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. 2016 Feb 10:223:215-223.
doi: 10.1016/j.jconrel.2015.12.048. Epub 2015 Dec 28.

TRAIL-coated leukocytes that prevent the bloodborne metastasis of prostate cancer

Elizabeth C Wayne  1 , Siddarth Chandrasekaran  1 , Michael J Mitchell  1 , Maxine F Chan  1 , Rachel E Lee  1 , Chris B Schaffer  1 , Michael R King  2
Affiliations

TRAIL-coated leukocytes that prevent the bloodborne metastasis of prostate cancer

Elizabeth C Wayne et al. J Control Release. .

Abstract

Prostate cancer, once it has progressed from its local to metastatic form, is a disease with poor prognosis and limited treatment options. Here we demonstrate an approach using nanoscale liposomes conjugated with E-selectin adhesion protein and Apo2L/TRAIL (TNF-related apoptosis-inducing ligand) apoptosis ligand that attach to the surface of leukocytes and rapidly clear viable cancer cells from circulating blood in the living mouse. For the first time, it is shown that such an approach can be used to prevent the spontaneous formation and growth of metastatic tumors in an orthotopic xenograft model of prostate cancer, by greatly reducing the number of circulating tumor cells. We conclude that the use of circulating leukocytes as a carrier for the anti-cancer protein TRAIL could be an effective tool to directly target circulating tumor cells for the prevention of prostate cancer metastasis, and potentially other cancers that spread through the bloodstream.

Keywords: Circulating tumor cells; Metastasis; Nanomedicine; TRAIL.

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Figures

Fig 1
Fig 1. Pharmacokinetic dynamics of TRAIL-coated leukocytes
(A) Scatter plots showing percentage of circulating mouse leukocytes staining positive for surface bound human TRAIL protein. (B) Confocal micrograph of a mouse leukocyte presenting human TRAIL protein on its surface at t=72 hours (Scale bar = 10μm).
Fig 2
Fig 2. Test of ES/TRAIL liposomes to prevent metastasis in an orthotopic model of prostate cancer
(A) Schematic of orthotopic xenograft model for metastatic prostate cancer progression. (B) Timeline for ES/T liposome efficacy trial in tumor-bearing mice. (C) Whole animal BLI of the ventral (left) and dorsal (right) side of representative animals from each treatment group at the end of the trial (week 9) (D) Average radiance from the primary tumor. Comparisons were made via one-way ANOVA with Tukey posttest. Error bars represent the mean ± SD at each timepoint. ES vs ES/TRAIL: %=(p < 0.05) %%=(p<0.01). Buffer vs ES/TRAIL: **=(p<0.05).
Fig 3
Fig 3. Quantification of bioluminescence signal of DU145 cells following orthotopic tumor implantation
(A) Increased bioluminescence signal from tumor growth over time. (B) Bioluminescent signal from excised organs 5 weeks after tumor implantation (left) and age-matched control (right). (Scale bar = 1cm) (C) Confocal micrographs of buffy coat isolated from control mice (age-matched non-tumor bearing SCID mice) and mice bearing orthotopic DU145 tumor six weeks after implantation (blue, cell nuclei and red, mCherry expressing DU145 cells). (Scale bar = 100μm) (D) Number of CTCs per volume of blood, measured weekly after orthotopic implantation of tumor. n=3 mice were analyzed each week. Error bars represent the mean ± SD at each timepoint.
Fig 4
Fig 4. ES/TRAIL liposome treatment is effective in significantly reducing the number of circulating tumor cells in blood
(A) Average number of CTCs in the peripheral circulation post treatment. n=3 mice for each group. Bars represent mean ± SD for each group. (B) Representative fluorescent micrographs showing mCherry positive DU145 cells isolated from whole blood of animals from different treatment groups at the end of the study. Scale bar = 100μm. n= 6, 6, 6, and 3 for treatment groups ES/T, ES, Buffer, Buffer(ES/T), respectively. Error bars represent the mean ± SD in each group. ***p<0.0001
Fig 5
Fig 5. Ex vivo BLI analysis reveals that ES/TRAIL liposomes block widespread metastasis
(A) Representative BLI images reveal the spread of DU145-Luc cells to lung, liver, kidney and spleen across Buffer, ES, and ES/T treatment groups (left-to-right). Scale bar=1cm. (B) Bioluminescent signal from each organ was quantified for each treatment groups: Buffer (n=8), ES-liposomes (n=6), and ES/T (n=6). Data are plotted on a log scale. Individual data points represent total organ signal from an individual animal. Superimposed box plots bound the 25th to 75th percentage of all data points and the whiskers extend 1.5 times the interquartile range beyond boxes. *P<0.05, **P<0.01 (one-way ANOVA with Tukey posttest).
Fig 6
Fig 6. ES/TRAIL treatment does not induce toxicity
(A) Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) liver enzymes in mice from different treatment groups and aged matched controls at the end of the study. Bars represent mean ± SD for enzyme levels from three mice in each treatment group. (B) AST/ALT ratio for mice from different treatment groups and aged matched controls. AST/ALT >2 indicates liver toxicity. (C) Systemic hematocrit of mouse blood. Each dot represents the hematocrit measurement from an individual animal. Blood was drawn prior to euthanasia. Control group (Control) represents age-matched and strain-matched animals that received no tumor or drug. (D) Weight of animals throughout the experiment. Each dot represents the average weight (grams) of each animal. Control group represents age-matched and strain-matched animals that received no tumor or drug. (E) Weight of excised organs post-mortem. (F) TUNEL staining of liver from ES/T liposome and Buffer treated animals. Error bars represent mean ± SD of each treatment group. NS= non-significant difference. Comparisons made using one way-ANOVA. *p<0.01, **p<0.001.
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