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Ann Surg Oncol. 2019 Jun 11. doi: 10.1245/s10434-019-07493-7. [Epub ahead of print]

Slippery Nanoparticles as a Diffusion Platform for Mucin Producing Gastrointestinal Tumors.

Author information

1
Department of Surgery, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
2
Department of Materials Science and Engineering, Drexel University, Philadelphia, PA, USA.
3
Department of Pathology, Drexel University, Philadelphia, PA, USA.
4
School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA.
5
Department of Surgery, Drexel University College of Medicine, Philadelphia, PA, 19102, USA. wbb28@drexel.edu.

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.

PMID:
31187366
DOI:
10.1245/s10434-019-07493-7

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