(512c) Tumor-Penetrating Aerosol Nanocomposite Microparticles for the Treatment of Lung Cancer

One of the major public health problems in the Unites States is cancer, where over 1 in 4 deaths is due to this disease each year. As of 2010, lung and bronchus cancers are the leading types of cancer-related deaths in all ages for males and females in the US. The five-year relative survival is 54% for localized cancer, 26% for regional, 4% for distant, and 17% in all stages of lung cancer diagnosed [1]. Therefore, there is an unmet need for the development of more effective forms of treatment for lung cancer.

A chemotherapeutic treatment often applied for lung cancer is intravenous (I.V.) paclitaxel (PTX) in the form of Taxol. In general, I.V. therapy exerts negative systemic side effects that can impact the entire body as it travels to its destination via the bloodstream, thereby leading to a need for improved delivery methods. Methods used to treat respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) successfully involve the use of aerosols devices and the first use of aerosolized chemotherapy was reported in 1968 [2]. The advantages of using aerosols treatment include targeting of the therapeutic directly to the lungs and the reduction of systemic side effects provoked by high doses of drug in the body.

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 treatments is the low concentration of drug in tumors due to distance and limited access [3]. Recently, it was identified that for tumors expressing αv integrins on their surface that 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 [4].

In this project we have developed a dry powder nanocomposite microparticle (nCmP) aerosol containing PTX-loaded nanoparticles comprised of acetalated dextran (Ac-Dex). Ac-Dex is easily biodegradable and results in fast release of therapeutic agents under acidic conditions as seen in tumor tissues [5]. In addition to the drug, a tumor-penetrating peptide (iRDG) was conjugated to Ac-Dex to help the targeting and penetration into the inner layers of solid tumors. Finally, we formulated nCmPs 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 (2-D) cell culture, which was followed by three-dimensional (3-D) 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 [3, 6]. Overall, the systems shows promise in the improved delivery of chemotherapeutic agents to the lung to allows for the more effective treatment of lung cancer.

REFERENCES 

1.         Siegel, R., et al., Cancer statistics, 2014. CA Cancer J Clin, 2014. 64(1): p. 9-29.

2.         Shevchen.It and G.E. Resnik, Inhalation of Chemical Substances and Oxygen in Radiotherapy of Bronchial Cancer. Neoplasma, 1968. 15(4): p. 419-&.

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

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

5.         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.

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