Nanoemulsion formulation of a novel taxoid DHA-SBT-1214 inhibits prostate cancer stem cell-induced tumor growth

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 hrs.) 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 CD133high/CD44+/high tumor-initiating cells both in vitro and in vivo.

<p>Nanomedicine-based formulations containing &omega;-3 polyunsaturated fatty acids: potential application in cardiovascular and neoplastic diseases</p>

“…Similarly to the results of the work by Zu et al, 65 where nanoformulations containing DHA bound to a taxane were tested in lung cancer, two studies performed on prostate cancer used an oil-in-water nanoemulsion formulation, 87,88 where the starting oil phase consisted of fish oil with a novel DHAtaxoid conjugate (DHA-SBT-1214) ( Table 4; Figure 3A). The oil phase was mixed with the water phase formed by egg phosphatidylcholine (Lipoid E80 ® ), polysorbate 80 (Tween80 ® ), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(amino[polyethylene glycol]-2000) (DSPE-PEG2000).…”

“…64,91,92 The newly designed nanoemulsion of DHA-SBT-1214 (NE-DHA-SBT-1214) was tested for its antineoplastic activity against human prostatic cancer PPT2 cells cultured in vitro, or transplanted subcutaneously in NOD/SCID mice. 87,88 These prostate cancer cells have the features of stem-like cells and are considered a good model for testing new drugs for prostate cancer. This is a highly recurrent tumor, which has been related to the presence of high levels of cancer stem cells with the potential of selfrenewing the tumor.…”

Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery

“…137 NE-DHA-SB-T-1214 exhibited remarkable in vivo efficacy against CSC-initiated PPT2 human prostate tumor xenografts in SCID mice, inducing tumor regression. 137 In the same experiment, Abraxane was not able to control the tumor growth of CSC-PPT2. Viable cells that survived this treatment regimen in vivo were no longer able to induce floating spheroids and holoclones, whereas control and Abraxane-treated tumor cells induced a large number of both.…”

“…In addition, any complication in histopathology of different mouse organs was observed and also there is no significant weight change over the period of the treatment regimen. 137 NE-DHA-SB-T-1214 is currently in a late stage preclinical development for IND filing, which will be done in the near future.…”

DHA-SBT-1214 Taxoid Nanoemulsion and Anti–PD-L1 Antibody Combination Therapy Enhances Antitumor Efficacy in a Syngeneic Pancreatic Adenocarcinoma Model

“…Because of poor water solubility of this drug and susceptibility of the ester bond in DHA-SBT-1214 to cleave in the presence of esterases in the systemic circulation, we have formulated the drug in omega-3 fish oil-rich nanoemulsion formulation. In previous studies, we have observed that nanoemulsion-encapsulated DHA-SBT-1214 (NE-DHA-SBT-1214) shows improved delivery efficiency, tumor residence, improved therapeutic efficacy, and less systemic toxicity in a subcutaneous stem cell-rich PPT-2 human prostate tumor xenograft model (11).…”