Elimination of the biphasic pharmacodynamics of 15d-PGJ2 by controlling its release from a nanoemulsion

Abstract

15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) has a dual action of stimulating anti-inflammation and anti-proliferation when exogenously administered at high doses. However, at lower doses, it can be toxic inducing opposite actions, ie, stimulation of both inflammation and cell proliferation. This biphasic phenomenon of 15d-PGJ2 is believed to be due to its multitarget behavior. In this study, we provide a strategy for controlling such biphasic pharmacodynamics by separating its dual actions while retaining the beneficial one by using a nanoemulsion (NE). The 15d-PGJ2 was encapsulated in the NE composed of triolein/distearoyl phosphatidylcholine/Tween 80 at a high encapsulation ratio (>83%). Furthermore, NE enhanced drug retention by slowing down its release rate, which was, unconventionally, inversely dependent on the total surface area of the NE system. Next, focusing on the biphasic effect on cell proliferation, we found that the 15d-PGJ2-loaded slow-release NE showed only a dose-dependent inhibition of the viability of a mouse macrophage cell line, RAW264.7, although a fast-release NE as well as free 15d-PGJ2 exerted a biphasic effect. The observed slow-release kinetics are believed to be responsible for elimination of the biphasic pharmacodynamics of 15d-PGJ2 mainly for two reasons: 1) a high proportion of 15d-PGJ2 that is retained in the NE was delivered to the cytosol, where proapoptotic targets are located and 2) 15d-PGJ2 was able to bypass cell membrane-associated targets that lead to the induction of cellular proliferation. Collectively, our strategy of eliminating the 15d-PGJ2-induced biphasic pharmacodynamics was based on the delivery of 15d-PGJ2 to its desired site of action, excluding undesired sites, on a subcellular level.

Keywords:

• drug release
• surface localization
• anti-proliferative effect
• cellular uptake
• subcellular delivery

Supplementary materials

Figure S1 Release profiles of SRNE and FRNE compared to that of 15d-PGJ2 solution.

Notes: After screening the effect of NE compositions and their ratios on drug release, two NE formulations were selected as candidates for evaluating pharmacological activity: FRNE and SRNE. Their release profiles were measured and compared to the release of 15d-PGJ2 dissolved in PBS as a control. Data are presented as mean ± SD (n=3).

Abbreviations: 15d-PGJ2, 15-deoxy-Δ12,14-prostaglandin J2; FRNE, fast-release NE; NE, nanoemulsion; PBS, phosphate-buffered saline; SRNE, slow-release NE.

Figure S2 The effect of DSPC on the release of 15d-PGJ2 in the presence of a low Tween 80 content.

Notes: The amounts of triolein, Tween 80, and 15d-PGJ2 were fixed at 21 μmol, 4 μmol, and 0.5 μmol, respectively.

Abbreviations: 15d-PGJ2, 15-deoxy-Δ12,14-prostaglandin J2; DSPC, 1,2-distearoyl-sn-glycero-3 phosphocholine.

Table S1 Geometrical parameters of the NE formulations

Table S2 Estimated R50 of the NE formulations

Table S3 Characterization of empty NE particles

Acknowledgments

This work was partially supported by grants from the Special Education and Research Expenses of the Ministry of Education, Culture, Sports, Science and Technology of Japan and by Japan Society for the Promotion of Science under the Japan–Korea Basic Scientific Cooperation Program. Finally, the authors thank Doctor MS Feather for his helpful advice in writing the manuscript in the English language.

Disclosure

The authors report no conflicts of interest in this work.