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

• Author / Creator

  Al-Hallak, MHD Kamal

• 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.

• Subjects / Keywords

  • Inhalable nanoparticles
  • Macrophages
  • Lung cancer

• Graduation date

  Fall 2012

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3RK6T

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.