Nitric Oxide Releasing d-α-Tocopheryl Polyethylene Glycol Succinate for Enhancing Antitumor Activity of Doxorubicin

Abstract

Nitric oxide (NO) has attracted much attention for its antitumor activity and synergistic effects when codelivered with anticancer agents. However, due to its chemical instability and short half-life, delivering gaseous NO directly to tumors is still challenging. Herein, we synthesized a NO releasing polymer, nitrate functionalized d-α-tocopheryl polyethylene glycol succinate (TNO3). TNO3 was able to self-assemble into stable micelles in physiological conditions, accumulate in tumors, and release ∼90% of NO content in cancer cells for 96 h. It further exhibited significant cancer cell cytotoxicity and apoptosis compared with nitroglycerine (GTN). Notably, TNO3 could also serve as an enhancer for the common chemotherapeutic drug doxorubicin (DOX). Codelivering TNO3 with DOX to hepatocarcinoma HepG2 cancer cells strengthened the cellular uptake of DOX and enabled the synergistic effect between NO and DOX to induce higher cytotoxicity (∼6.25-fold lower IC50). Moreover, for DOX-based chemotherapy in tumor-bearing mice, coadministration with TNO3 significantly extended the blood circulation time of DOX (14.7-fold t1/2, 6.5-fold mean residence time (MRT), and 13.7-fold area under curve (AUC)) and enhanced its tumor accumulation and penetration, thus resulting in better antitumor efficacy. In summary, this new NO donor, TNO3, may provide a simple but effective strategy to enhance the therapeutic efficacy of chemotherapeutic drugs.

Combination of nitric oxide and drug delivery systems: tools for overcoming drug resistance in chemotherapy

“…The potential of NO delivery systems in overcoming MDR was first demonstrated in vivo by the Si and Zhang groups (Figure 1) [66]. They developed NO-releasing micelles (TNO 3 ) by modifying the hydrophilic polyethylene glycol (PEG) end group of FDA-approved d -α-tocopheryl polyethylene glycol succinate (TPGS) with NO-releasing nitrate (-ONO 2 ).…”

“…Third, it is largely unknown whether the combined NO and drug delivery systems can exert synergistic effect in anticancer therapy. Although all strategies discussed above showed higher cytotoxicity than NO or drug treatment alone, only one study demonstrated that co-treatment had a CDI of less than 0.7 [66]. Fourth, proper range of NO concentrations for overcoming MDR should be demonstrated.…”

“…The nanoparticles showed enhanced anticancer effects in vivo compared to the control groups. Reprinted with permission from [66]. Copyright 2014, American Chemical Society.…”

Transferrin receptor-targeted vitamin E TPGS micelles for brain cancer therapy: preparation, characterization and brain distribution in rats

“…It was thus demonstrated that the BBB might be overcome by micelles with a size of $550 nm and cause non-selective accumulation of DTX in brain. The TPGS micelles were able to inhibit p-glycoprotein (p-gp)-based drug efflux in BBB that leads to enhancement in brain DTX concentrations (Zhao et al, 2013a;Song et al, 2014). Further, the control DTX showed the lowest concentration in the brain as a result of the resistance from the BBB as well as the enhanced elimination rate from the body.…”

D-α-tocopherol polyethylene glycol succinate-based derivative nanoparticles as a novel carrier for paclitaxel delivery

“…After treatment for 24, 48, and 72 hours, respectively, the relative cell viability was assessed by an MTT assay as described in our previous work. 31 IC 50 (concentration resulting in 50% inhibition of cell growth) value was determined by SPSS software (version 19.0). The experiment was repeated thrice.…”