Drug-loaded Oxygen Microbubbles Induced Vascular Normalization in Pancreatic Cancer

1Yi-Jia Jhou 2Yi-Ju Ho

Department of Biological Science and Technology, National Yang Ming Chiao Tung University 

Pancreatic ductal adenocarcinoma presents serious resistance in cancer therapy due to the deficient drug delivery. Recent research has found that inducing the tumor vascular normalization (VN) can improve vessel function to enhance the delivery and penetration of chemotherapeutic drugs. Ultrasound can be used for local therapy to reduce the side effects of chemotherapy drugs. In this study, we investigated the feasibility of pancreatic tumor VN induced by chemotherapeutic drug gemcitabine-loaded oxygen microbubbles (GEM-OMBs) under ultrasound sonication. The local release O2 might inhibit tumor hypoxia to induce VN, then improve the delivery efficiency of GEM. Our homemade GEM-OMBs loaded with C3F8 and O2 gases in a 1:1 volume ratio which were encapsulated into a phospholipid shell. Murine subcutaneous pancreatic tumor model (C57BL/6 implanted with Panc02 cells) was used to evaluate the feasibility of VN when tumor volume reached to 50 mm3. After iv injection of OMBs (1×108 per mouse), a 2-MHz high-intensity focused ultrasound was used to trigger local release of O2 within tumors under ultrasound imaging system monitor. Tumor perfusion imaging was traced vessel function before and after treatment to evaluate whether VN was occurred. The fabrication of GEM-OMBs with average diameter of 576±37 nm, the loading capacity of GEM and O2 was 0.55±0.07 mg and 10.45±0.65 mg/mL, respectively. The tracing of tumor perfusion at 0 to 4 day was 169 to 160 in the control group (N=1), and 222±4 to 231±40 in the OMB group (N=2). The slight enhancement of tumor perfusion after OMB treatment provided some probability to induce VN in pancreatic tumors. Subsequent tumor perfusion tracing, histological assessment for vascular morphology change, and immune activation will be evaluated to further demonstrate our propose.