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

Ross C Smith; Jerikho C Bulanadi; Anthony J Gill; Kerry-Anne Rye; Thomas Hugh; Nicholas Proschogo; Sarah F Smith; Leo Phillips; Xiaojuan Gong; Sohel M Julovi; Aiqun Xue; Minoo J Moghaddam

doi:10.1016/j.canlet.2020.08.045

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

Cancer Lett. 2020 Dec 28:495:112-122. doi: 10.1016/j.canlet.2020.08.045. Epub 2020 Sep 16.

Authors

Affiliations

¹ 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.
² 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.
³ 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.
⁴ School of Medical Sciences, Faculty of Medicine, University of New South Wales, NSW 2052, Australia. Electronic address: k.rye@unsw.edu.au.
⁵ 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.
⁶ Mass Spectrometry Core Facility, School of Chemistry, University of Sydney, NSW 2006, Australia. Electronic address: nicholas.proschogo@sydney.edu.au.
⁷ 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.
⁸ Mass Spectrometry Core Facility, School of Chemistry, University of Sydney, NSW 2006, Australia. Electronic address: leop@tpg.com.au.
⁹ NanoMed Pty Ltd, 2/11-13 Orion Road, Lane Cove West 2066, New South Wales, Australia. Electronic address: nelly.gong@nanomed.com.au.
¹⁰ 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.
¹¹ 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.
¹² 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.

PMID: 32949679
DOI: 10.1016/j.canlet.2020.08.045

Abstract

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.

Keywords: Lipid prodrug; PDAC; Scavenger receptor B-1; Synthetic HDL; Targeting drug delivery.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apolipoprotein A-II / administration & dosage*
Apolipoprotein A-II / chemistry
Apolipoprotein A-II / pharmacology
Carcinoma, Pancreatic Ductal / drug therapy*
Carcinoma, Pancreatic Ductal / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Deoxycytidine / administration & dosage
Deoxycytidine / analogs & derivatives*
Deoxycytidine / chemistry
Deoxycytidine / pharmacology
Dose-Response Relationship, Drug
Drug Synergism
Gemcitabine
Humans
Lipoproteins, HDL / chemistry
Male
Mice
Nanoparticles
Pancreatic Neoplasms / drug therapy*
Particle Size
Prodrugs / administration & dosage*
Prodrugs / chemistry
Prodrugs / pharmacology
Scavenger Receptors, Class B / metabolism*
Xenograft Model Antitumor Assays

Substances

Apolipoprotein A-II
Lipoproteins, HDL
Prodrugs
SCARB1 protein, human
Scavenger Receptors, Class B
Deoxycytidine
Gemcitabine