Graduation Date

Summer 8-9-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Daryl J. Murry

Abstract

Osteosarcoma is the most common primary bone tumor in children and adolescents. Metastasis is prevalent in 25% of patients, at diagnosis, with the lungs being the most common metastatic site. Pulmonary metastatic osteosarcoma is a significant therapeutic challenge with a 5-year survival rate of ≤30%. Patients with pulmonary metastatic disease at diagnosis receive the same standard of care as patients with local disease, which hasn’t changed over the past 30 years. The treatment and prevention of pulmonary metastatic osteosarcoma represents a significant critical and unmet need.

MO-OH-Nap tropolone is a novel small molecule with cytotoxic activity across multiple human osteosarcoma cell lines, yet poor solubility limits its clinical development. We developed a MO-OH-Nap tropolone liposomal nanoparticle formulation to enhance delivery to pulmonary tissue for the treatment of pulmonary metastatic osteosarcoma.

The nanoparticle formulation was prepared using a lipid film hydration method. Dynamic light scattering and ultra-centrifugation were used to determine the average particle size and encapsulation efficiency. The pharmacokinetics and biodistribution of MO-OH-Nap tropolone were determined in CD-1 mice following a single intraperitoneal dose of MO-OH-Nap tropolone aqueous solution or MO-OH-Nap tropolone liposomes nanoparticle formulation (5 mg/kg). Serial plasma and tissue samples were collected over 48 hours. MO-OH-Nap tropolone concentrations were determined utilizing a validated LC-MS/MS method. Phoenix® software was used to determine pharmacokinetic parameters utilizing non-compartmental analysis and a 3-compartment pharmacokinetic model to better characterize the MO-OH-Nap tropolone liposomes nanoparticle plasma and tissue concentrations. The finalized model was used to simulate different dosing regimen responses utilizing Monte Carlo simulations.

The liposomes nanoparticle average particle size was 188.3 ± 54 d.nm with 99% encapsulation efficiency. Following single dose administration in mice, MO-OH-Nap tropolone systemic drug exposure was significantly increased (~10 fold) for the nanoparticle formulation (28229 hr*ng/mL) compared to the MO-OH-Nap (2846 hr*ng/mL). The observed clearance was 184.4 mL/hr/kg for the nanoparticle formulation and 1738.6 mL/hr/kg for the drug in aqueous solution. Drug concentrations in lung tissue 24 hours post dose (165.5 ng/g) were significantly increased following nanoparticle formulation administration compared to drug in aqueous solution (1.20 ng/g, student t-test, p-value < 0.001).

The developed pharmacokinetic model accurately described the plasma concentration time profile and pulmonary drug accumulation. The model revealed a biphasic absorption pattern with a rapid initial drug release followed by a sustained drug release phase, indicating the controlled release properties of the nanoparticle formulation. Monte Carlo simulation for multiple dosing scenarios identified that the 7.5 mg/kg twice-weekly regimen would significantly improve lung coverage while moderately enhancing plasma levels, aligning better with the goal of maintaining pulmonary concentrations above the IC50 for a 75% of the dosing interval of 28 days. The model's fit was validated through bootstrap analysis, confirming the reliability of the pharmacokinetic parameters. Overall, this pharmacokinetic model provides critical insights into the behavior of MO-OH-Nap tropolone nanoparticle formulation, facilitating the development of effective dosing strategies for enhanced treatment of pulmonary metastatic osteosarcoma.

The developed formulation substantially increased systemic exposure and pulmonary delivery of MO-OH-Nap tropolone. Further studies will assess the safety profile of 7.5 mg/kg IP dose twice weekly, as well as evaluate efficacy in mouse models of metastatic OS.

Comments

Copyright 2024, the author

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Available for download on Thursday, July 30, 2026

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