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.
View: Text | PDF
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

×

Figure 3

iRGD coadministration enhances the uptake and efficacy of irinotecan-loaded silicasome in the KPC-derived orthotopic model.

Options: View larger image (or click on image) Download as PowerPoint
iRGD coadministration enhances the uptake and efficacy of irinotecan-loa...
(A) Schedule of the efficacy study in the luciferase-expressing KPC-derived orthotopic tumors (n = 6). The chosen irinotecan-loaded silicasome dose (40 mg/kg irinotecan; 80 mg/kg MSNP) is based on a previous efficacy study (27). This dose of the irinotecan-loaded silicasome was i.v. injected, with or without coadministration of 8 μmol/kg iRGD. The injections were repeated every 3 days, for a total of 4 administrations. The controls involved animal groups receiving identical doses of free iRGD or the irinotecan-loaded silicasome alone. (B) Representative ex vivo imaging of the bioluminescence intensity in the mice prior to sacrifice to show the primary tumor burden and metastases. The images show that iRGD coadministration could enhance the silicasome efficacy. Ir-silicasome, irinotecan-loaded silicasome. (C) Heat map summarizing the impact on tumor and tumor metastasis inhibition of the experiment shown in B. (D) iRGD coadministration improved the survival impact of the irinotecan-loaded silicasome, as shown by Kaplan-Meier analysis. The effect of silicasome alone is highly significant compared with that of PBS and free iRGD (P = 0.001, log-rank test). iRGD coadministration further enhances survival (P = 0.027, log-rank test). (E) HPLC analysis of the irinotecan content in the tumor 24 hours after a one-time dose of irinotecan-loaded silicasome (40 mg/kg drug) was injected, with or without coadministration of 8 μmol/kg iRGD. Data represent mean ± SD (n = 3). *P < 0.05, 2-tailed Student’s t test.