P. Rychahou1,2, Y. Bae4, Y. Zaytseva1, E. Y. Lee1,3, H. L. Weiss1, B. Evers1,2 1University Of Kentucky,Markey Cancer Center,Lexington, KY, USA 2University Of Kentucky,Department Of Surgery,Lexington, KY, USA 3University Of Kentucky,Pathology And Laboratory Medicine,Lexington, KY, USA 4University Of Kentucky,Department Of Pharmaceutical Sciences,Lexington, KY, USA
Introduction: Colorectal cancer (CRC) is the second leading cause of cancer deaths in the US. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is important for CRC progression and metastasis; SN-38 is an active metabolite of irinotecan with 1000 times more activity than irinotecan itself. The purpose of our study was to: (i) develop an effective nanocarrier for lung-selective delivery of pan-PI3K inhibitor PX-866 and SN-38 as a targeted therapy for CRC lung metastasis, and (ii) evaluate the effect of lung selective delivery of PX-866 and SN-38 loaded nanoparticles on CRC metastasis.
Methods: (1) HT29 LungM3 cell line was derived from the human colorectal cancer cell line HT29 following multiple rounds of in vivo selection for lung metastasis in immunodeficient mice. (2) Polymeric nanoparticles were constructed and loaded with fluorescent dye (Alexa 547), pan-PI3K inhibitor PX-866 or SN-38. (4) HT29 LungM3 cell line was injected intravenously to establish lung metastasis. Lung metastasis was treated with PX-866 and SN-38 loaded nanoparticles.
Results: (1) Lung selective accumulation of Alexa-546 fluorescently-labeled nanoparticles was confirmed by confocal imaging of frozen tissue sections from lung, liver and spleen. (2) Selective PI3K inhibition in lung tissue was confirmed by western blot of protein extracts after intravenous administration of PX-866-loaded nanoparticles. (3) Treatment with PX-866, an irreversible pan-PI3K inhibitor currently being evaluated in clinical trials, demonstrated a marked suppression of lung metastasis growth. Combination treatment with PX-866 and SN-38 loaded nanoparticles (four intravenous doses) completely eliminated lung metastases.
Conclusion: We demonstrate selective and efficient delivery of drug-loaded nanocarriers to lungs, suggesting that lung selective drug delivery is a viable treatment strategy for CRC lung metastasis.