Reduced Toxicity and Superior Therapeutic Activity of a Mitomycin C Lipid-Based Prodrug Incorporated in Pegylated Liposomes

Abstract

Purpose: A lipid-based prodrug of mitomycin C [MMC; 2,3-(distearoyloxy)propane-1-dithio-4V-benzyloxycarbonyl-MMC] was designed for liposome formulation. The purpose of this study was to examine the in vitro cytotoxicity, pharmacokinetics, in vivo toxicity, and in vivo antitumor activity of this new lipid-based prodrug formulated in polyethylene glycol^coated (pegylated) liposomes. Experimental Design: MMC was released from the MMC lipid^based prodrug (MLP) by thiolytic-induced cleavage with a variety of thiol-containing reducing agents. MLP was incorporated with nearly 100% efficiency in cholesterol-free pegylated liposomes with hydrogenated phosphatidylcholine as the main component and a mean vesicle size of f90 nm.This formulation was used for in vitro and in vivo tests in rodents. Results: In vitro, the cytotoxic activity of pegylated liposomal MLP (PL-MLP) was drastically reduced compared with free MMC. However, in the presence of reducing agents, such as cysteine or N-acetyl-cysteine, its activity increased to nearly comparable levels to those of free MMC. Intravenous administration of PL-MLP in rats resulted in a slow clearance indicating stable prodrug retention in liposomes and long circulation time kinetics, with a pharmacokinetic profile substantially different from that of free MMC. In vivo, PL-MLP was f3-fold less toxic than free MMC.The therapeutic index and absolute antitumor efficacy of PL-MLP were superior to that of free MMC in the three tumor models tested. In addition, PL-MLP was significantly more active than a formulation of doxorubicin in pegylated liposomes (DOXIL) in the M109R tumor model, a mouse tumor cell line with a multidrug-resistant phenotype. Conclusions: Delivery of MLP in pegylated liposomes is a potential approach for effective treatment of multidrug-resistant tumors while significantly buffering the toxicity of MMC.

Lipid prodrug nanocarriers in cancer therapy

“…9). The superior efficacy of these liposomes compared to the free parent drug, free Dox and Doxil ® has been demonstrated in vivo on mice bearing MDR murine lung carcinoma (M109R) [94], and resistant human ovarian carcinoma (A2780/AD) [95]. Further studies on subcutaneous models of gastric (N87), colon (HCT15) and pancreatic (Panc1) carcinoma confirmed the greater efficacy compared to standard treatments (i.e., irinotecan and Gem).…”

Effect of microemulsion formulation on biodistribution of 99mTc-Aprotinin in acute pancreatitis models induced rats

“…DOI: 10.3109/10717544.2016.1145306 toxicological properties, such as organ targeting, increased efficacy, reduced toxicity, from bulk material of the same composition due to their nanoscale size (Gabizon et al, 2006;Ellis-Behnke et al, 2007;Kim, 2007). Whereas the larger micelles with the size range of 50-100 nm were removed by the liver and spleen, polymeric micelles smaller than 5 and 5-10 nm were easily eliminated through the renal glomeruli (Kedar et al, 2010).…”

A Review of Study Designs and Outcomes of Phase I Clinical Studies of Nanoparticle Agents Compared with Small-Molecule Anticancer Agents

“…In vitro and preclinical studies have shown that the toxicity of PEGylated liposomal agents and other nontargeted nanoparticles carriers is less than the comparative small molecule (3,36,37). For example, the cytotoxicity of mitomycin C was drastically reduced when prepared in PEGylated liposomes (38). It also has been clinically noted that the biodistribution pattern of liposomes can lead to a relative reduction of drug concentrations in tissues that are known to be sensitive to the drug (39).…”