Cyclodextrin-mediated entrapment of curcuminoid 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] or CLEFMA in liposomes for treatment of xenograft lung tumor in rats

Abstract

We recently reported a novel curcuminoid 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] or CLEFMA as a potent anti-proliferative agent, and showed that it induces autophagic cell death in lung cancer cells. We are now reporting a drug-in-CD-in-liposome approach to formulate CLEFMA liposomes that could be labeled with Tc-99m radionuclide for non-invasive imaging of their biodistribution. CLEFMA encapsulation was enabled by hydroxypropyl-β-cyclodextrin. In vitro studies showed that CLEFMA possessed more potent anti-proliferative activity in lung adenocarcinoma H441 cells than naturally occurring curcumin. At the same time, it had no effect on the proliferative capacity of normal lung fibroblasts. CLEFMA liposomes retained the antiproliferative potency of free CLEFMA, while maintaining its non-toxic nature in normal lung fibroblasts. In nude rats bearing xenograft H441 tumors, the tumor volume significantly reduced after i.v. treatment with CLEFMA liposomes (p<0.05); the tumor inhibition was determined to be 94%. The anti-tumor activity of CLEFMA liposomes was confirmed by the observation that F-18-fluorodeoxyglucose uptake in tumors of treated rats was reduced as compared to those of control rats. Tc-99m-labeled CLEFMA liposomes accumulated in liver (33.7%); spleen showed the largest accumulation on per gram tissue basis (6.2 %/g). Upon histopathological examination of liver, lung and kidney, we found no apparent toxicity from multiple CLEFMA liposome administrations. The results demonstrate the utility of liposomes to serve as a carrier for CLEFMA. This study is the first to demonstrate the efficacy of novel curcuminoid CLEFMA in a preclinical model.

Emerging role of nanocarriers to increase the solubility and bioavailability of curcumin

“…Further, several research efforts have been undertaken in this line and few are under clinical trials. For instance, in a recent study by Agashe et al, curcuminoid CLEFMA entrapped liposomal formulation was prepared to improve the bioavailability of curcuminoid [109]. In nude rats bearing a H441 xenograft, about 94% reduction in tumor volume was evident following intravenous administration with CLEFMA liposomes.…”

“…Currently, most traditional anticancer drugs/therapeutic agents have been encapsulated in liposomes using different technologies and many of them have entered clinical trials or being marketed for human use [108]. In the context for improving the bioavailability and bioactivity of curcumin, recently Agashe et al developed a liposomal carrier system for curcumin analog named CLEFMA (4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid]) and their result indicates an improved antitumor activity and bioavailability of CLEFMA-loaded nanoformulations than that of native curcumin [109]. Systemic administration of liposomal curcumin has shown an increase in bioavailability and tumor-suppressing effect in various cancers [110].…”

Curcumin nanoformulations: a future nanomedicine for cancer

“…Silk fibroin NPs less than 100 nm entrap more than 96% of curcumin molecules within their nanostructures, compared with all other silk fibroin chitosan blend NPs [98]. Modified curcuminoid (i.e., 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid]; CLEFMA) was successfully entrapped within a CD-liposome [99]. In nude rats bearing a H441xenograft, a 94% reduction in tumor volume was noticed after intravenous treatment with CLEFMA liposomes (Figure 4).…”

Characterization of 9-nitrocamptothecin-in-cyclodextrin-in-liposomes modified with transferrin for the treating of tumor

“…Encapsulation antitumor drug into DCL resulted in improved antitumor efficacy in vivo (Agashe et al, 2011). Following intravenous injection of different doxorubicin (DOX) formulations, DCL provided the inhibitory effect on the tumor growth more than DOX solution and liposome (Arima et al, 2006).…”