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Cytoreductive Surgery and Intraoperative Administration of Paclitaxel-loaded Expansile Nanoparticles Delay Tumor Recurrence in Ovarian Carcinoma

  • Gynecologic Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

ABSTRACT

Background

Locoregional recurrence significantly impacts survival and quality of life in patients with ovarian carcinoma. We hypothesize that local administration of paclitaxel-loaded expansile nanoparticles (pax-eNP) at the time of cytoreductive surgery decreases local tumor recurrence.

Methods

In vitro cytotoxicity of pax-eNP was assessed against both the OVCAR-3 human ovarian cancer cell line and tumor cells isolated from a malignant pleural effusion from a patient with multidrug-resistant ovarian cancer. A murine xenogenic model involving surgical cytoreduction of established OVCAR-3 intra-abdominal tumor was used to evaluate in vivo efficacy of intraoperative intraperitoneal (IP) injection of 10 mg/kg of paclitaxel either as pax-eNP or paclitaxel in Cremophor EL/ethanol solution (pax-C/E) versus empty eNP controls. Cytoreductive surgery and intraoperative treatment were performed 4 weeks after established tumor. All animals were sacrificed when empty eNP controls displayed extensive evidence of disease progression.

Results

Labeled-eNP entered tumor cells in vitro within 4 h and specifically accumulated at sites of tumor in vivo. Pax-eNP exhibited dose-dependent cytotoxicity in both OVCAR-3 and patient tumor cells isolated from a malignant pleural effusion and effectively prevented tumor recurrence following debulking (p = 0.003 vs. empty eNP). Furthermore, pax-eNP-treated animals did not develop severe recurrent carcinomatosis compared with 43 % of the pax-C/E-treated cohort, suggesting that single-dose intracavitary pax-eNP is more effective than an equivalent dose of pax-C/E.

Conclusions

Expansile nanoparticles readily enter human ovarian tumor cells and localize to sites of tumor in vivo with pax-eNP cytotoxicity resulting in superior inhibition of locoregional tumor recurrence following cytoreductive surgery.

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ACKNOWLEDGMENT

The authors express their appreciation to Brigham and Women’s Hospital, the Dana-Farber Cancer Institute Animal Facility, and Beth Israel Deaconess Medical Center Confocal Imaging Core who kindly provided their expertise and guidance. This work was supported by the Center for Integration of Medicine and Innovative Technology, the Cross-Disciplinary Training in Nanotechnology for Cancer, NIH R25 CA153955, and the NSF DMR-1006601.

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Authors and Affiliations

  1. Division of Thoracic Surgery, Department of Surgery, Brigham and Women’s Hospital, Boston, MA, USA

    Denis Gilmore MD, Morgan Schulz MD, Rong Liu MD, PhD & Yolonda L. Colson MD, PhD

  2. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    Robert F. Padera MD

  3. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Paul J. Catalano ScD

  4. Departments of Biomedical Engineering and Chemistry, Boston University, Boston, MA, USA

    Kimberly Ann V. Zubris PhD & Mark W. Grinstaff PhD

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  1. Denis Gilmore MD
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Correspondence to Denis Gilmore MD.

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Gilmore, D., Schulz, M., Liu, R. et al. Cytoreductive Surgery and Intraoperative Administration of Paclitaxel-loaded Expansile Nanoparticles Delay Tumor Recurrence in Ovarian Carcinoma. Ann Surg Oncol 20, 1684–1693 (2013). https://doi.org/10.1245/s10434-012-2696-5

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