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 May 1, 2017; First 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 1

Synthesis and characterization of silicasomes for drug loading and visualization.

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Synthesis and characterization of silicasomes for drug loading and visua...
(A) The top panel provides a schematic that shows the synthesis steps for constructing silicasomes and remote drug loading (26, 27). Briefly, MSNP cores were synthesized by sol-gel chemistry and soaked in a solution containing the protonating agent, TEA8SOS. These particles were coated with an LB, using a sonication procedure in the presence of a lipid biofilm (27). This was followed by remote irinotecan loading across the proton gradient provided by TEA8SOS. Box 1: schematic of the different silicasome components. Box 2: iRGD peptide conjugation to the LB, using a thiol-maleimide reaction to link the cysteine-modified iRGD peptide to DSPE-PEG2000–maleimide. Box 3: cryoEM images to show the bare particles and the silicasomes, with and without the embedding of approximately 10 nm Au cores (for TEM visualization). Synthesis procedures are described in Supplemental Materials and Methods. Scale bars: 50 nm. (B) Autopsy and IVIS images of the KPC-derived orthotopic PDAC model in immunocompetent B6/129 mice. The orthotopic implantation involves minor surgery to inject 2 × 106 KPC-luc cells in the tail of the pancreas (left panel). The autopsy and bioluminescence imaging reveal primary tumor growth after 1 to 2 weeks, followed by tumor metastases by 3 to 5 weeks. Macrometastases are marked by arrows.