(W0930-03-16) Comparative Bioavailability Study of Jaspine B: Impact of Nano-Liposomal Drug Delivery System on Pharmacokinetics

Purpose: Jaspine B (JB) is an anhydrophytosphingosine which inhibits sphingosine kinases and suppresses their proliferative actions [1]. It is known to have an effective anticancer properties in different types of carcinomas and sarcomas [2,3]. Previous studies have shown that maintaining high or optimum intracellular concentration of JB is important for its cytotoxic activity [4]. Despite the potent cytotoxic activity of the drug, it has a low oral bioavailability (6.2%) [5]. In previous pharmacodynamic (PD) study, it was shown that liposomal formulation of JB was more effective in reducing primary tumor, compared to JB itself [3]. We hypothesize that the liposomal formulation of JB is more effective due to the improved pharmacokinetic (PK) properties that the liposomal formulation offers. The purpose of this study was to prepare a liposomal formulation of JB and study the comparative oral bioavailability of the liposomal formulation in comparison to plain JB in healthy rats through development of a selective and sensitive LC-MS/MS method.

Methods: >JB liposomes were formulated using the microfluidic technique, using NanoAssembr^TM platform. A solution of Lipids (5mg/ml) and JB (1mg/ml) in methanol were used as an organic phase, and PBS was used as aqueous phase. Two phases were mixed in the ratio of 1:2 and the total flow rate was set to 8ml/min. The obtained mixture was filtered and characterized using Transmission Electron Microscopy (TEM), and its entrapment efficiency (EE) was calculated by LC-MS/MS method. The PK study was performed on two groups of Sprague Dawley rats (N = 3/group): JB oral suspension in a vehicle containing DMSO: PEG2000: PBS (2:4:4) and JB liposomes oral. The blood samples were drawn at 5, 15, 30, 60, 120, 360, 720 and 1440-min post-dose. A selective and sensitive LC-MS/MS method was developed, validated, and utilized to measure the concentration of JB in rat plasma.

Results: The TEM analysis showed that the liposomes were spherical with an average diameter of 127 nm. The EE was found to be 97%. The formulated JB liposomes were found to be stable in PBS at pH 7.4 for more than 2 months. The analytical method was linear at range of 0.5 -16 ng/mL, LLOQ less than 0.5 ng/mL and with intra- and inter-day CV% < 10%.

Conclusion: In this study, we developed a nano-liposomal formulation of JB and analyzed it in rat plasma with a sensitive and selective LC-MS/MS. The PK study results show that nano-liposomal formulation of JB was able to improve PK parameters by increasing its oral bioavailability and MRT therefore improve the therapeutic outcome of the drug. This observation was in concert with previous PD study results [3].

References: 1. Yoshimitsu, Y.; Oishi, S.; Miyagaki, J.; Inuki, S.; Ohno, H.; Fujii, N. Pachastrissamine (jaspine B) and its stereoisomers inhibit sphingosine kinases and atypical protein kinase C. Bioorganic & Medicinal Chemistry 2011, 19, 5402-5408, doi:https://doi.org/10.1016/j.bmc.2011.07.061.
2. Salma, Y.; Lafont, E.; Therville, N.; Carpentier, S.; Bonnafé, M.-J.; Levade, T.; Génisson, Y.; Andrieu-Abadie, N. The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism. Biochemical Pharmacology 2009, 78, 477-485, doi:https://doi.org/10.1016/j.bcp.2009.05.002.
3. Khajeh Pour, S.; Mateen, S.; Pashikanti, S.; Barrott, J.J.; Aghazadeh-Habashi, A. Formulation, Characterization, and In Vitro/In Vivo Efficacy Studies of a Novel Liposomal Drug Delivery System of Amphiphilic Jaspine B for Treatment of Synovial Sarcoma. Mar Drugs 2022, 20, doi:10.3390/md20080509.
4. Lee, J.; Choi, K.; Kwon, M.; Lee, D.; Choi, M.-K.; Song, I.-S. Differential cytotoxic effects of Jaspine B in various cancer cells. 생명과학회지 2016, 26, 1392-1399.
5. Choi, M.-K.; Lee, J.; Nam, S.J.; Kang, Y.J.; Han, Y.; Choi, K.; Choi, Y.A.; Kwon, M.; Lee, D.; Song, I.-S. Pharmacokinetics of Jaspine B and Enhancement of Intestinal Absorption of Jaspine B in the Presence of Bile Acid in Rats. Marine Drugs 2017, 15, doi:10.3390/md15090279.

Acknowledgements: The animal study protocol was approved by Idaho State University’s Institutional Animal Care Committee under legal and ethical standards established by the National Research Council and published in the Guide for the Care and Use of Laboratory Animals.
The authors declare no conflict of interest.


Table 1. PK parameters after oral dose of 5 mg/kg JB suspension or as liposomal formulation.