PT-024 - PHARMACOKINETICS AND TISSUE DISTRIBUTION OF A LIPID-BASED EXTENDED-RELEASE NANO-FORMULATION OF MO-OH-NAP TROPOLONE TO ENHANCE PULMONARY DELIVERY.

W. Aldhafiri, Y. Chhonker, S. Haney, N. Ahmed, J. Ford, S. Holstein, D. Murry; University of Nebraska Medical Center, Omaha, NE, USA.

Background: Pulmonary metastatic osteosarcoma (OS) is a significant therapeutic challenge. MO-OH-Nap tropolone (MO-OH-Nap) is a novel small molecule with cytotoxic activity across multiple OS cell lines, yet poor solubility limits its clinical development[1]. We developed a MO-OH-Nap lipid-based nanoparticle (NP) formulation to enhance delivery to pulmonary tissue for the treatment of pulmonary metastatic OS.

Methods: The NP formulation was prepared using a lipid film hydration method. Dynamic light scattering (DLS) and ultra-centrifugation were used to determine NPs average particle size and encapsulation efficiency. The pharmacokinetics and biodistribution of MO-OH-Nap were determined in CD-1 mice following a single intraperitoneal (IP) dose of MO-OH-Nap or NP formulation (5 mg/kg). Serial plasma and tissue samples were collected over 48 hours. MO-OH-Nap concentrations were determined utilizing a validated LC-MS/MS method. Pharmacokinetic parameters were determined utilizing non-compartmental analysis with Phoenix® software.

Results: NP average particle size was 349 ± 34.5 d.nm with 98% of the drug efficiently encapsulated. Following IP administration, MO-OH-Nap systemic drug exposure was significantly higher (~10 fold) for the NP formulation (28229 hr*ng/mL) when compared to the drug alone in the aqueous solution (2846 hr*ng/mL). The observed clearance was 184.4 for the NP and 1738.6 mL/hr/kg for drug alone. Drug concentrations in lung tissue 24 hours post IP injection were significantly increased following NP administration (165.5 ng/g) compared to drug alone (1.20 ng/g, t-test, p-value < 0.001).

Conclusion: The developed NP formulation substantially increased systemic exposure and pulmonary delivery of MO-OH-Nap. Further studies will assess the formulation activity in treating metastatic pulmonary OS.

Haney, Staci L et al. “Tropolone-induced effects on the unfolded protein response pathway and apoptosis in multiple myeloma cells are dependent on iron.” Leukemia research vol. 77 (2019)