Abstract
PurposeThe 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.MethodsAntitumor activity was assessed in xenograft mouse models of human pancreatic cancer. The pharmacokinetics of GEM and its active metabolite dFdCTP were also evaluated.ResultsIn 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.ConclusionThis 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.
Highlights
Pancreatic cancer is a major cause of cancer-related deaths [1]
All the parameters were calculated for mean values of dFdCTP concentration profile (n = 4 animals/each time point) a) Maximum dFdCTP concetration in tumor b) AUC up to last measured concentration time point in tumor c) Mean residence time up to last measured concentration time point in tumor d) Dose equivalent to GEM
FF-10832 appeared to be extravasated from blood to tumors, possibly by enhanced permeability and retention (EPR), and internalized in tumor-associated macrophages (TAMs), in which the FF-10832 was processed in lysosomes to release GEM
Summary
Pancreatic cancer is a major cause of cancer-related deaths [1]. Surgical resection is a potentially curative treatment, but only a small percentage of patients undergo resection, because most diagnoses occur at an advanced stage and are unresectable [2]. Cells are targeted in the synthesis phase (S phase) of the cell cycle [8,9,10] Because of these pharmacological and pharmacokinetic properties, a continuous infusion of GEM to produce sustained plasma levels of GEM has been investigated in clinical trials, and the findings revealed that the infusion provided longer median survival rates than those achieved using standard administration. Using this approach, an increased incidence of hematological adverse events was observed in patients with advanced pancreatic cancer [11, 12]. The concentration of the drug was increased in the bone marrow, resulting in increased hematological toxicity
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