Cationic micelle-based siRNA delivery for efficient colon cancer gene therapy

Abstract

Small interfering RNA (siRNA)-based gene therapy has provided an alternative strategy for cancer therapy. One of the key components within gene therapy process is the delivery system. As a novel non-viral gene vector, DMP, prepared by modifying mPEG-PCL micelle with cationic DOTAP lipid, has been prepared and successfully applied in plasmid DNA-based colon cancer gene therapy study. However, its potential in siRNA delivery is unknown. In this study, the preparation process of DMP was optimized and the anti-cancer efficacies of the DMP/siMcl1 and DMP/siBcl-xl complexes were studied on a mouse colon cancer model. Our results demonstrated that DMP cationic micelle-delivered siRNAs could effectively inhibit the growth of C26 colon cancer cells in vitro . Meanwhile, intratumoral administration of DMP/siMcl1 and DMP/siBcl-xl complexes obviously suppressed subcutaneous tumor model in vivo. These results suggest the DMP/siRNA complex to be a potential candidate for cancer gene therapy.

In vivo gene delivery mediated by non-viral vectors for cancer therapy

“…mPEG-PCL copolymer has been widely studied due to the biocompatibility and biodegradability as a carrier for different drugs [246,247]. Modifying this copolymer with amphiphilic DOTAP (DMP) has shown remarkable stability and safety for colon cancer gene therapy [248,249]. DOTAP containing DMP micelles has shown great stability over 96 hours with remarkable transfection efficiency.…”

“…This phenomenon causes the shielding of the positively charged head groups of DOTAP. Moreover, it is resulted in less serum protein binding and ultimately more transfection efficiency [248]. Also, DMP micelles were used for the delivery of the survivinT34A gene (S-T34A, a suicide gene) for colon cancer gene therapy [249].…”

“…Survivin is an apoptosis inhibitor [126,250,251] through phosphorylation of its threonine 34 (Thr34) [247], resulting in the stimulation of tumor growth and resistance to cancer therapy. However, the lack of Thr34 phosphorylation leads to the breakdown of caspase-9-survivin protein complex and activation of caspase-dependent apoptosis [247][248][249]. In order to prepare a nonphosphorylated mimic of survivin, Thr34 was changed to Ala (T34A) via site-directed mutagenesis, [252,253].…”

Lipid-Based Drug Delivery Nanoplatforms for Colorectal Cancer Therapy

“…As cationic liposomes often form stable liposome-nucleic acid complexes (named lipoplexes) with negatively charged nucleotides, cationic liposomes are expected to be a promising non-viral platform for delivering nucleic acid drugs for gene therapy [ 90 ] ( Figure 2 A). Compared to the viral nucleic acid delivery platform, cationic liposomes exhibit relatively low toxicity and are easy to produce and structurally simple (without immunogenic viral proteins) [ 91 ]. K.L.…”

“…Y. Lu et al investigated the siRNA delivery efficiency of a cationic PEG–lipid micelle [ 91 ]. The authors prepared the micelle by modifying a methoxy-poly(ethylene glycol)-poly(ε-caprolactone) copolymer (mPEG-PCL) micelle with a cationic lipid (DOTAP), and loaded the prepared micelle with siMcl1 or siBcl-xl.…”