(M1430-09-57) Engineering of Docetaxel Smart Crystalline Solid Dispersion for Prostate Cancer Therapy

Purpose: Prostate cancer is the second leading cause of cancer death in men in the United States. Prostate-Specific Membrane Antigen (PSMA) is an anchored and overexpressed transmembrane protein found on the surface of over 95% of prostate tumors. Hence, PSMA is a valuable target for prostate cancer therapy. Docetaxel (DXT) is one of the few treatment options for Prostate cancer following the failure of androgen deprivation therapy. Currently, little is known about the docetaxel smart crystalline solid dispersion (CSD) effectiveness for prostate cancer therapy. It is hypothesized that smart docetaxel crystalline solid dispersion potentiates the accumulation of DXT in prostate cancer cells, resulting in increased DXT effectiveness and reduced side effects.

Methods: The smart CSD is engineered by dissolving DXT (25 mg) in sodium acetate/Glacial acetic solution (50 mg/mL/5 mL) and subsequently freeze-dried for 24 hrs. The resulting formulation (F) is redispersed in (1%v/v, 5mL) ethyl phenyl phosphinate aqueous solution, a potential PSMA ligand, and subsequently freeze-dried to produce the smart CSD formulation (SF). The resulting CSDs' physical and chemical properties are characterized by ZetaSizer Advanced Pro, Fourier Transform Infrared, and Spectrophotometry (F). The cytotoxicity on a prostate cancer cell line (C4-2) is assessed by MTS assay

Results: The entrapment efficiency of formulation F and SF is 94.9±2.6% and 99.9±7.7%, respectively. The size (Fig.1) and the zeta potential of F and SF are 2341±619 nm, 1203.33±29.26 nm, and -6.14±0.92 mV, -21.86±1.8mV, respectively. The drug loading of formulation F and SF is 8.83.±.0.6 % w/w and 8.62±0.19 %w/w, respectively. The FTIR confirms that DXT is successfully dispersed and coated with sodium acetate as evidenced by the two bands observed at 1573 cm-1 and 1412 cm-1, which are characteristic of the resonance of electrons within the carboxylate ion -COO as shown in Fig.2. Blank B and SB, which do not contain docetaxel, are not cytotoxic to the C4-2 , CRPC cell line, with cell viability above 80%. The cytotoxicity of F and strongly cytotoxic to C4-2, a castration resistance prostate cancer cell line. The C4-2 cell viability after 48 hours of exposure to F and SF ( 0.1 µg/ml) is 26.1±5.4% and 26.8±5.5%, respectively as shown in Fig.3.

Conclusion: In conclusion, we have successfully engineered the smart crystalline solid dispersion with high drug entrapment efficiency. The cytotoxicity of the crystalline solid dispersion is dose-dependent. This new approach of developing a docetaxel crystalline solid dispersion will provide a new horizon for developing future safe and effective formulations for prostate cancer therapy.

References: 1. Ngo AN.; Thomas, D.; Murowchick, J.; Ayon, N. J.; Jaiswal, A.; Youan, B. C., Engineering fast dissolving sodium acetate mediated crystalline solid dispersion of docetaxel. Int J Pharm 2018, 545 (1-2), 329-341.
2. Ngo, AN.; Chatman, K. K.; Douglas, D.; Mosley-Kellum, K. M.; Wu, K.; Vadgama, J., Engineering of layer-by-layer acetate-coated paclitaxel loaded poly(lactide-co-glycolide) acid nanoparticles for prostate cancer therapy- in vitro. J Pharm Sci 2024, 113 (11), 3375-3383.

Acknowledgements: The research reported was supported by Florida A&M University start-up Award #101, program 11, the RCMI Grant 5U54MD007582 from the National Institute on Minority Health and Health Disparities.

Particle size distribution by intensity