The performance of expansile nanoparticles in a murine model of peritoneal carcinomatosis

Our plain-English summary of The performance of expansile nanoparticles in a murine model of peritoneal carcinomatosis, by Y.L. Colson, R. Liu, E.B. Southard, et al (Biomaterials, 2011).

The study

• Authors: Y.L. Colson, R. Liu, E.B. Southard, M.D. Schulz, J.E. Wade, A.P. Griset, K.A. Zubris, R.F. Padera, M.W. Grinstaff
• Journal: Biomaterials
• Published: 2011;32(3):832-40
• Cited by: 45 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Carcinomatosis from peritoneal surface malignancies, such as mesothelioma, appendiceal carcinoma or ovarian metastases, significantly decreases survival and quality of life. Given a 60-80% locoregional recurrence rate after surgical debulking for mesothelioma, the current study explores the use of polymeric nanoparticles, specifically engineered to expand and locally deliver chemotherapeutic agents at endosomal pH, for the prevention of progressive carcinomatosis. Anti-tumor efficacy of paclitaxel-loaded pH-responsive expansile nanoparticles (Pax-eNP) was evaluated in vitro and in in vivo murine models of malignant peritoneal mesothelioma. Pax-eNP inhibited mesothelioma growth in vitro, markedly decreased tumor growth and disease severity in vivo, prevented initial intraperitoneal tumor implants, and significantly prolonged survival compared to other intraperitoneal drug delivery methods. These outcomes suggest that the mechanism of pH-triggered drug delivery and tumor affinity associated with eNP may effectively improve the local control of residual microscopic disease following surgical debulking of locoregionally aggressive malignancies.

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In plain English

This laboratory and animal study did not examine asbestos exposure. The authors tested polymer particles (expansile nanoparticles) designed to swell and release the cancer drug paclitaxel in mildly acidic conditions inside cells. They used a human malignant pleural mesothelioma cell line, MSTO-211H, grown in dishes and injected into the abdomens of female athymic nude mice. The authors describe this as a murine model of human malignant peritoneal mesothelioma. In dishes, free paclitaxel killed cells at lower doses than either nanoparticle form. In mice given 20 micrograms of paclitaxel, the expansile nanoparticle group (12 mice) had an average disease severity score of 3 (range 0 to 7). The score was 15.5 (11 to 18) for paclitaxel in Cremophor and ethanol and 14 (8 to 18) for saline controls. Median survival was 54 days with expansile nanoparticles, compared with 39 days with non-expansile nanoparticles and 26 days with paclitaxel in Cremophor and ethanol, in groups of 6 mice. Labeled particles gathered at tumor nodules. Tumors eventually developed in all animals. The authors concluded that the expansile nanoparticles were superior to intraperitoneal paclitaxel in Cremophor at preventing tumor implants.

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 (in vitro) and animal experiment testing a drug-delivery method; no human subjects and no asbestos exposure studied
• Who was studied: Human malignant pleural mesothelioma cell lines MSTO-211H and luciferase-labeled MSTO-211H/luc, injected intraperitoneally into female athymic nude (Nu/J) mice aged 6 to 8 weeks. Tumor-growth groups: PBS n=9, unloaded eNP n=8, Pax-C/E n=6, Pax-neNP n=7, Pax-eNP n=12. Survival study: n=6 per group.
• Exposure: Treatment, not asbestos: paclitaxel delivered in pH-responsive expansile nanoparticles (Pax-eNP), compared with non-expansile nanoparticles (Pax-neNP), paclitaxel in Cremophor EL and ethanol (Pax-C/E), unloaded nanoparticles, or saline (PBS). The paclitaxel dose was 20 micrograms in mice.
• Main results:
  • In vitro, the IC50 (dose that halved cell viability) was 36.85 ng/mL for Pax-eNP and 12.41 ng/mL for Pax-neNP; this difference was not statistically significant. Both were significantly less efficient than free paclitaxel (IC50 6.56 ng/mL, p less than 0.05).
  • Disease severity score in mice: Pax-eNP averaged 3 (range 0 to 7), p less than 0.01 vs. either control. PBS controls scored 14 (8 to 18) and unloaded eNP controls 12 (10 to 18). Pax-C/E scored 15.5 (11 to 18), p less than 0.001 vs. Pax-eNP. Pax-neNP scored 5 (1 to 13) and was not superior to Pax-C/E or other controls.
  • Tumor mass in mice: Pax-eNP averaged 0.05 plus or minus 0.02 g when detectable. This was significantly less than PBS (2.32 plus or minus 0.41 g), Pax-C/E (2.14 plus or minus 0.04 g) and unloaded eNP (1.52 plus or minus 0.20 g), p less than 0.001 vs. each. Pax-neNP tumor mass (0.4 plus or minus 0.2 g) was nearly 10 times greater than with Pax-eNP but not statistically significant at that time point.
  • Median survival was 54 days with Pax-eNP, compared with 39 days with Pax-neNP and 26 days with Pax-C/E (p = 0.0021 and p = 0.0037 vs. Pax-eNP). There were 6 mice per group.
  • Rhodamine-labeled expansile nanoparticles injected into the abdomen were concentrated only at sites of tumor nodules in all animals (n=4).
  • No Pax-eNP-treated animal showed evidence of major systemic toxicities.
• The authors' conclusion: The authors concluded that, in a murine model of human malignant peritoneal mesothelioma, Pax-eNP were superior to intraperitoneal paclitaxel in Cremophor EL in preventing the establishment and growth of intraperitoneal tumor implants. They also concluded that Pax-eNP significantly increased survival compared with equivalent paclitaxel doses delivered in Cremophor EL.
• Limitations the authors state:
  • Peritoneal mesothelioma eventually developed in all animals after a single low dose.
  • Drug resistance, particularly to a single agent, may develop and make therapy less effective over time.
  • Whether Pax-eNP is tumor-specific, and how its affinity for tumor arises, remains to be studied.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Carcinoma, Quality of Life, Peritoneal Mesothelioma.

Related studies

• Paclitaxel-loaded expansile nanoparticles in a multimodal treatment model of malignant mesothelioma — M.D. Schulz, K.A. Zubris, et al. (2011)
• 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)
• Multicenter comprehensive methodological and technical analysis of 832 pressurized intraperitoneal aerosol chemotherapy (PIPAC) interventions performed in 349 patients for peritoneal carcinomatosis treatment: An international survey study — M. Nowacki, M. Alyami, et al. (2018)
• Repeat Cytoreductive Surgery and HIPEC for Peritoneal Surface Malignancy and Peritoneal Carcinomatosis — J.F. Wong, G.H. Tan, et al. (2015)
• Nanoparticle drug-delivery systems for peritoneal cancers: a case study of the design, characterization and development of the expansile nanoparticle — A.H. Colby, N.H. Oberlies, et al. (2017)

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