Products Cited in Publications Worldwide Orally Inhaled Lipid-based Combination Therapy for the Treatment of Osteosarcoma Lung Metastasis

Orally Inhaled Lipid-based Combination Therapy for the Treatment of Osteosarcoma Lung Metastasis

Federica Carnamucio; Victoria A. Garcia; Fatemah S. Sunbul; Ottavia Giuffrè; Sandro R. P. da Rocha

DOI:

Abstract

Osteosarcoma (OS) is the most prevalent primary bone malignancy and ranks as the third most common cancer in children, almost exclusively metastasizing to the lungs. Upon initial OS diagnosis, approximately 20% of patients are also diagnosed with clinically detectable lung metastases (OSLM). Systemic gemcitabine (GMT) is the second line therapy for OSLM, but it has limited efficacy due to poor lung distribution. Orally inhaled GMT is in clinical studies and has been shown to upregulate the apoptotic Fas receptor (FasR) expression in OS cells in the lungs, but fails to eradicate lung mets due to its poor lung disposition. Traditional liposomal GMT formulations may offer improved lung safety and retention, but struggle with storage stability and drug loading. We have developed a new GMT unilmellar liposomal formulation that has enhanced GMT loading, high storage stability (<5% GMT leakage in six months storage at 2-8 °C), and is also suitable for oral inhalation. Importantly, we have subsequently developed a strategy for reproducible preparation of the formulation using as single step, GMP-ready, continuous microfluid platform. We also evaluated the efficacy of the formulation in promoting cell death and to rescuing FasR expression in OSLM tumor cells, and we demonstrated that GMT activity is preserved. We also demonstrated that our formulation is well tolerated at repeated doses upon local delivery to the lungs in healthy mice, since no change in body weight or health status have been observed.

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Gemcitabine

A43364295058-81-499%

Gemcitabine

10.0/50mg

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Cholesterol

A61246757-88-598%

Cholesterol

142.0/500g

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DL-Dipalmitoylphosphatidylcholine

A13554652644-64-695%

DL-Dipalmitoylphosphatidylcholine

125.0/250mg

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