Pancreatic adenocarcinoma preferentially takes up and is suppressed by synthetic nanoparticles carrying apolipoprotein A-II and a lipid gemcitabine prodrug in mice.

Autor: Smith RC; Cancer Surgery Research Laboratory, University of Sydney at the Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia; Department of Gastrointestinal Surgery, University of Sydney at the Kolling Institute of Medical Research, St Leonards NSW 2065 Australia; NanoMed Pty Ltd, 2/11-13 Orion Road, Lane Cove West 2066, New South Wales, Australia. Electronic address: ross.smith@sydney.edu.au., Bulanadi JC; Cancer Surgery Research Laboratory, University of Sydney at the Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia; CSIRO Manufacturing, 11 Julius Ave, North Ryde NSW 2113, Australia. Electronic address: jbul3075@alumni.sydney.edu.au., Gill AJ; Department of Pathology, The University of Sydney at Royal North Shore Hospital, Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia. Electronic address: Anthony.Gill@health.nsw.gov.au., Rye KA; School of Medical Sciences, Faculty of Medicine, University of New South Wales, NSW 2052, Australia. Electronic address: k.rye@unsw.edu.au., Hugh T; Department of Gastrointestinal Surgery, University of Sydney at the Kolling Institute of Medical Research, St Leonards NSW 2065 Australia. Electronic address: tom.hugh@sydney.edu.au., Proschogo N; Mass Spectrometry Core Facility, School of Chemistry, University of Sydney, NSW 2006, Australia. Electronic address: nicholas.proschogo@sydney.edu.au., Smith SF; Cancer Surgery Research Laboratory, University of Sydney at the Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia; NanoMed Pty Ltd, 2/11-13 Orion Road, Lane Cove West 2066, New South Wales, Australia. Electronic address: sally.smith@nanomed.com.au., Phillips L; Mass Spectrometry Core Facility, School of Chemistry, University of Sydney, NSW 2006, Australia. Electronic address: leop@tpg.com.au., Gong X; NanoMed Pty Ltd, 2/11-13 Orion Road, Lane Cove West 2066, New South Wales, Australia. Electronic address: nelly.gong@nanomed.com.au., Julovi SM; Cancer Surgery Research Laboratory, University of Sydney at the Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia. Electronic address: sohel.jelovi@sydney.edu.au., Xue A; Cancer Surgery Research Laboratory, University of Sydney at the Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia; Department of Gastrointestinal Surgery, University of Sydney at the Kolling Institute of Medical Research, St Leonards NSW 2065 Australia. Electronic address: aiqun.xue@sydney.edu.au., Moghaddam MJ; CSIRO Manufacturing, 11 Julius Ave, North Ryde NSW 2113, Australia; NanoMed Pty Ltd, 2/11-13 Orion Road, Lane Cove West 2066, New South Wales, Australia. Electronic address: minoo.moghaddam@nanomed.com.au.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2020 Dec 28; Vol. 495, pp. 112-122. Date of Electronic Publication: 2020 Sep 16.
DOI: 10.1016/j.canlet.2020.08.045
Abstrakt: We hypothesised that synthetic HDL nanoparticles carrying a gemcitabine prodrug and apolipoprotein A-II (sHDLGemA2) would target scavenger receptor-B1 (SR-B1) to preferentially and safely deliver gemcitabine into pancreatic ductal adenocarcinoma (PDAC). We designed, manufactured and characterised sHDLGemA2 nanoparticles sized ~130 nm, incorporating 20 mol% of a gemcitabine prodrug within the lipid bilayer, which strengthens on adding ApoA-II. We measured their ability to inhibit growth in cell lines and cell-derived and patient-derived murine PDAC xenografts. Fluorescent-labelled sHDLGemA2 delivered gemcitabine inside xenografts. Xenograft levels of active gemcitabine after sHDLGemA2 were similar to levels after high-dose free gemcitabine. Growth inhibition in mice receiving 4.5 mg gemcitabine/kg/d, carried in sHDLGemA2, was equivalent to inhibition after high-dose (75 mg/kg/d) free gemcitabine, and greater than inhibition after low-dose (4.5 mg/kg/d) free gemcitabine. sHDLGemA2 slowed growth in semi-resistant cells and a resistant human xenograft. sHDLGemA2 targeted xenografts more effectively than sHDLGemA1. SR-B1 was over-expressed in PDAC cells and xenografts. Targeting by ApoA-II was suppressed by anti-SR-B1. Because sHDLGemA2 provided only ~6% of the free gemcitabine dose for an equivalent response, patient side effects can be greatly reduced, and the sHDLGemA2 concept should be developed through clinical trials.
(Copyright © 2020. Published by Elsevier B.V.)
Databáze: MEDLINE
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