Distinct solubility and cytotoxicity regimes of paclitaxel-loaded cationic liposomes at low and high drug content revealed by kinetic phase behavior and cancer cell viability studies.

Autor: Steffes VM; Chemistry and Biochemistry Department, University of California, Santa Barbara, CA 93106, USA; Materials Department, University of California, Santa Barbara, CA 93106, USA., Murali MM; Materials Department, University of California, Santa Barbara, CA 93106, USA., Park Y; Materials Department, University of California, Santa Barbara, CA 93106, USA., Fletcher BJ; Materials Department, University of California, Santa Barbara, CA 93106, USA., Ewert KK; Materials Department, University of California, Santa Barbara, CA 93106, USA., Safinya CR; Materials Department, University of California, Santa Barbara, CA 93106, USA; Physics Department, University of California, Santa Barbara, CA 93106, USA; Molecular, Cellular & Developmental Biology Department, University of California, Santa Barbara, CA 93106, USA. Electronic address: Safinya@mrl.ucsb.edu.
Jazyk: angličtina
Zdroj: Biomaterials [Biomaterials] 2017 Nov; Vol. 145, pp. 242-255. Date of Electronic Publication: 2017 Aug 17.
DOI: 10.1016/j.biomaterials.2017.08.026
Abstrakt: Lipid-based particles are used worldwide in clinical trials as carriers of hydrophobic paclitaxel (PTXL) for cancer chemotherapy, albeit with little improvement over the standard-of-care. Improving efficacy requires an understanding of intramembrane interactions between PTXL and lipids to enhance PTXL solubilization and suppress PTXL phase separation into crystals. We studied the solubility of PTXL in cationic liposomes (CLs) composed of positively charged 2,3-dioleyloxypropyltrimethylammonium chloride (DOTAP) and neutral 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) as a function of PTXL membrane content and its relation to efficacy. Time-dependent kinetic phase diagrams were generated from observations of PTXL crystal formation by differential-interference-contrast microscopy. Furthermore, a new synchrotron small-angle x-ray scattering in situ methodology applied to DOTAP/DOPC/PTXL membranes condensed with DNA enabled us to detect the incorporation and time-dependent depletion of PTXL from membranes by measurements of variations in the membrane interlayer and DNA interaxial spacings. Our results revealed three regimes with distinct time scales for PTXL membrane solubility: hours for >3 mol% PTXL (low), days for ≈ 3 mol% PTXL (moderate), and ≥20 days for < 3 mol% PTXL (long-term). Cell viability experiments on human cancer cell lines using CL PTXL nanoparticles (NPs) in the distinct CL PTXL solubility regimes reveal an unexpected dependence of efficacy on PTXL content in NPs. Remarkably, formulations with lower PTXL content and thus higher stability show higher efficacy than those formulated at the membrane solubility limit of ≈3 mol% PTXL (which has been the focus of most previous physicochemical studies and clinical trials of PTXL-loaded CLs). Furthermore, an additional high-efficacy regime is seen on occasion for liposome compositions with PTXL ≥9 mol% applied to cells at short time scales (hours) after formation. At longer time scales (days), CL PTXL NPs with ≥3 mol% PTXL lose efficacy while formulations with 1-2 mol% PTXL maintain high efficacy. Our findings underscore the importance of understanding the relationship of the kinetic phase behavior and physicochemical properties of CL PTXL NPs to efficacy.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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