The Promising Nanocarrier for Doxorubicin and siRNA Co-delivery by PDMAEMA-based Amphiphilic Nanomicelles

Abstract

Synergistic effects of anticancer drug and siRNA have displayed superior advantages for cancer therapy. Herein, we deeply analyzed the feasibility that whether doxorubicin (DOX) and siRNA could be co-delivered by mPEG-PCL-graft-PDMAEMA (PECD) micelles, which mediated excellent DNA/siRNA delivery in vitro and in vivo reported in our previous work. DOX-loaded NPs (PECD-D) were developed by nanoprecipitation technology and exhibited high drug loading content (DLC, 9.5%). In vitro cytotoxicity study in MDA-MB-231 cells, PECD-D treated groups had lower IC50 compared to free DOX groups (F-DOX) at different transfection time (24, 48, and 72h), which maybe attribute to its high cellular uptake and endosomal escape properties. The speculation was confirmed with the results of drug release profile in acidic media, flow cytometry analysis and confocal images. Futhermore, Cy5 labeled siRNA was introduced in PECD-D micelles (PECD-D/siRNA) to track the behavior of dual-loaded nanodrug in vitro and in vivo. Flow cytometry analysis presented that DOX and siRNA were successfully co-delivered into cells, the positive cells ratio were 94.6 and 99.5%, respectively. Confocal images showed that not only DOX and siRNA existed in cytoplasm, but DOX traversed endosome/lysosome and entered into cell nucleus. For in vivo tumor-targeting evaluation in BALB/c nude mice, both DOX and Cy5-siRNA could be detected in tumor sites after intravenous injection with PECD-D/siRNA formulation. Therefore, we believed that PECD micelles have a potential ability as DOX and siRNA co-delivery carrier for cancer therapy.

Nucleolin-targeted Extracellular Vesicles as a Versatile Platform for Biologics Delivery to Breast Cancer

“…Also, siRNA target-specific gene silencing has been attempted for cancer therapy because cancers often overexpress a specific growth factor as well as rely on relevant receptor proteins for their growth and progression 11. Use of siRNAs to specifically silence genes for treating cancers or other diseases may have value 12-17, but successful implementation of nucleic acid drugs as new therapeutic tools largely depends on the appropriate delivery system.…”

Co‐Delivery of Drugs and Genes Using Polymeric Nanoparticles for Synergistic Cancer Therapeutic Effects

“…Dong and co-workers improved their PCL-g-PDMAEMA nanoparticles by coating PEG on the surface of PCL-g-PDMAEMA nanoparticles and obtained a new nanocarrier (PEG-b-(PCL-g-PDMAEMA)) for co-delivery of DOX and siRNA. [89] The PEG-b-(PCL-g-PDMAEMA) nanoparticles not only successfully co-delivered DOX and siRNA into MDA-MB-231 cells but also assisted in the endosome/lysosome escape process (Figure 7). In vivo experiments revealed that the PEG-b-(PCL-g-PDMAEMA) nanocarriers targeted and delivered both drug and gene to tumor tissues.…”

An Integrated Therapeutic Delivery System for Enhanced Treatment of Hepatocellular Carcinoma

“…Multiple functions are integrated into a single carrier, including codelivery and pH‐responsive triggered release of drugs/small interfering RNA (siRNA), hepatic targeting, fluorescent tracking, as well as biocompatibility and safety. The cationic poly[(2‐dimethylamino)ethyl methacrylate] (PDMAEMA), a promising transporter for the nucleic acids delivery, was chosen to condense nucleic acids which are negatively charged to form stable complexes against enzymatic degradation with its amino groups . In addition, pH‐responsive PDMAEMA can transfect genes function when polymer swelling and endosomal escape due to the sponge effect is triggered in an acidic environment .…”