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Slippery Nanoparticles as a Diffusion Platform for Mucin Producing Gastrointestinal Tumors

  • Marian Khalili
  • Hao Zhou
  • Anusha Thadi
  • Lynsey Daniels
  • Zhiyuan Fan
  • William F. Morano
  • Joanne Ang
  • Eve Goldstein
  • Boris Polyak
  • Beth C. Mapow
  • Hao Cheng
  • Wilbur B. BowneEmail author
Peritoneal Surface Malignancy

Abstract

Background

Treatment failure in pseudomyxoma peritonei (PMP) is partly attributed to the ineffective delivery of therapeutics through dense mucinous tumor barriers. We modified the surface of Poly (lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG-NPs) with a low-density, second PEG layer (PLGA-TPEG-NPs-20) to reduce their binding affinity to proteins and improve diffusion through mucin.

Methods

Nanoprecipitation was used to fabricate PLGA-PEG-NPs. To construct the second PEG layer of PLGA-TPEG-NPs-20, PEG-Thiol was conjugated to PLGA-PEG-NPs composed of 80% methoxy PLGA-PEG and 20% of PLGA-PEG-Maleimide. DiD-labeled nanoparticles (NPs) were added to the inner well of a trans-well system containing cultured LS174T or human PMP tissue. Diffusion of NPs was measured via fluorescence signal in the bottom well. In an ex vivo rat model, small intestine was treated with DiD-labeled NPs. In an in vivo murine LS174T subcutaneous tumor model, Nu/Nu nude mice received supratumoral injections (subcutaneous injection above the tumor) of DiD-labeled NPs. Thirty minutes after injection, mice were sacrificed, and tumors were collected. All tissue was cryosectioned, mounted with DAPI-containing media, and inspected via confocal microscopy.

Results

Diffusion profiles of NPs through PMP and cultured LS174T cells were generated. PLGA-TPEG-NPs-20 diffused faster with ~ 100% penetration versus PLGA-PEG-NPs with ~ 40% penetration after 8 h. Increased diffusion of PLGA-TPEG-NPs-20 was further observed in ex vivo rat small intestine as evidenced by elevated luminal NP fluorescence signal on the luminal surface. Subcutaneous LS174T tumors treated with PLGA-TPEG-NPs-20 demonstrated greater diffusion of NPs, showing homogenous fluorescence signal throughout the tumor.

Conclusions

PLGA-TPEG-NPs-20 can be an effective mucin penetrating drug delivery system.

Notes

Acknowledgment

This work has received funding from the National Organization of Rare Disorders (NORD) (Grant number 260696) through Appendix Cancer Pseudomyxoma Peritonei (ACPMP) Research Foundation.

Disclosure

The authors have no commercial interests to disclose.

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Copyright information

© Society of Surgical Oncology 2019

Authors and Affiliations

  • Marian Khalili
    • 1
  • Hao Zhou
    • 2
  • Anusha Thadi
    • 1
  • Lynsey Daniels
    • 1
  • Zhiyuan Fan
    • 2
  • William F. Morano
    • 1
  • Joanne Ang
    • 4
  • Eve Goldstein
    • 1
  • Boris Polyak
    • 1
  • Beth C. Mapow
    • 4
  • Hao Cheng
    • 2
    • 3
  • Wilbur B. Bowne
    • 1
    Email author
  1. 1.Department of SurgeryDrexel University College of MedicinePhiladelphiaUSA
  2. 2.Department of Materials Science and EngineeringDrexel UniversityPhiladelphiaUSA
  3. 3.School of Biomedical Engineering, Science and Health SystemsDrexel UniversityPhiladelphiaUSA
  4. 4.Department of PathologyDrexel UniversityPhiladelphiaUSA

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