Physicochemical characterization, toxicity and in vivo biodistribution studies of a discoidal, lipid-based drug delivery vehicle: Lipodisq nanoparticles containing doxorubicin

Many promising pharmaceutically active compounds have low solubility in aqueous environments and their encapsulation into efficient drug delivery vehicles is crucial to increase their bioavailability. Lipodisq nanoparticles are approximately 10 nm in diameter and consist of a circular phospholipid bilayer, stabilized by an annulus of SMA (a hydrolysed copolymer of styrene and maleic anhydride). SMA is used extensively in structural biology to extract and stabilize integral membrane proteins for biophysical studies. Here, we assess the potential of these nanoparticles as drug delivery vehicles, determining their cytotoxicity and the in vivo excretion pathways of their polymer and lipid components. Doxorubicin-loaded Lipodisqs were cytotoxic across a panel of cancer cell lines, whereas nanoparticles without the drug had no effect on cell proliferation. Intracellular doxorubicin release from Lipodisqs in HeLa cells occurred in the low-pH environment of the endolysosomal system, consistent with the breakdown of the discoidal structure as the carboxylate groups of the SMA polymer become protonated. Biodistribution studies in mice showed that, unlike other nanoparticles injected intravenously, most of the Lipodisq components were recovered in the colon, consistent with rapid uptake by hepatocytes and excretion into bile. These data suggest that Lipodisqs have the potential to act as delivery vehicles for drugs and contrast agents.Competing Interest StatementThe authors have declared no competing interest.AbbreviationsDLPE1,2-dilauroyl-sn-glycero-3-phosphoethanolamineDLPE-Cy5Cy5 dye covalently conjugated to 1,2-dilauroyl-sn-glycero-3-phosphoethanolamineDLSdynamic light scatteringDMPC1,2-dimyristoyl-sn-glycero-3-phosphocholineDMPG1,2-dimyristoyl-sn-glycero-3-phospho-(1’-rac-glycerol)DOXDoxorubicinEPRenhanced permeability and retention effectLipodisqLQNMRnuclear magnetic resonanceNPnanoparticleRTroom temperatureSMAhydrolysed co-polymer of styrene and maleic anhydrideSMA-Cy5Cy5 dye covalently conjugated to a thiol derivative of SMASMAnhnon-hydrolysed co-polymer of styrene and maleic anhydrideSMAnh-SHthiol derivative of SMAnhSMA-SHthiol derivative of SMAView Full Text