Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma.
The treatment outcomes for malignant peritoneal mesothelioma are poor and associated with high co-morbidities due to suboptimal drug delivery. Thus, there is an unmet need for new approaches that concentrate drug at the tumor for a prolonged period of time yielding enhanced antitumor efficacy and improved metrics of treatment success. A paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) system is described that addresses two unique challenges to improve the outcomes for peritoneal mesothelioma. First, following intraperitoneal administration, eNPs rapidly and specifically localize to tumors. The rate of eNP uptake by tumors is an order of magnitude faster than the rate of uptake in non-malignant cells; and, subsequent accumulation in autophagosomes and disruption of autophagosomal trafficking leads to prolonged intracellular retention of eNPs. The net effect of these combined mechanisms manifests as rapid localization to intraperitoneal tumors within 4 h of injection and persistent intratumoral retention for >14 days. Second, the high tumor-specificity of PTX-eNPs leads to delivery of greater than 100 times higher concentrations of drug in tumors compared to PTX alone and this is maintained for at least seven days following administration. As a result, overall survival of animals with established mesothelioma more than doubled when animals were treated with multiple doses of PTX-eNPs compared to equivalent dosing with PTX or non-responsive PTX-loaded nanoparticles.
['Liu|Rong|R|', 'Colby|Aaron H|AH|', 'Gilmore|Denis|D|', 'Schulz|Morgan|M|', 'Zeng|Jialiu|J|', 'Padera|Robert F|RF|', 'Shirihai|Orian|O|', 'Grinstaff|Mark W|MW|', 'Colson|Yolonda L|YL|']
D000818:Animals D000972:Antineoplastic Agents, Phytogenic D000071182:Autophagosomes D045744:Cell Line, Tumor D004337:Drug Carriers D016503:Drug Delivery Systems D005260:Female D006801:Humans D008654:Mesothelioma D008819:Mice, Nude D053758:Nanoparticles D017239:Paclitaxel D010534:Peritoneal Neoplasms D010537:Peritoneum
Nanoparticle Tumor localization Autophagosome Drug delivery Mesothelioma Paclitaxel