Abstract
Gene replacement therapy with oncosuppressor microRNAs (miRNAs) is a promising alternative to interfere with cancer progression. However, miRNAs are highly inefficient in a biological environment, hampering a successful translation to clinics. Nanotechnology can tackle this drawback by providing delivery systems able to efficiently deliver them to cancer cells. Thus, the objective of this work was to develop biocompatible nanosystems based on sphingomyelin (SM) for the intracellular delivery of miRNAs to colorectal cancer cells. We pursued two different approaches to select the most appropriate composition for miRNA delivery. On the one hand, we prepared sphingomyelin-based nanosystems (SNs) that incorporate the cationic lipid stearylamine (ST) to support the association of miRNA by the establishment of electrostatic interactions (SNs–ST). On the other hand, the cationic surfactant (DOTAP) was used to preform lipidic complexes with miRNA (Lpx), which were further encapsulated into SNs (SNs-Lpx). Restitution of miRNA145 levels after transfection with SNs-Lpx was related to the strongest anticancer effect in terms of tumor proliferation, colony forming, and migration capacity assays. Altogether, our results suggest that SNs have the potential for miRNA delivery to develop innovative anticancer therapies.
Highlights
Nowadays, cancer is one of the leading causes of death [1]
It is well known that various miRNAs, for instance, miRNA-10a, miRNA-34b/c, miRNA-137, miRNA-143, and miRNA-145, are downregulated in colorectal cancer cells compared to healthy tissues, and modulation of the corresponding gene expressions is gaining interest for the development of anticancer therapeutics [9,10,11,12,13]
We proposed the encapsulation of preformed DOTAP-miRNA lipid complexes (Lpx) into sphingomyelin-based nanosystems (SNs) (SNs-Lpx) to provide additional protection for the associated miRNA mimics, following a similar approach to that described for plasmid DNA, complexed via hydrophobic ion pairing utilizing surfactants and further incorporated into self-nanoemulsifying drug delivery systems [20,21]
Summary
Cancer is one of the leading causes of death [1]. Cancer treatments can still be improved, making use of novel technologies and biotechnological drugs. The major barriers of miRNA delivery are (i) poor systemic stability, (ii) rapid clearance, (iii) degradation by nucleases, (iv) risk of systemic toxicity, (v) elimination by phagocytic immune cells, and (vi) lack of efficient delivery to targeted cells to achieve the desired therapeutic outcome [14]. For overcoming these constraints, different delivery systems have been proposed to date, such as PLGA/PEI/miRNA/HA nanoparticles, protamine nanoparticles, and magnetic nanoparticles [15,16,17]
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