Krebswissenschaft und -therapie

Repurposing an Erstwhile Cancer Drug: A Quantitative and Therapeutic Evaluation of Alternative Nanosystems for the Delivery of Colchicine to Solid Tumors

Abstract

Shifalika Tangutoori, Akio Ohta, Samuel Gatley and Robert B. Campbell

Background: Antimitotic drugs represent some of the most popular vascular disrupting agents used today in the fight against cancer. Colchicine is the first known alkaloid. The drug binds to tubulin protein and depolymerizes microtubules. Despite the impressive therapeutic activity as an antimitotic agent, colchicine is fatally toxic when administered to cancer patients intravenously due to its low therapeutic index. This study supports the early development of a relatively safe and target-specific nanoparticle for the IV administration of colchicine to lung tumors.

Methods: For in vitro studies, lung cancer (LLC, Chago-k-1 and MCA-205), and endothelial cell lines (MS1- VEGF, HMEC-1) were employed. The qualitative and quantitative analyses of the cytoskeleton and nuclear areas were performed using FITC-labeled β-tubulin antibody; the mean area of cytoskeleton and nucleus per cell was determined by fluorescence microscopy and BIOQUANT. In vivo, the biodistribution and therapeutic efficacy studies of the pegylated cationic liposomes (PCLs) were performed in C57BL/6 mice bearing pseudo-orthotopic lung tumors. The biodistribution of colchicine and PCL-colchicine was determined by dual labeling. 111In labeled PCLs and 3H-Colchicine were employed to simultaneously track the vehicle and drug, respectively. The therapeutic efficacy was determined by monitoring animal survival.

Results: The disruption of microtubules was most evident when colchicine was loaded in DOTAP-PCLs. We report a ~2 fold (p=0.0214, 95% CI is 2.923 to 13.247) increase in the accumulation of PCL-colchicine in tumor-bearing lung compared to the normal lung, resulting in significantly extended survival times in PCL treated group (p=0.0052, Log Rank (Mantel-Cox test)).

Conclusions: The PCL-based colchicine-loaded nanosystem can renew the clinical potential of abandoned antimitotic agents such as colchicine. The PCL platform can enable the accumulation of clinically relevant doses of colchicine in solid tumors. This will ensure antimitotic activity while decreasing the uptake of the drug in healthy tissues.