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Inhalable nanoparticles in lung cancer treatment; efficacy, safety, distribution and nanoparticle-macrophage interactions Open Access


Other title
inhalable nanoparticles
Lung cancer
Type of item
Degree grantor
University of Alberta
Author or creator
Al-Hallak, MHD Kamal
Supervisor and department
Loebenberg, Raimar (Faculty of Pharmacy)
Examining committee member and department
Finaly, Warren (Mechanical engineering)
El-Kadi, Ayman (Faculty of Pharmacy)
Siraki, Arno (Faculty of Pharmacy)
Roa, Wilson (Cross cancer institute)
Faculty of Pharmacy and Pharmaceutical Sciences
Pharmaceutical sciences
Date accepted
Graduation date
Doctor of Philosophy
Degree level
In 2002, lung cancer was responsible for 17.6% of the total worldwide deaths from cancer. Beyond the three traditional forms of cancer treatment, surgery, radiation therapy, and chemotherapy, targeted drug delivery therapy has shown to be a potential treatment option. The design of a successful delivery system requires consideration of many factors, some of which include (i) the location and main organ(s) affected; (ii) the complexity of the associated physiological changes; (iii) the changes in receptor expression in cancerous cells; (iv) the physiochemical properties of the delivery system; (v) the interactions between the cancerous cells and other adjuvant cells, such as macrophages, with the delivery system; and (vi) the safety and tolerability of the delivery system. Considering the above factors of a successful delivery system, the aim of the present work was to design an innovative delivery system for lung cancer treatment incorporating inhalable nanoparticles (NP). To achieve this goal, several objectives were developed: (i) to investigate the interactions of different NP formulations with macrophages and the resulting effects on the behavior of macrophages; (ii) to assess and correlate the pulmonary toxicity of inhalable NPs using in vivo and in vitro methods; (iii) to develop a method to assess in real-time the effect of the formulation modifications on the uptake by macrophages of NPs; (iv) to assess the in vivo efficacy of an innovative formulation of effervescent inhalable NPs, thus actively releasing NPs; and finally, (v) to investigate the distribution of effervescent inhalable NPs after pulmonary delivery. Our results demonstrate that after exposure to NPs, macrophages undergo cellular changes to gain the ability to produce Th1 cytokines that are able to affect the viability of cancerous cells. The tolerability of inhalable NPs was related mainly to the additives used in the NP formulation. There was a good correlation between the in vivo and in vitro results. Effervescent inhalable NPs proved to be an effective and tolerable treatment for lung cancer treatment. Whole body autoradiography showed that inhalable NPs were able to achieve deep lung deposition and become distributed in time over the whole lung with some extra-pulmonary distribution.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Al-Hallak, M.K., et al., Pulmonary delivery of inhalable nanoparticles: Dry powder inhalers. Therapeutic Delivery, 2011. 2(10): p. 1313-1324Al-Hallak, M.K., et al., Distribution of effervescent inhalable nanoparticles after pulmonary delivery: an in vivo study. Therapeutic Delivery, 2012. 3(6): p. 725-734.Al-Hallak, M.H., et al., Pulmonary toxicity of polysorbate-80-coated inhalable nanoparticles; in vitro and in vivo evaluation. AAPS J, 2010. 12(3): p. 294-9.Al-Hallak, M.H., et al., Microcalorimetric method to assess phagocytosis: macrophage-nanoparticle interactions. AAPS J, 2011. 13(1): p. 20-9.Al-Hallak, K.M., et al., Secondary cytotoxicity mediated by alveolar macrophages: a contribution to the total efficacy of nanoparticles in lung cancer therapy? Eur J Pharm Biopharm, 2010. 76(1): p. 112-9.Roa, W.H., et al., Inhalable nanoparticles, a non-invasive approach to treat lung cancer in a mouse model. J Control Release, 2011. 150(1): p. 49-55.

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