Enhanced distribution of NK012, a polymeric micelle‐encapsulated SN‐38, and sustained release of SN‐38 within tumors can beat a hypovascular tumor

Abstract

Human pancreatic cancer is generally hypovascular in nature and rich in interstitium. These pathological barriers may contribute to the intractable nature of pancreatic cancer by binding the penetration of anticancer agents throughout the tumor tissue. The aim of the present study was to determine whether NK012 is an appropriate formulation for the treatment of hypovascular tumors. Among pancreatic tumor xenografts, PSN1 appeared to have the richest tumor vasculature and the least number of stromal cells and matrix. In contrast, Capan1 had the poorest tumor vasculature and most abundant stromal tissue. Fluorescence microscopy and high-performance liquid chromatography analysis demonstrated that although NK012 accumulated and continued to be distributed for more than 48 h throughout the entire body of both tumors, CPT-11 disappeared almost entirely from both tumors within 6 h. In addition, efficient sustained release of SN-38 was maintained for more than 96 h in both tumors following administration of NK012. Following the administration of CPT-11, SN-38 was no longer detectable after 24 h in the Capan1 tumor or after 48 h in the PSN1 tumor. All tumors were eradicated in the mice treated with NK012 but not in those treated with CPT-11. Because the antitumor activity of SN-38 is time dependent, NK012, which combines enhanced distribution with sustained release of SN-38 within tumors, may be ideal for the treatment of hypovascular tumors, such as pancreatic cancer.