An Innovation for Treating Orthotopic Pancreatic Cancer by Preoperative Screening and Imaging-Guided Surgery
Pancreatic cancer is still associated with a poor outcome and low patient quality of life, which are mainly attributed to the late detection and requirement of distal pancreatectomy with extended resection of pancreatic tumors. Therefore, novel strategies for early screening and precise tumor resection are urgently needed. In this study, we evaluated the feasibility of a low-density lipoprotein receptor (LDLR)-targeted small-molecule contrast agent (peptide-22-Cy7) for early screening with photoacoustic tomography and near-infrared (NIR) imaging as guided surgical navigation to achieve precise resection.
Normal pancreatic cells (HPDE6-C7) and cancer cells (PANC-1) were respectively used in the in vitro targeting evaluations. The ability of peptide-22-Cy7 for preoperative in vivo pancreatic tumor detection was investigated in a mouse orthotopic pancreatic cancer model (n = 10) using photoacoustic tomography; 18 tumor-bearing mice were further divided into three groups for different treatments. After intravenous injection of peptide-22-Cy7, surgical navigation was conducted through laparotomy. Histopathological analysis was used to further confirm the tumor area and the state of surgical margins.
Flow cytometry demonstrated that peptide-22 is highly specific to pancreatic cancer cells, with a fluorescence intensity of approximately 87.3 %. Orthotopic pancreatic tumors with a size of 4 mm could be accurately detected by photoacoustic tomography. Surgical navigation effectively achieved R0 resection and minimized the range of resection, which led to increased body weight of the mice following surgery.
Overall, our newly developed targeted contrast agent facilitated the accurate positioning and resection of pancreatic tumors. Photoacoustic tomography and optical imaging-guided surgical navigation may be a novel direction for improving the survival, quality of life, and disease management of pancreatic cancer patients.
Key wordsLow-density lipoprotein receptor (LDLR) Photoacoustic imaging Optical-guided surgery Peptide-22
The authors thank Tianpei Guan, Guanhua Lu, and Ting Ai for assistance with data collection.
This work was supported by the National Natural Science Foundation of China under Grant Nos. 81227901, 81627805, 61231004, 61671449, 81501540, and 81527805; National Key R&D Program of China Grant under No. 2017YFA0205200; The Science and Technology Plan Project of Guangzhou (No. 201604020144); Digital Theranostic Equipment Research Special Program of The “13th five-year” National Key Research Plan (No. 2016YFC0106500); and The United Fund of National Natural Science Foundation of China and Government of Guangdong Province (Grant No. U1401254).
Compliance with Ethical Standards
Conflict of Interest
The authors declare no conflict of interest.
- 9.Nitschke P, Volk A, Welsch T, Hackl J, Reissfelder C, Rahbari M, Distler M, Saeger HD, Weitz J, Rahbari NN (2017) Impact of intraoperative re-resection to achieve R0 status on survival in patients with pancreatic cancer: a single-center experience with 483 patients. Ann Surg 265:1219–1225CrossRefGoogle Scholar
- 15.Malcor JD, Payrot N, David M, Faucon A, Abouzid K, Jacquot G, Floquet N, Debarbieux F, Rougon G, Martinez J, Khrestchatisky M, Vlieghe P, Lisowski V (2012) Chemical optimization of new ligands of the low-density lipoprotein receptor as potential vectors for central nervous system targeting. J Med Chem 55:2227–2241CrossRefGoogle Scholar
- 24.Guillaumond F, Bidaut G, Ouaissi M, Servais S, Gouirand V, Olivares O, Lac S, Borge L, Roques J, Gayet O, Pinault M, Guimaraes C, Nigri J, Loncle C, Lavaut MN, Garcia S, Tailleux A, Staels B, Calvo E, Tomasini R, Iovanna JL, Vasseur S (2015) Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. Proc Natl Acad Sci U S A 112:2473–2478CrossRefGoogle Scholar
- 26.de Geus SWL, Boogerd LSF, Swijnenburg RJ, Mieog JSD, Tummers WSFJ, Prevoo HAJM, Sier CFM, Morreau H, Bonsing BA, van de Velde CJH, Vahrmeijer AL, Kuppen PJK (2016) Selecting tumor-specific molecular targets in pancreatic adenocarcinoma: paving the way for image-guided pancreatic surgery. Mol Imaging Biol 18:807–819CrossRefGoogle Scholar
- 29.Lamberts LE, Koch M, de Jong JS, Adams ALL, Glatz J, Kranendonk MEG, Terwisscha van Scheltinga AGT, Jansen L, de Vries J, Lub-de Hooge MN, Schröder CP, Jorritsma-Smit A, Linssen MD, de Boer E, van der Vegt B, Nagengast WB, Elias SG, Oliveira S, Witkamp AJ, Mali WPTM, van der Wall E, van Diest PJ, de Vries EGE, Ntziachristos V, van Dam GM (2017) Tumor-specific uptake of fluorescent bevacizumab-IRDye800CW microdosing in patients with primary breast cancer: a phase I feasibility study. Clin Cancer Res 23:2730–2741CrossRefGoogle Scholar