title: Ultrasonic nanotherapy of pancreatic cancer: lessons from ultrasound imaging.
abstract: Pancreatic ductal adenocarcinoma (PDA) is the fourth most common cause of cancer death in the United States, with a median survival time of only 3-6 months for forty percent of patients. Current treatments are ineffective, and new PDA therapies are urgently needed. In this context, ultrasound-mediated chemotherapy by polymeric micelles and/or nanoemulsion/microbubble encapsulated drugs may offer an innovative approach to PDA treatment. PDA xenografts were orthotopically grown in the pancreas tails of nu/nu mice by surgical insertion of red fluorescence protein (RFP)-transfected MiaPaCa-2 cells. Tumor growth was controlled by fluorescence imaging. Occasional sonographic measurements correlated well with the formal tumor tracking by red fluorescence. Tumor accumulation of paclitaxel-loaded nanoemulsion droplets and droplet-to-bubble transition under therapeutic ultrasound was monitored by diagnostic ultrasound imaging. MiaPaCa-2 tumors manifested resistance to treatment by gemcitabine (GEM). This drug is the gold standard for PDA therapy. The GEM-resistant tumors proved sensitive to paclitaxel. Among six experimental groups studied, the strongest therapeutic effect was exerted by the following drug formulation: GEM + nanodroplet-encapsulated paclitaxel (nbGEN) combined with tumor-directed 1-MHz ultrasound that was applied for 30 s four to five hours after the systemic drug injection. Ultrasound-mediated PDA therapy by either micellar or nanoemulsion encapsulated paclitaxel resulted in substantial suppression of metastases and ascites, suggesting ultrasound-enhanced killing of invasive cancerous cells. However, tumors relapsed after the completion of therapy, indicating survival of some tumor cells. The recurrent tumors manifested development of paclitaxel resistance. Ultrasound imaging suggested nonuniform distribution of nanodroplets in the tumor volume due to irregular vascularization, which may result in the development of zones with subtherapeutic drug concentration. This is implicated as a possible cause of the resistance development, which may be pertinent to various modes of tumor nanotherapy.
authors.affiliation: Department of Bioengineering, University of Utah, and Departments of Clinical Radiology and Surgery, School of Medicine, University of Utah, Salt Lake City, Utah 84112, USA. natasha.rapoport@utah.edu
authors.forename: Natalya
authors.initials: N
authors.lastname: Rapoport
authors.forename: Anne M
authors.initials: AM
authors.lastname: Kennedy
authors.forename: Jill E
authors.initials: JE
authors.lastname: Shea
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Scaife
authors.forename: Kweon-Ho
authors.initials: KH
authors.lastname: Nam
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D045423:Microbubbles; D053758:Nanoparticles; D017239:Paclitaxel / Q000008:administration & dosage; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D014162:Transfection; D014463:Ultrasonography; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine; D000097573:Red Fluorescent Protein
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D008164:Luminescent Proteins; D008823:Micelles; D017239:Paclitaxel; D011994:Recombinant Proteins; D000093542:Gemcitabine; D000097573:Red Fluorescent Protein