LIPID PRODRUG NANOPARTICLES CARRYING A MIMETIC PEPTIDE OF APOLIPOPROTEIN A-II TARGET PANCREATIC ADENOCARCINOMA
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Abstract
The easy production, improved efficacy, and low toxicity of lipid prodrug nanoparticles (LPNP) represent a promising new drug delivery technology for pancreatic ductal adenocarcinoma (PDAC), when carrying gemcitabine (Gem-LPNP).
This paper follows on from our previous study where we showed that lipid-based nanoparticles carrying a gemcitabine prodrug inhibit growth of human and cell-line PDAC xenografted onto mice. Using only 4.5mg/Kg of the clinical dose of gemcitabine in the prodrug, Gem-LPNP inhibited tumour growth as much as the significantly greater clinical dose of free gemcitabine (75-100mg/Kg). When apolipoprotein A-II (ApoA-II) was added to Gem-LPNP, growth was inhibited further. We determined that ApoA-II was actively targeting PDAC cells via the scavenger receptor-B1.
To improve the safety and cost of our targeting nanoparticles, we have now designed a short peptide of ApoA-II (SQ31) to be attached to Gem-LPNP (Gem-LPNP-SQ31) and aimed to compare the effects of Gem-LPNP with Gem-LPNP-SQ31 in a murine xenograft model.
Cell-line PDAC xenografts were implanted in one loin of twenty five immunodeficient mice. When the xenografts reached a measurable size, the mice were randomly assigned into five groups. They were given 200µL twice weekly of either 1) IV saline, 2) IP free gemcitabine 75mg/kg, 3) IV free gemcitabine 4.5mg/kg (equivalent dose to the nanoparticles), 4) IV Gem-LPNP or 5) IV Gem-LPNP-SQ31.
Transdermal xenograft measures showed that over four weeks, Gem-LPNP-SQ31 inhibited PDAC growth as much as high-dose free gemcitabine, but using only a fraction of the high free gemcitabine dose. Although xenograft sizes after Gem-LPNP-SQ31 were significantly smaller than those after Gem-LPNP treatment, this was only a small difference. Both Gem-LPNP and Gem-LPNP-SQ31 xenografts were significantly smaller than xenografts after the equivalent low-dose free gemcitabine. There was no histological evidence of complications in the mice. It is concluded that the addition of SQ31 to Gem-LPNP increased the inhibition of PDAC growth and this nanoparticle construct should be developed for clinical evaluation in humans.
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