(15c) Calcium Phosphate-Polymeric Nanoparticle System for Co-delivery ofmicroRNA-21 Inhibitor and Doxorubicin

The development of nano-scaled carriers as a drug delivery platform has made tremendous progress in the fight against cancer. Despite the progress, drug resistance remains one of the major challenges of nanotechnology-based cancer therapeutics. Due to gradually developed resistance of traditional anti-cancer drugs, new drugs that can target specific carcinogenic pathways are being sought based on molecular biology, such as small molecules, antibodies, RNAs, and DNAs. Among these, microRNA inhibitors (miRi) hold great promise in cancer therapeutics by down-regulating the proteins promoting multi-drug resistance. miRNA is a short non-coding RNA that can effectively inhibit protein translation or degrade specific mRNA transcripts. One unique feature of miRNA is that one miRNA can regulate multiple gene expressions. A key miRNA can act as a master switch for multiple pathways. An approach of a NP design carrying miRNA-21 inhibitor (miR-21i) and a chemotherapeutic agent is expected to effectively treat the current challenges of drug resistance. However, the synthesis of a co-delivery system encapsulating miRNA inhibitor and a chemotherapeutic agent is quite challenging, due to the opposite nature of the hydrophilicity of RNAs and the hydrophobicity of anti-cancer drugs.

In this study, we developed a calcium phosphate (CaP)-coated nanoparticle (NP) formulation to co-deliver miR-21i along with Dox. This NP design can be used to deliver the two agents with different physiochemical properties. The NP formulation was optimized for particle size, polydispersity, Dox loading, and miR-21i loading. The NP formulation was confirmed to downregulate miR-21 levels and upregulate tumor suppressor gene levels. The cytotoxic efficacy of the combined miR-21i and Dox-containing NPs was found to be higher than that of Dox. Therefore, the CaP-coated hybrid lipid-polymeric NPs hold potential for the delivery of miR-21i and Dox..