(260t) Tumor-Penetrating Aerosol Nanocomposite Microparticles for the Treatment of Lung Cancer

Lung cancer is the leading cause of cancer-related deaths in the United States, representing more than one-quarter of all cancer-related deaths. It is estimated that 433 deaths per day will be due to lung and bronchus cancers in 2016. The five-year relative survival is currently 18%, because most of the cases are diagnosed at a distant stage, for which the 5-year survival is only 4% [1]. Despite the advances in cancer treatment over the past 40 years, the survival rates for lung cancer patients still remains devastatingly low. Therefore, there is an unmet need for the development of more effective forms of treatment for lung cancer.

A chemotherapeutic treatment commonly applied for lung cancer is intravenous (I.V.) paclitaxel (PTX) in the form of Taxol. In general, I.V. therapy results in negative systemic side effects in route to its destination via the bloodstream, which spurs the need for improved delivery techniques. Aerosols have been successfully used for the treatment of pulmonary diseases such as asthma and chronic obstructive pulmonary disease (COPD), and the first use of aerosolized chemotherapy was reported in 1968 [2]. The advantages of using aerosol treatment include better targeting to the lungs and reduced systemic side effects often seen with high systemic drug doses [3].

Cancer cells tend to form solid tumors that are characterized for having hypoxic cells and a necrotic core, which gives them high resistance to the treatments. One reason for the failure of cancer treatment is the low concentration of drug in tumors due to limitations in drug diffusion into the cancerous tissue [4]. Recently, it was identified that tumors expressing αv integrins on their surface can be effectively targeted for treatment. The use of the tumor-homing and penetrating peptide iRGD (CRGDKGPDC) as a targeting moeity to integrins helps to overcome the penetration limitations into these tumors via targeting and tumor penetration [5].

In this project we developed a dry powder nanocomposite microparticle (nCmP) aerosol containing PTX-loaded nanoparticles synthesized with a biodegradable polymer, acetalated dextran (Ac-Dex). The byproducts of the degradation of Ac-Dex are harmless to the body and results in controlled release of therapeutic agents under acidic conditions as seen in tumor tissues [6]. In addition to the drug, a tumor-penetrating peptide (iRDG) was conjugated to Ac-Dex to aid in targeting and penetration into the inner layers of solid tumors. Finally, we formulated nCmP in mannitol via spray drying. The physicochemical properties of the nano- and microparticles (size, charge, drug loading) were evaluated. The effectiveness of the complex drug produced was tested in lung cancer cells (A459 lung adenocarcinoma) in two-dimensional (2D) cell culture, which was followed by three-dimensional (3D) cell culture studies that reflect many of the properties of solid tumors and mimic better all the barriers to drug diffusion, transport and distribution in tumors [4, 7]. Overall, the system shows promise in the improved delivery of chemotherapeutic agents to the lungs and allows for a more effective treatment of lung cancer.

References

[1] Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA Cancer J Clin, 2016. 66(1): p. 7-30.

[2] Shevchenko, I.T. and G.E. Resnik, Inhalation of chemical substances and oxygen in radiotherapy of bronchial cancer. Neoplasma, 1968. 15(4): p. 419-26.

[3] Patil, J.S. and S. Sarasija, Pulmonary drug delivery strategies: A concise, systematic review. Lung India, 2012. 29(1): p. 44-9.

[4] Minchinton, A.I. and I.F. Tannock, Drug penetration in solid tumours. Nat Rev Cancer, 2006. 6(8): p. 583-92.

[5] Teesalu, T., K.N. Sugahara, and E. Ruoslahti, Tumor-penetrating peptides. Front Oncol, 2013. 3: p. 216.

[6] Kauffman, K.J., et al., Synthesis and characterization of acetalated dextran polymer and microparticles with ethanol as a degradation product. ACS Appl Mater Interfaces, 2012. 4(8): p. 4149-55.

[7] Sutherland, R.M., Cell and environment interactions in tumor microregions: the multicell spheroid model. Science, 1988. 240(4849): p. 177-84.