Nanoemulsion formulation of a novel taxoid DHA-SBT-1214 inhibits prostate cancer stem cell-induced tumor growth. (10th October 2017)

• Record Type: Journal Article
• Authors: Ahmad, Gulzar; El Sadda, Rana; Botchkina, Galina; Ojima, Iwao; Egan, James; Amiji, Mansoor
• Is Part Of: Cancer letters. Volume 406(2017)
• Page Start: 71
• Page End: 80
• Publication Date: 2017-10-10
• Subjects: Prostate cancer -- Cancer stem cells -- Taxoid -- Nanoemulsion formulation; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.08.004
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The main aim of this study was to evaluate the therapeutic efficacy of an oil-in-water nanoemulsion formulation encapsulating DHA-SBT-1214, a novel omega-3 fatty acid conjugated taxoid prodrug, against prostate cancer stem cells. Nanoemulsions of DHA-SBT-1214 (NE-DHA-SBT-1214) were prepared and characterized. In vitro delivery efficiency and cytotoxicity of NE-DHA-SBT-1214 was compared with solution formulation in PPT2 cells. In vivo studies included analysis of comparative efficacy of NE-DHA-SBT-1214 with Abraxane ® and placebo nanoemulsions as well as post-treatment alternations in clonogenic and sphere-forming capabilities of the tumor cells. Qualitative intracellular uptake studies of dye encapsulated NEs by confocal imaging showed uptake by both monolayer and spheroid cultured PPT2 cells. Treatment of PPT2 cells with NE DHA-SBT-1214 (1nM-1μM for monolayer culture of cells grown on collagen-coated dishes for 48 h) induced complete cell death, showing higher efficacy as compared to the drug solution. This nanoemulsion (10nM-10μM) also showed toxicity in 3D culture of floating spheroids. Weekly intravenous administration of the NE-DHA-SBT-1214 to NOD/SCID mice bearing subcutaneous PPT2 tumor xenografts led to dramatic suppression of tumor growth compared to Abraxane ® and placebo nanoemulsion formulation. Viable cells that survived from this in vivo treatment regimen were no longer able to induce floating spheroids and holoclones, whereas control and Abraxane ® treated tumor cells induced a large number of both. The results show that NE-DHA-SBT-1214 possesses significant activity against prostate CD133 high /CD44+/ high tumor-initiating cells both in vitro and in vivo. Highlights: Novel DHA-conjugated taxoid SBT-1214 was synthesized and encapsulated in fish oil-containing nanoemulsion. NE-DHA-SBT-1214 showed improved cell-kill efficacy in vitro, in PPT2 cells with cancer stem cell (CSC)-like phenotype. NE-DHA-SBT-1214 showed improved therapeutic efficacy in vivo, in PPT2 tumor xenografts upon intravenous administration. NE-DHA-SBT-1214 treated viable cells from in vivo xenograft were unable to induce spheroids and holoclone formation.