Targeting pancreatic ductal adenocarcinoma with rHDL/Apolipoprotein A-II nanoparticles for drug delivery — The Association Specialists
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Targeting pancreatic ductal adenocarcinoma with rHDL/Apolipoprotein A-II nanoparticles for drug delivery (427)

Jerikho Bulanadi 1 2 , Aiqun Xue 1 , Sohel Julovi 1 , Minoo Moghaddam 2 , Ross Smith 1
  1. Cancer Surgery and Metabolism, Kolling Institute, St Leonards, NSW, Australia
  2. CSIRO Materials Science and Engineering, CSIRO, North Ryde, NSW, Australia

Background:

Many of the current chemotherapeutic drugs employed to treat pancreatic ductal adenocarcinoma (PDAC) are ineffective at treating the disease due to a combination of low bioavailability and poor pharmacokinetic profiles. As a result, novel methods to overcome these limitations are being explored. The Cancer Surgery group at Kolling Institute (University of Sydney) in conjunction with the CSIRO Materials Science and Engineering are exploring the use of biomimetic, targeted recombinant high density lipoprotein (rHDL) nanoparticles as a delivery system for drugs such as gemcitabine and cisplatin.  These nanoparticles have been shown to be accepted by the HDL receptor, the scavenger receptor class B type I (SR-BI), which are over expressed in cancer tumours.1  So far, a great deal of focus has been placed on Apolipoprotein A-I rHDLs. However, serum levels of Apolipoprotein A-II (ApoA-II) have been found to be lower in patients with PDAC, indicating a possible role in lipid transport and metabolism in PDAC tumours.2   Our approach is on the use of the less common ApoA-II to construct the ApoA-II rHDL with the aim that the ApoA-II rHDL nanoparticles is able to selectively deliver high payloads of chemotherapeutic drugs to tumours with limited side effects.

Methods:

A membrane comprised of prodrug lipids of gemcitabine and cisplatin, cholesterol and phospholipids was prepared by mixing in chloroform, followed by evapouration. The membrane was then hydrated in tris-buffered saline and sonicated into a nanoparticle dispersion. The dispersion was then extruded through a filter membrane, followed by incubation with ApoA-II, resulting in the ApoA-II rHDL nanoparticle. In vivo results for the patient-derived xenograft animal model was established by implanting fresh patient PDAC underneath the capsule of kidneys of NOD/SCID mice. Fluorescent labelled ApoA-II rHDL nanoparticles were injected intravenously into mice and biodistribution was observed 48 hours after injection.

Results:

Gemcitabine and cisplatin prodrug lipids were able to be synthesized. Preliminary in vivo work into the biodistribution of the ApoA-II rHDL delivery system (without the prodrug lipid) in a patient-derived xenograft animal model has suggested an increase in the amount of ApoA-II rHDL nanoparticles within tumours in comparison to rHDL nanoparticles without ApoA-II.

Conclusion:

These preliminary results indicate the potential of ApoA-II rHDL nanoparticles as a drug delivery system. Future work will be to test the efficacy in vivo of the ApoA A-II rHDL nanoparticle with the prodrug lipid incorporated into the ApoA-II rHDL.

Keywords: Recombinant high density lipoprotein, Apolipoprotein A-II, gemcitabine, cisplatin

  1. Zhang, Z., et al., HDL-mimicking peptide-lipid nanoparticles with improved tumor targeting. Small, 2010. 6(3): p. 430-7.
  2. Xue, A., et al., Discovery of serum biomarkers for pancreatic adenocarcinoma using proteomic analysis. Br J Cancer, 2010. 103(3): p. 391-400.