Detailed Distribution of NK012, an SN-38–Incorporating Micelle, in the Liver and Its Potent Antitumor Effects in Mice Bearing Liver Metastases

Abstract

Purpose: To clarify and compare the antitumor effects and specific biodistribution of NK012, an SN-38-incorporating polymeric micelle, in mice bearing multiple liver metastases of human colon cancer HT-29 cells with irinotecan hydrochloride (CPT-11).Experimental Design: The maximum tolerable dose of NK012 (30 mg/kg) or CPT-11 (66.7 mg/kg) was i.v. administered three times every 4 days to mice bearing metastases to the liver colonized 7 days after the portal administration of HT-29 cells (n = 6). In vivo antitumor effects were evaluated by bioluminescence imaging and histopathologic examination. Drug biodistribution was analyzed by high-performance liquid chromatography and fluorescence microscopy (n = 3).Results: NK012 eradicated the liver metastases and produced a significant longer survival rate than CPT-11 (P = 0.0006). High-performance liquid chromatography showed the prolonged distribution of NK012 and free SN-38 released from NK012 in the tumors, liver, and spleen for weeks after NK012 administration. On the other hand, the accumulation levels of CPT-11 and free SN-38 converted from CPT-11 rapidly decreased within 1 day after CPT-11 administration. In the liver metastases, fluorescence microscopy and immunohistochemistry showed that administered NK012 was distributed mainly adjacent to tumor vessels after 1 day. As for the normal liver, NK012 was distributed in Kupffer cells instead of hepatocytes for at least 7 days after administration.Conclusion: This study suggests that NK012 is strongly effective against liver metastases and does not damage the liver despite the long retention time of NK012 in Kupffer cells.

Anticancer nanomedicine and tumor vascular permeability; Where is the missing link?

“…[176][177][178][179][180][181][182][183][184][185][186][187][188][189][190][191]. (C) Comparison of the ratio of free to nanoconstruct associated drugs in tumor tissue normalized across studies as % of injected dose per gram of tissue relative to the animal model used [176,177,184,189,[192][193][194][195].…”

SN-38-Cyclodextrin Complexation and Its Influence on the Solubility, Stability, and In Vitro Anticancer Activity Against Ovarian Cancer

“…Several approaches to overcome the problem of SN-38 solubility and stability have been proposed, including incorporation into nanoparticles (2,4,5), liposomes (6), and polymeric micelles (7)(8)(9), conjugating with water-soluble polymers like polyethylene glycol (10), PAMAM dendrimers (11), peptides (1), carbohydrates (12), etc. All these approaches involve tedious processing or synthetic steps and expert skills and industrialization or scale-up is also an important problem.…”

Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT)

“…In addition, the results of 3 previously unpublished studies were included. In these 15 studies, PK data were available for 17 CMAs and 15 SMs (Chu et al 2013; Desjardins et al 2001; Farrell 2011; Feng et al 2013; Forssen et al 1992; Gabizon et al 1997; Konishi et al2012; Ma et al 2013; Mayer et al 1990; Sapra et al 2008; Takahashi et al 2010; Valery et al 1999; Walsh et al 2012; Zamboni et al 2004, 2007). Two of the studies compared two separate CMA formulations to a single SM formulation, which explains why there were data available for 2 more CMA than SM (Chu et al 2013; Farrell 2011).…”