Excellence for Translational Medicine, University of Tartu, Ravila 14b, 50411 Tartu, Estonia., Steffes VM; Materials Department, Molecular, Cellular, and Developmental Biology Department, Physics Department, and Biomolecular Science and Engineering Program, University of California, Santa Barbara, California 93106, United States., Ewert KK; Materials Department, Molecular, Cellular, and Developmental Biology Department, Physics Department, and Biomolecular Science and Engineering Program, University of California, Santa Barbara, California 93106, United States., Safinya CR; Materials Department, Molecular, Cellular, and Developmental Biology Department, Physics Department, and Biomolecular Science and Engineering Program, University of California, Santa Barbara, California 93106, United States., Teesalu T; Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, Centre of Excellence for Translational Medicine, University of Tartu, Ravila 14b, 50411 Tartu, Estonia.; Materials Research Laboratory, University of California, Santa Barbara, California 93106, United States. |
| Abstrakt: |
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, in vivo 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 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 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. |
