miRNA nanotherapeutics for cancer

Abstract

MicroRNAs (miRNAs) are noncoding RNA molecules that regulate gene expression through diverse mechanisms. Increasing evidence suggests that miRNA-based therapies, either restoring or repressing miRNA expression and activity, hold great promise. However, the efficient delivery of miRNAs to target tissues is a major challenge in the transition of miRNA therapy to the clinic. Cationic polymers or viral vectors are efficient delivery agents but their systemic toxicity and immunogenicity limit their clinical usage. Efficient targeting and sustained release of miRNAs/anti-miRNAs using nanoparticles (NPs) conjugated with antibodies and/or peptides could reduce the required therapeutic dosage while minimizing systemic and cellular toxicity. Given their importance in clinical oncology, here we focus on the development of miRNA nanoformulations to achieve enhanced cellular uptake, bioavailability, and accumulation at the tumor site.

Figure 1

[DE11]Scientific evidence and nano-based delivery of miRNAs for cancer therapeutics. (A) Publications reporting miRNA (green bars) and miRNA delivery (red bars in insert) using nanoparticle (NP) formulations from 2005 to July 2016. Data was collected from PubMed on July 26, 2016. (B) Structural differences in nanoparticle formulations used for miRNA delivery. (i) Polyethyleneimine (PEI) or cationic polymer-based nanoassemblies; (ii) liposomal formulations; (iii) polymer micelles; (iv) polymer NPs; (v) metal or magnetic NPs; and (vi) dendrimer-based formulations. (C) Possible routes of miRNA uptake mechanisms in cells: clathrin, caveolin, and receptor-mediated endocytosis. The proton sponge effect leads to the release of miRNAs from NPs.

Figure 2

[DE12]miRNA-mediated chemosensitization of cancer cells for improved therapeutics. Schematic representation: Step 1: loading of nanoparticles (NPs) with miRNA and drug molecules. Step 2: antibody conjugation reaction for targeted delivery; Step 3: targeted binding and intracellular release of miRNA induces chemosensitization; and Step 4: drug release promotes apoptosis in cancer cells.

Figure 3

Hyaluronic acid (HA) conjugation offers superior targeted delivery of miRNAs in breast cancer cells. (A) Schematic representation of a miR-34a-targeted nanoformulation preparation and in vitro specific targeting of triple-negative breast cancer cells. (B) In vivo whole-mice imaging of miR-34a nanoparticles (NPs) in an orthotopic breast cancer mouse model at different time points after intravenous injection. (C) Photon intensity of tumor region after injection of NPs. (D) Ex vivo excised tumor tissue exhibiting superior targeting potential of HA-conjugated NPs. Reproduced, with permission, from [72].