Tumor-penetrating peptide enhances transcytosis of silicasome-based chemotherapy for pancreatic cancer
Xiangsheng Liu, … , Andre E. Nel, Huan Meng
Xiangsheng Liu, … , Andre E. Nel, Huan Meng
Published April 17, 2017
Citation Information: J Clin Invest. 2017;127(5):2007-2018. https://doi.org/10.1172/JCI92284.
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Research Article Oncology

Tumor-penetrating peptide enhances transcytosis of silicasome-based chemotherapy for pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal; however, some improvement in overall survival has been achieved with the introduction of nanocarriers that deliver irinotecan or paclitaxel. Although it is generally assumed that nanocarriers rely principally on abnormal leaky vasculature for tumor access, a transcytosis transport pathway that is regulated by neuropilin-1 (NRP-1) has recently been reported. NRP-1–mediated transport can be triggered by the cyclic tumor-penetrating peptide iRGD. In a KRAS-induced orthotopic PDAC model, coadministration of iRGD enhanced the uptake of an irinotecan-loaded silicasome carrier that comprises lipid bilayer–coated mesoporous silica nanoparticles (MSNPs); this uptake resulted in enhanced survival and markedly reduced metastasis. Further, ultrastructural imaging of the treated tumors revealed that iRGD coadministration induced a vesicular transport pathway that carried Au-labeled silicacomes from the blood vessel lumen to a perinuclear site within cancer cells. iRGD-mediated enhancement of silicasome uptake was also observed in patient-derived xenografts, commensurate with the level of NRP-1 expression on tumor blood vessels. These results demonstrate that iRGD enhances the efficacy of irinotecan-loaded silicasome–based therapy and may be a suitable adjuvant in nanoparticle-based treatments for PDAC.

Authors

Xiangsheng Liu, Paulina Lin, Ian Perrett, Joshua Lin, Yu-Pei Liao, Chong Hyun Chang, Jinhong Jiang, Nanping Wu, Timothy Donahue, Zev Wainberg, Andre E. Nel, Huan Meng

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Figure 5

Ultrastructural viewing of the silicasome transport system initiated by iRGD coadministration.

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Ultrastructural viewing of the silicasome transport system initiated by ...
(A) Mice bearing orthotopic tumors were injected with 50 mg/kg Au-silicasomes, with or without coadministration of 8 μmol/kg iRGD. Tumors were harvested at 24 hours and immediately fixed for TEM analysis. At least 10 ROI in each group were viewed to quantitatively express the abundance of grouped, interconnected vesicles (yellow arrows) in the blood vessel endothelial cells. We calculated the number of vesicles per 1 μm2 of the intracellular surface area (left panel). Data represent mean ± SD. *P < 0.05, 2-tailed Student’s t test. Representative TEM pictures with high and low magnification are shown. L, lumen; R, red blood cell. Scale bars: 2 μm (left panels); 0.5 μm (right panels showing high-magnification images). (B) TEM visualization of silicasome transcytosis in tumor-bearing mice that received 50 mg/kg Au-silicasome and were sacrificed 24 hours later. The electron micrograph shows silicasomes in (i) the lumen of a tumor blood vessel (red arrows), (ii) transport in the endothelial vesicles (pink arrow), and (iii) deposition in the tumor interstitium (blue arrows). High-magnification images of regions 1 through 3 are provided in the panels on the right. E, endothelial cell; P, pericyte. Scale bar: 2 μm (left panel); 50 nm (right panels). (C) TEM image showing the presence of silicasomes in a perinuclear distribution inside a cancer cell. N, nucleus; M, mitochondrion. Scale bars: 2 μm (left panel); 100 nm (right panels).