• Hongyi Lei, Sophie C Hofferberth, Rong Liu, Aaron Colby, Kristie M Tevis, Paul Catalano, Mark W Grinstaff, and Yolonda L Colson.
• Division of Thoracic Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, Mass; Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
• J. Thorac. Cardiovasc. Surg. 2015 May 1; 149 (5): 1417-24; discussion 1424-25.e1.

ObjectivesIntraperitoneal administration of paclitaxel-loaded expansile nanoparticles (Pax-eNPs) significantly improves survival in an in vivo model of malignant mesothelioma compared with conventional drug delivery with the clinically utilized Cremophor EL/ethanol (C/E) excipient. However, in vitro monolayer cell culture experiments do not replicate this superior efficacy, suggesting Pax-eNPs utilize a unique mechanism of drug delivery. Using a mesothelioma spheroid model, we characterized the mechanisms of enhanced tumor cytotoxicity leveraged by Pax-eNPs.MethodsHuman malignant mesothelioma (MSTO-211H) spheroids were co-incubated for 24 hours with Oregon Green-conjugated paclitaxel dissolved in C/E or loaded into eNPs. Oregon Green-paclitaxel uptake was measured as Oregon Green intensity via confocal microscopy and kinetics of tumor cytotoxicity were assessed via propidium iodide staining. Pharmacologic endocytotic inhibitors were used to elucidate mechanisms of eNP uptake into spheroids.ResultsIncreased drug penetration and a 38-fold higher intraspheroidal drug concentration were observed 24 hours after MSTO-211H spheroids were treated with Oregon Green-conjugated paclitaxel loaded into eNPs compared with Oregon Green-conjugated paclitaxel dissolved in C/E (P < .01). Macropinocytosis was the dominant endocytotic pathway of eNP uptake. Spheroids were more susceptible to paclitaxel when delivered via eNP, exhibiting more than twice the propidium iodine intensity compared with an equivalent paclitaxel-C/E dose.ConclusionsCompared with monolayer cell culture, the in vitro 3-D tumor spheroid model better reflects the superior in vivo efficacy of Pax-eNPs. Persistent tumor penetration and prolonged intratumoral release are unique mechanisms of Pax-eNP cytotoxicity. 3-D spheroid models are valuable tools for investigating cytotoxic mechanisms and nanoparticle-tumor interactions, particularly given the costs and limitations of in vivo animal studies.Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

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