Evaluation of the feasibility of intrapancreatic delivery of drug-loaded microparticles via EUS-guided fine needle injection using a swine model

Abstract

Background and study aims Patients with pancreatic cancer often have locally advanced or metastatic disease and are not candidates for curative surgery. Polymer-based microparticles (MPs) represent a drug delivery system that offers sustained release of a chemotherapeutic drug after intralesional injection for local tumor management. The aim of this study was to determine the feasibility of endoscopic ultrasound-guided fine-needle injection (EUS-FNI) of drug-loaded MPs tagged with a fluorophore and fiducial markers for locating the injection site. Secondary aims were to determine the tissue-specific effects of MPs.

Methods Five pigs underwent EUS with selection of an injection site within the pancreas that was marked by placing fiducial markers prior to the MPs injection. EUS-FNI of either blank microparticles (BMPs), containing no drug, or gemcitabine-loaded microparticles (GMPs) was performed. A saline flush containing Spot Endoscopic Marker was used to expel any residual MPs in the needle shaft and tattoo the injection site.

Results A green fluorescent protein flashlight was used to successfully identify the site of MP injection sites in the dissected pancreas. Frozen sections of pig pancreas demonstrated a defined deposit, confirming the delivery of the MPs. Finally, fluorescence microscopy showed activation of caspase-mediated cell death in pancreases of animals that received injections of GMPs.

Conclusions This pilot study demonstrated that fiducial marker placement and pancreatic EUS-FNI of MPs was successful in all pigs with no animals demonstrating pancreatitis. Further studies are needed to determine the role for intralesional injection of drug-loaded MPs in borderline resectable or unresectable pancreatic cancer.

^* Drs. Caceres and Munoz-Sagastibelza: These authors contributed equally.

• References

• 1 National Cancer Institute. SEER Cancer Stat Facts: Pancreas Cancer. Available at https://seer.cancer.gov/statfacts/html/pancreas.html
• 2 Kozuch P, Petryk M, Evans A. et al. Therapy for regionally unresectable pancreatic cancer. Surg Clin North Am 2001; 81: 691-697
• 3 Ashida R, Chang KJ. Interventional EUS for the treatment of pancreatic cancer. J Hepatobiliary Pancreat Surg 2009; 16: 592-597
• 4 Cunningham D, Chau I, Stocken DD. et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 2009; 27: 5513-5518
• 5 Han J, Chang KJ. Endoscopic Ultrasound-Guided Direct Intervention for Solid Pancreatic Tumors. Clin Endosc 2017; 50: 126-137
• 6 Noda Y, Goshima S, Kawada H. et al. Modified National Comprehensive Cancer Network criteria for assessing resectability of pancreatic ductal adenocarcinoma. AJR Am J Roentgenol 2018; 210: 1252-1258
• 7 Karaca C, Cizginer S, Konuk Y. et al. Feasibility of EUS-guided injection of irinotecan-loaded microspheres into the swine pancreas. Gastrointest Endosc 2011; 73: 603-606
• 8 Sun S, Wang S, Ge N. et al. Endoscopic ultrasound-guided interstitial chemotherapy in the pancreas: results in a canine model. Endoscopy 2007; 39: 530-534
• 9 Seo DW. EUS-guided antitumor therapy for pancreatic tumors. Gut Liver 2010; 4 (Suppl. 01) S76-81
• 10 Davila Fajardo R, Lekkerkerker SJ, van der Horst A. et al. EUS-guided fiducial markers placement with a 22-gauge needle for image-guided radiation therapy in pancreatic cancer. Gastrointest Endosc 2014; 79: 851-855
• 11 Varadarajulu S, Trevino JM, Shen S. et al. The use of endoscopic ultrasound-guided gold markers in image-guided radiation therapy of pancreatic cancers: a case series. Endoscopy 2010; 42: 423-425
• 12 Varde NK, Pack DW. Microspheres for controlled release drug delivery. Expert Opin Biol Ther 2004; 4: 35-51
• 13 Danhier F, Ansorena E, Silva JM. et al. PLGA-based nanoparticles: an overview of biomedical applications. J Control Release 2012; 161: 505-522
• 14 Yu X, Di Y, Xie C. et al. An in vitro and in vivo study of gemcitabine-loaded albumin nanoparticles in a pancreatic cancer cell line. Int J Nanomedicine 2015; 10: 6825-6834
• 15 Silva AL, Rosalia RA, Sazak A. et al. Optimization of encapsulation of a synthetic long peptide in PLGA nanoparticles: low-burst release is crucial for efficient CD8(+) T cell activation. Eur J Pharm Biopharm 2013; 83: 338-345
• 16 Yang YY, Chung TS, Ng NP. Morphology, drug distribution, and in vitro release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation method. Biomaterials 2001; 22: 231-241
• 17 American Cancer Society. Cancer Facts and Figures. Available at https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2018.html
• 18 Kaplan J, Khalid A, Cosgrove N. et al. Endoscopic ultrasound-fine needle injection for oncological therapy. World J Gastrointest Oncol 2015; 7: 466-472
• 19 Verna EC, Dhar V. Endoscopic ultrasound-guided fine needle injection for cancer therapy: the evolving role of therapeutic endoscopic ultrasound. Therap Adv Gastroenterol 2008; 1: 103-109
• 20 Sanders MK, Moser AJ, Khalid A. et al. EUS-guided fiducial placement for stereotactic body radiotherapy in locally advanced and recurrent pancreatic cancer. Gastrointest Endosc 2010; 71: 1178-1184
• 21 Bergenfeldt M, Albertsson M. Current state of adjuvant therapy in resected pancreatic adenocarcinoma. Acta Oncol 2006; 45: 124-135
• 22 Wilkowski R, Thoma M, Bruns C. et al. Chemoradiotherapy with gemcitabine and continuous 5-FU in patients with primary inoperable pancreatic cancer. JOP 2006; 7: 349-360
• 23 Levy MJ, Alberts SR, Bamlet WR. et al. EUS-guided fine-needle injection of gemcitabine for locally advanced and metastatic pancreatic cancer. Gastrointest Endosc 2017; 86: 161-169
• 24 Takekuni K, Sakon M, Kishimoto S. et al. [A patient with unresectable cancer of pancreas head, effectively treated by a local injection of the mixture of OK-432, fibrinogen and thrombin]. Gan To Kagaku Ryoho 1996; 23: 1621-1623
• 25 Mulvihill S, Warren R, Venook A. et al. Safety and feasibility of injection with an E1B-55 kDa gene-deleted, replication-selective adenovirus (ONYX-015) into primary carcinomas of the pancreas: a phase I trial. Gene Ther 2001; 8: 308-315
• 26 Hecht JR, Bedford R, Abbruzzese JL. et al. A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin Cancer Res 2003; 9: 555-561
• 27 Linghu E, Matthes K, Mino-Kenudson M. et al. Feasibility of endoscopic ultrasound-guided OncoGel (ReGel/paclitaxel) injection into the pancreas in pigs. Endoscopy 2005; 37: 1140-1142
• 28 Matthes K, Mino-Kenudson M, Sahani DV. et al. EUS-guided injection of paclitaxel (OncoGel) provides therapeutic drug concentrations in the porcine pancreas (with video). Gastrointest Endosc 2007; 65: 448-453
• 29 Koay EJ, Baio FE, Ondari A. et al. Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer. Phys Biol 2014; 11: 065002
• 30 Neesse A, Michl P, Frese KK. et al. Stromal biology and therapy in pancreatic cancer. Gut 2011; 60: 861-868