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

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.

• Authors: 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
• Journal: Cancer letters (Cancer Lett) Vol. 495 Pg. 112-122 (12 28 2020) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 32949679 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020. Published by Elsevier B.V.

Chemical References

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

Topics

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