Preliminary data of the antipancreatic tumor efficacy and toxicity of long-circulating and pH-sensitive liposomes containing cisplatin Fernanda N. Carlesso a , Raquel S. Araújo a , Leonardo L. Fuscaldi a , Sued E. Mendes Miranda a , Domenico Rubello d , Cláudia S. Teixeira a , Diego C. dos Reis b , Elaine A. Leite a , Josianne N. Silveira a , Simone O.A. Fernandes a , Geovanni D. Cassali c , Mônica C. de Oliveira a , Patrick M. Colletti e , André L.B. de Barros a and Valbert N. Cardoso a Purpose Pancreatic cancer is the fourth most common cause of cancer-related death in the USA. This is mainly because of the chemoresistance of this type of tumor; thus, the development of novel therapeutic modalities is needed. Methods Long-circulating and pH-sensitive liposomes containing cisplatin (SpHL-CDDP) were administered systemically into pancreatic tumor-bearing mice for a period of 14 days. The antitumor efficacy and toxicity of this new treatment method on the basis of cisplatin-loaded liposomes was compared with the classical free-CDDP method. 99m Tc-HYNIC-βAla-bombesin (7–14) tumor uptake and histopathologic findings were used to monitor and compare the two treatment modalities. Results The antitumor activity of SpHL-CDDP treatment was shown by (a) decrease in tumor volume, (b) development of tumor necrotic areas, and (c) decrease in 99m Tc-HYNIC-βAla-bombesin (7–14) tumor uptake. Toxicity was evaluated by the development of inflammation and necrotic areas in the kidneys, liver, spleen, and intestine: toxic effects were greater with free-CDDP than SpHL-CDDP. Conclusion SpHL-CDDP showed significant antitumor activity in pancreatic cancer-bearing mice, with lower toxicity in comparison with free-CDDP. Nucl Med Commun 37:727–734 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Nuclear Medicine Communications 2016, 37:727–734 Keywords: antitumoral efficacy, antitumoral toxicity, free-cisplatin, pancreatic tumor, pH-sensitive liposome-containing cisplatin a Department of Clinical and Toxicological Analyses, b Department of Pharmaceutical Products, Faculty of Pharmacy, c Department of Pathology, Biological Science Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, d Department of Nuclear Medicine, Santa Maria della Misericordia Hospital, Rovigo, Italy and e Department of Nuclear Medicine, University of Southern California, Los Angeles, California, USA Correspondence to Domenico Rubello, MD, Department of Nuclear Medicine, PET/CT Center, Radiology, NeuroRadiology, Interventional Radiology, Medical Physics, Clinical Laboratory, Biomarkers Laboratory, Microbiology, Pathology, Santa Maria della Misericordia Hospital, 45100 Rovigo, Italy Tel: + 39 425 394 428; fax: + 39 425 394 434; e-mail: domenico.rubello@libero.it Received 16 February 2016 Revised 22 February 2016 Accepted 22 February 2016 Introduction In 2012, in the USA, 14.1 million of new cases of cancer were diagnosed and 8.2 million cancer-related deaths were registered. Pancreatic adenocarcinoma is character- ized by a very high mortality rate [1]: one of the most relevant adverse prognostic factors of pancreatic tumor is its chemoresistance, probably because the tumoral tissue is characterized by dense stroma and poor vascularization that decrease the input of antitumoral drugs [2,3]. Few chemotherapeutics have shown efficacy in treating pancreatic tumor, such as gemcitabine and its association with cisplatin (CDDP) [4,5]. Beyond this, chemoresis- tance has stimulated the development for novel ther- apeutic strategies, such as nanocarriers. The use of CDDP-loaded liposomes (Lipoplatin) associated with free gemcitabine showed encouraging results in advanced pancreatic tumor that were refractory to pre- viously administered chemotherapeutic regimens [6]. CDDP is a platinum-based drug commonly used to treat a variety of human cancers. However, relevant side effects have been reported with free-CDDP, including renal, gastrointestinal, and neurological toxicity. This has limited the use of free-CDDP in the oncological field [7,8]. In an attempt to overcome these difficulties, many efforts have been made to develop CDDP deli- very systems, such as carbon nanotubes, nanocapsules, nanospheres, and liposomes, that modify the pharmaco- kinetics of CDDP, reducing toxicity and improving drug bioavailability [9–14]. On this basis, we developed a cisplatin-loaded, long-circulating and pH-sensitive liposome (SpHL-CDDP) consisting of dioleoylpho- sphatidylethanolamine (DOPE), cholesteryl hemisuccinate (CHEMS), and distearoyl phosphatidyl-ethanolamine polyethylene glycol 2000 (DSPE-PEG 2000 ). In acidic media, as in tumor cell accumulations, CHEMS undergoes protonation, followed by the destabilization of liposomes, Original article 0143-3636 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MNM.0000000000000505 Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.