Nanoparticle drug-delivery systems for peritoneal cancers: a case study of the design, characterization and development of the expansile nanoparticle

Our plain-English summary of Nanoparticle drug-delivery systems for peritoneal cancers: a case study of the design, characterization and development of the expansile nanoparticle, by A.H. Colby, N.H. Oberlies, C.J. Pearce, et al (Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology, 2017).

The study

• Authors: A.H. Colby, N.H. Oberlies, C.J. Pearce, V.L. Herrera, Y.L. Colson, M.W. Grinstaff
• Journal: Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology
• Published: 2017;9(3)
• Type of article: Review
• Cited by: 44 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Nanoparticle (NP)-based drug-delivery systems are frequently employed to improve the intravenous administration of chemotherapy; however, few reports explore their application as an intraperitoneal therapy. We developed a pH-responsive expansile nanoparticle (eNP) specifically designed to leverage the intraperitoneal route of administration to treat intraperitoneal malignancies, such as mesothelioma, ovarian, and pancreatic carcinomatoses. This review describes the design, evaluation, and evolution of the eNP technology and, specifically, a Materials-Based Targeting paradigm that is unique among the many active- and passive-targeting strategies currently employed by NP-delivery systems. pH-responsive eNP swelling is responsible for the extended residence at the target tumor site as well as the subsequent improvement in tumoral drug delivery and efficacy observed with paclitaxel-loaded eNPs (PTX-eNPs) compared to the standard clinical formulation of paclitaxel, Taxol®. Superior PTX-eNP efficacy is demonstrated in two different orthotopic models of peritoneal cancer-mesothelioma and ovarian cancer; in a third model-of pancreatic cancer-PTX-eNPs demonstrated comparable efficacy to Taxol with reduced toxicity. Furthermore, the unique structural and responsive characteristics of eNPs enable them to be used in three additional treatment paradigms, including: treatment of lymphatic metastases in breast cancer; use as a highly fluorescent probe to visually guide the resection of peritoneal implants; and, in a two-step delivery paradigm for concentrating separately administered NP and drug at a target site. This case study serves as an important example of using the targeted disease-state's pathophysiology to inform the NP design as well as the method of use of the delivery system. WIREs Nanomed Nanobiotechnol 2017, 9:e1451. doi:10.1002/wnan.1451 For further resources related to this article, please visit the WIREs website.

© 2017 Wiley Periodicals, Inc.

In plain English

This review covered the authors' own earlier laboratory and animal studies of an 'expansile nanoparticle' (eNP). The eNP, a polymer particle that swells in mild acid, was designed to carry the cancer drug paclitaxel inside the abdomen. The article did not study asbestos. In mice with abdominal mesothelioma, paclitaxel-loaded eNPs delivered 10-fold more paclitaxel to tumors than Taxol, the standard formulation, over 24 hours, and over 100-fold more at 7 days. With four weekly injections, median survival was 72 days with eNPs, 46 with Taxol and 38 with saline. Over a planned eight weeks of weekly injections, median survival was 103 days with eNPs and 49 with Taxol; all but one Taxol-treated animal died or was euthanized before finishing. In an ovarian cancer model treated after surgical tumor removal, significant recurrence at four weeks was 0% with paclitaxel-loaded eNPs and 40% with Taxol. In a rat pancreatic cancer model, survival did not differ significantly from Taxol, though toxicity was lower. The authors concluded that the particles' materials, not antibodies, produced tumor-specific localization. They cautioned that test-tube results may not predict animal results.

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: Review of the authors' own prior laboratory (in vitro) and animal experiments on a drug-delivery nanoparticle
• Who was studied: Cancer cell lines and animal models: mice with intraperitoneal mesothelioma tumors, mouse models of ovarian and breast cancer, a rat model of pancreatic carcinomatosis, and a pig. The number of animals is not given in this review.
• Exposure: Treatment, not asbestos exposure: paclitaxel-loaded expansile nanoparticles (PTX-eNPs), mostly at 10 mg/kg, compared with Taxol (the clinical formulation of paclitaxel) and with control particles or saline. Asbestos is mentioned only in passing in the introduction.
• Main results:
  • Mice with intraperitoneal mesothelioma, single injection: PTX-eNPs delivered 10-fold more paclitaxel to tumors than Taxol over the first 24 h, and over 100-fold more at 7 days.
  • Mesothelioma mice, four weekly treatments: median survival was 72 days with PTX-eNPs versus 46 days with Taxol.
  • Mesothelioma mice: median survival was 46 days with Taxol versus 38 days with saline.
  • Mesothelioma mice given PTX-eNPs: about 30% of animals had a complete clinical response.
  • Mesothelioma mice, planned eight weekly treatments: median survival was 103 days with PTX-eNPs, compared with 72 days for the 4-week PTX-eNP group and 49 days for the 8-week Taxol group.
  • In the planned eight-week regimen, all but one Taxol-treated animal died or was euthanized before completing treatment.
  • Ovarian cancer model, treated after surgical debulking and assessed 4 weeks later: significant tumor recurrence was 0% with PTX-eNPs versus 40% with Taxol.
  • Rat pancreatic carcinomatosis model: survival did not differ significantly between the PTX-eNP and Taxol groups.
  • Rat pancreatic carcinomatosis model: PTX-eNP treatment caused significantly less toxicity and fewer side effects than Taxol.
  • Breast cancer mouse model: lymph node metastases occurred in 33% of PTX-eNP-treated animals versus 100% of animals given unloaded eNPs.
  • Fluorescent eNPs used to identify tumors in the pancreatic model, compared with histology: specificity 99%, sensitivity 92%, overall accuracy 95%.
• The authors' conclusion: The authors concluded that their 'Materials-Based Targeting' gave tumor-specific localization without the need for targeting molecules or antibodies.
• Limitations the authors state:
  • The predictive power of in vitro (test-tube) uptake assays must be treated with caution.
  • Drug resistance of the pancreatic tumors was presumed but not experimentally verified.
  • The two-step delivery method needs further development.

Topics

Medical terms in this study, explained in our Lexicon: Chemotherapy, Mesothelioma, Ovarian Cancer.

Related studies

• Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma — R. Liu, A.H. Colby, et al. (2016)
• Paclitaxel-loaded expansile nanoparticles enhance chemotherapeutic drug delivery in mesothelioma 3-dimensional multicellular spheroids — H. Lei, S.C. Hofferberth, et al. (2015)
• Paclitaxel-loaded expansile nanoparticles in a multimodal treatment model of malignant mesothelioma — M.D. Schulz, K.A. Zubris, et al. (2011)
• The performance of expansile nanoparticles in a murine model of peritoneal carcinomatosis — Y.L. Colson, R. Liu, et al. (2011)
• Targeted drug delivery and penetration into solid tumors — A. Corti, F. Pastorino, et al. (2012)
• Delivery of expression constructs of secreted frizzled-related protein 4 and its domains by chitosan-dextran sulfate nanoparticles enhances their expression and anti-cancer effects — V. Perumal, F. Arfuso, et al. (2018)

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