Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma

Our plain-English summary of Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma, by R. Liu, A.H. Colby, D. Gilmore, et al (Biomaterials, 2016).

The study

• Authors: R. Liu, A.H. Colby, D. Gilmore, M. Schulz, J. Zeng, R.F. Padera, O. Shirihai, M.W. Grinstaff, Y.L. Colson
• Journal: Biomaterials
• Published: 2016;102:175-86
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

Copyright © 2016 Elsevier Ltd. All rights reserved.

In plain English

This was a laboratory and mouse study of a drug-delivery method for peritoneal mesothelioma. It did not study asbestos exposure. The authors loaded the chemotherapy drug paclitaxel into tiny pH-responsive 'expansile' nanoparticles. They compared these with paclitaxel alone and with paclitaxel in another nanoparticle type (PLGA). In dishes, over 98% of human mesothelioma cells (line MSTO-211H) took up the particles within 2 hours. Among non-malignant mesothelial cells (LP-3), 2% had taken them up at 2 hours and 28% at 8 hours. In female nude mice with human mesothelioma cells growing in the abdomen, the particles gathered at tumors within 1 to 4 hours and stayed for 14 days. With eight weekly doses, median survival was 103 days with the expansile particles versus 49 days with paclitaxel alone. The authors concluded the system was superior to paclitaxel or the PLGA particles in treating established intraperitoneal mesothelioma in this model. They noted that their tumor-localization images were qualitative and should be interpreted with caution.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (cell culture) experiments and animal experiments in a mouse model of established intraperitoneal mesothelioma
• Who was studied: Human malignant pleural mesothelioma cells (MSTO-211H) and healthy mesothelial cells (LP-3) in culture. The animals were 6 to 8 week old female athymic nude (NU/J) mice injected in the abdomen with 5 million MSTO-211H cells. The number of mice per survival group is not stated in the text.
• Exposure: Paclitaxel delivered into the abdomen in expansile nanoparticles (PTX-eNPs), in PLGA nanoparticles, or alone (in Cremophor EL/ethanol, like the clinical formulation Taxol). Doses were 10 mg/kg per week for four or eight weeks, or 20 mg/kg per week for four weeks, compared with unloaded particles and saline. No asbestos exposure was studied.
• Main results:
  • With a 4-hour exposure, paclitaxel in expansile nanoparticles was more potent against MSTO-211H cells than paclitaxel alone (IC50 44.6 ng/mL vs 1009 ng/mL; 23-fold lower).
  • Over 98% of malignant MSTO-211H cells took up the nanoparticles within 2 hours. In non-malignant LP-3 cells uptake was 2% at 2 hours and 28% at 8 hours.
  • In mice, fluorescent expansile nanoparticles co-localized with tumors as early as 1 to 4 hours after injection, and co-localization persisted for 14 days. Images were representative of three animals per time point.
  • In cells, expansile nanoparticles increased LC3-II, a marker of autophagosomes. Adding bafilomycin did not increase this further. The authors interpreted this as the particles blocking autophagic degradation.
  • Three days after a single 10 mg/kg injection, the share of the injected paclitaxel dose remaining in tumor was 20 ± 6% with expansile nanoparticles, 6 ± 7% with PLGA nanoparticles, and 0.1 ± 0.1% with paclitaxel alone.
  • Over 1 hour to 7 days, tumor paclitaxel concentrations were 4- to over 100-fold higher with expansile nanoparticles than with paclitaxel alone (P < 0.001).
  • With four weekly 10 mg/kg doses, median survival was 74 days with expansile nanoparticles, 43 days with PLGA nanoparticles and 46 days with paclitaxel alone (P < 0.005). The saline group's median was 38 days.
  • With four weekly 20 mg/kg doses, median survival was 64 days with expansile nanoparticles and 36 days with paclitaxel alone.
  • With eight weekly 10 mg/kg doses, median survival was 103 days with expansile nanoparticles versus 49 days with paclitaxel alone (P < 0.01).
  • A preliminary histology check found no tissue damage in the liver, spleen or kidneys of mice given eight weekly doses of paclitaxel in expansile nanoparticles.
• The authors' conclusion: The authors concluded that the paclitaxel expansile nanoparticle system was superior to paclitaxel or paclitaxel PLGA nanoparticles in treating established intraperitoneal mesothelioma in their mouse model. They described it as a potentially viable adjunct to multimodality therapy for malignant peritoneal mesothelioma.
• Limitations the authors state:
  • The comparison of tumor localization between particle types was qualitative and must be interpreted with caution.
  • p62 levels may not be a reliable indicator of autophagic flux, because p62 can be regulated at the transcription level during autophagy.
  • The toxicity assessment was described as preliminary.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Overall Survival, Mesothelioma.

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• Paclitaxel-loaded expansile nanoparticles in a multimodal treatment model of malignant mesothelioma — M.D. Schulz, K.A. Zubris, et al. (2011)
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