ABSTRACT
PURPOSE: The clinical application of gemcitabine (GEM) is limited by its pharmacokinetic properties. The aim of this study was to characterize the stability in circulating plasma, tumor targeting, and payload release of liposome-encapsulated GEM, FF-10832. METHODS: Antitumor activity was assessed in xenograft mouse models of human pancreatic cancer. The pharmacokinetics of GEM and its active metabolite dFdCTP were also evaluated. RESULTS: In mice with Capan-1 tumors, the dose-normalized areas under the curve (AUCs) after FF-10832 administration in plasma and tumor were 672 and 1047 times higher, respectively, than after using unencapsulated GEM. The tumor-to-bone marrow AUC ratio of dFdCTP was approximately eight times higher after FF-10832 administration than after GEM administration. These results indicated that liposomal encapsulation produced long-term stability in circulating plasma and tumor-selective targeting of GEM. In mice with Capan-1, SUIT-2, and BxPC-3 tumors, FF-10832 had better antitumor activity and tolerability than GEM. Internalization of FF-10832 in tumor-associated macrophages (TAMs) was revealed by flow cytometry and confocal laser scanning microscopy, and GEM was efficiently released from isolated macrophages of mice treated with FF-10832. These results suggest that TAMs are one of the potential reservoirs of GEM in tumors. CONCLUSION: This study found that FF-10832 had favorable pharmacokinetic properties. The liposomal formulation was more effective and tolerable than unencapsulated GEM in mouse xenograft tumor models. Hence, FF-10832 is a promising candidate for the treatment of pancreatic cancer.
Subject(s)
Antimetabolites, Antineoplastic/blood , Deoxycytidine/analogs & derivatives , Drug Compounding/methods , Drug Delivery Systems/methods , Pancreatic Neoplasms/blood , Xenograft Model Antitumor Assays/methods , Animals , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/chemical synthesis , Cell Line, Tumor , Deoxycytidine/administration & dosage , Deoxycytidine/blood , Deoxycytidine/chemical synthesis , Drug Stability , Female , Humans , Liposomes , Male , Mice , Mice, Inbred BALB C , Mice, Inbred ICR , Mice, Nude , Pancreatic Neoplasms/drug therapy , Treatment Outcome , GemcitabineABSTRACT
A tractor-based robot with the capability of real-time assessing and visualizing the radioactive material density and fertility distribution of farmlands has been developed to accelerate the recovery process of the farmlands suffered by the accident of the Fukushima Daiichi Nuclear Power Plant (FDNPP). In a field test at a decontaminated farmland near FDNPP, within-field heterogeneities of soil contamination and fertility are clarified almost in real-time. Results obtained by this robot are consistent with the map by the conventional soil sampling or the history of decontamination activities.