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Liposomal Encapsulation of Deguelin: Evidence for Enhanced Antitumor Activity in Tobacco Carcinogen–Induced and Oncogenic K-ras–Induced Lung Tumorigenesis

Authors' Affiliations: ¹ Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ² Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas

Requests for reprints: Ho-Young Lee, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Unit 432, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-0769; Fax: 713-792-0430; E-mail: hlee{at}mdanderson.org.

Deguelin has shown promising chemopreventive and therapeutic activities in diverse types of cancers. However, the potential side effect of deguelin over a certain dose could be the substantial hurdle in the practical application of the drug. One of the successful strategies for the use of deguelin in clinical trials could be lung-specific delivery of the drug. The present study evaluates the efficacy of liposome-encapsulated deguelin with a dose of 0.4 mg/kg, which is 10 times less than the dose (4 mg/kg) for preventive and therapeutic activities validated in previous in vivo studies. Liposomal deguelin revealed cytotoxic activity in vitro in premalignant and malignant human bronchial epithelial cells and non–small cell lung cancer cells through the same mechanistic pathway previously reported for deguelin (i.e., suppression of the heat shock protein 90 chaperone function and induction of apoptosis). Delivery of liposomal deguelin at a dose of 0.4 mg/kg by intranasal instillation resulted in markedly increased drug partitioning to the lungs compared with that of 4 mg/kg deguelin or 0.4 mg/kg liposomal deguelin administered by oral gavage. Lung-specific delivery of deguelin (0.4 mg/kg) via nasal or intratracheal instillation in a liposomal formulation also showed significant chemopreventive and therapeutic activities in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone/benzo(a)pyrene–treated A/J mice and K-rasLAC57Bl6/129/sv F1 mice with no detectable toxicity. Our findings support the potential use of deguelin in a liposomal formulation via lung-specific delivery to improve efficacy and to reduce the potential side effects of the agent.

Key Words: liposome-encapsulated deguelin • chemoprevention • therapy • lung cancer • instillation

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