Paclitaxel-loaded expansile nanoparticles in a multimodal treatment model of malignant mesothelioma

Our plain-English summary of Paclitaxel-loaded expansile nanoparticles in a multimodal treatment model of malignant mesothelioma, by M.D. Schulz, K.A. Zubris, J.E. Wade, et al (The Annals of Thoracic Surgery, 2011).

The study

• Authors: M.D. Schulz, K.A. Zubris, J.E. Wade, R.F. Padera, X. Xu, M.W. Grinstaff, Y.L. Colson
• Journal: The Annals of Thoracic Surgery
• Published: 2011;92(6):2007-13; discussion 2013-4
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant mesothelioma has a poor prognosis even when treated aggressively with multimodal therapy. Traditional murine tumor models can be used to evaluate drug efficacy and toxicity in malignant mesothelioma, but not to assess the effect of a multimodal approach that includes the surgical resection of tumor. We therefore developed a murine model of multimodal therapy in which we evaluated paclitaxel-loaded expansile nanoparticles (Pax-eNP) for delivering intracavitary chemotherapy in malignant mesothelioma.

Methods: Paclitaxel-loaded expansile nanoparticles (Pax-eNP) of 100 nm, designed to release drug at an endosomal pH below 5, were synthesized. Xenografts of human malignant mesothelioma were established intraperitoneally in nude mice, followed by cytoreductive surgery (CRS) via laparotomy, and with omentectomy and resection of abdominal fat pads done 14 days later. At fascial closure, 10 mg/kg paclitaxel was delivered as traditional paclitaxel/paclitaxel Cremophor-EL (Pax-CE) or Pax-eNP. Morbidity and survival were assessed over a period of 90 days.

Results: Cytoreductive surgery in mice was feasible and reproducible, and incurred less than 5% operative mortality. By itself, CRS did not significantly prolong survival; however, the addition of intraoperative Pax-CE or Pax-eNP significantly increased survival as compared with that of mice with untreated disease. In the case of Pax-eNP, the increase in survival was also statistically significant as compared with that following resection alone.

Conclusions: A murine model of CRS for malignant mesothelioma allows the in vivo assessment of multimodal therapy, including nanoparticle delivery. Combination therapy was superior to no treatment or CRS alone in prolonging survival. Treatment with Pax-eNP improved overall survival in the setting of CRS, suggesting that Pax-eNP merits further evaluation for intracavitary drug delivery following the surgical resection of malignant mesothelioma.

Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

In plain English

This was an animal experiment testing a treatment for malignant mesothelioma. It did not study asbestos exposure. The authors injected a human mesothelioma cell line into the abdomens of female athymic nude mice. Fourteen days later, most mice had surgery to remove visible tumor. At the end of surgery they received saline, empty nanoparticles, 10 mg/kg of the chemotherapy drug paclitaxel in a standard formulation (Pax-CE), or the same dose carried in pH-sensitive nanoparticles (Pax-eNP). One mouse died during surgery. Untreated mice survived a median of 35 days. Mice given surgery with saline survived a median of 42 days, which was not a statistically significant improvement. Surgery plus Pax-CE gave a median of 52 days. That was significantly longer than no treatment but not significantly longer than surgery alone. Surgery plus Pax-eNP gave a median of 54 days, significantly longer than both no treatment and surgery alone, though not significantly different from Pax-CE. The authors concluded that this mouse surgery model allows testing of combined treatments and that Pax-eNP merits further evaluation after surgical removal of mesothelioma.

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: Animal experiment: a mouse model of cytoreductive (tumor-removing) surgery for human mesothelioma tumors grown in the abdomen, comparing five treatment groups
• Who was studied: Female athymic nude mice aged 4 to 6 weeks, given abdominal (intraperitoneal) xenografts of the human malignant mesothelioma cell line MSTO-211H/luc. Group sizes in the survival comparisons were 11 untreated, 8 surgery with saline, 8 surgery with unloaded nanoparticles, and 9 each for the two paclitaxel groups.
• Exposure: No asbestos exposure was studied. The treatments compared were: no surgery; surgery with saline; surgery with 200 mg/kg drug-free nanoparticles; surgery with 10 mg/kg paclitaxel in Cremophor EL/ethanol (Pax-CE); and surgery with 10 mg/kg paclitaxel in expansile nanoparticles (Pax-eNP). Each drug or control was given into the abdomen at the end of surgery.
• Main results:
  • Surgery achieved macroscopically complete removal of tumor in more than 90% of mice, and one mouse died during surgery.
  • Mice that did not have surgery survived a median of 35 days (range 32 to 48 days).
  • Mice given surgery with saline survived a median of 42 days (range 34 to 65 days). This was not statistically significant compared with untreated mice (p value printed as 0.137).
  • Median survival did not differ between mice given surgery with saline and those given surgery with drug-free nanoparticles (42 vs 44 days).
  • Mice given surgery plus Pax-CE survived a median of 52 days (range 29 to 66 days). This was significantly longer than untreated mice but not significantly longer than surgery alone.
  • Mice given surgery plus Pax-eNP survived a median of 54 days (range 49 to 104 days). This was significantly longer than both untreated mice and surgery controls with drug-free nanoparticles.
  • Survival did not differ significantly between the Pax-CE and Pax-eNP groups.
  • Staining of the chest found pleural or pericardial tumor implants, or both, in 6 of 7 (86%) Pax-CE-treated mice examined, compared with 1 of 5 (20%) Pax-eNP-treated mice examined.
• The authors' conclusion: The authors concluded that the mouse model allows testing of multimodal therapy including nanoparticle delivery. They found that combination therapy prolonged survival more than no treatment or surgery alone, and they stated that Pax-eNP merits further evaluation for intracavitary drug delivery after surgical resection of malignant mesothelioma.
• Limitations the authors state:
  • The authors stated that no conclusions could be drawn about differences in drug delivery from the greater spread of tumor into the chest seen in Pax-CE-treated mice.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Prognosis, Multimodal Therapy, Surgical Resection, Chemotherapy, Cytoreductive Surgery, Laparotomy, Overall Survival.

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