Report
Teaser, summary, work performed and final results
Periodic Reporting for period 1 - MIRNANO (Multifunctional miRNA-targeting nanodevices for pluripotent cancer theranostics)
Teaser
“MIRNANO†is a multidisciplinary program at the forefront of nanotechnology and nanomedicine. The foundation of the project is the combination of materials chemistry and biomolecular (DNA/RNA) engineering, aiming to develop innovative technologies with unique hybrid...
Summary
“MIRNANO†is a multidisciplinary program at the forefront of nanotechnology and nanomedicine. The foundation of the project is the combination of materials chemistry and biomolecular (DNA/RNA) engineering, aiming to develop innovative technologies with unique hybrid properties. The action centers on the use of porous silicon nanoparticles and engineered nucleic acids to craft smart nanomaterials, nanodevices, and molecular systems that can all contribute to advancing the field of bionanotechnology and personalized medicine. A special focus is on microRNAs as molecular targets.
Rationale:
• Nanotechnology has revolutionized modern research. From biomolecular engineering to nanostructured materials, nanoscale science has led to unparalleled achievements in a plethora of fields, including biomedicine and bioengineering.
• MiRNAs are short endogenous noncoding RNAs that, by regulating gene expression at the post-transcriptional level, govern vital cellular processes, including cell metabolism, differentiation, proliferation, and apoptosis. There is established evidence that dysregulation and aberrant expression of certain miRNAs (oncomiRs) is associated with cancer, from early development to advanced stage. Therefore, miRNAs have emerged as promising targets for silencing-based anticancer therapies (anti-miR) and as biomarkers for early diagnosis.
• Nucleic acid engineering allows for: i) Improving in vivo stability of molecular drugs by using new classes of chemically modified nucleic acid structures or artificial oligonucleotide mimics; ii) Generating advanced functionality by designing programmable, dynamic DNA nanodevices.
• Delivery systems are needed that can guarantee efficient release of nucleic acid payloads, improve bioavailability, biocompatibility, and reduce off-target effects. Porous silicon nanoparticles (pSiNPs) present tunable pore sizes, allow for control of their physicochemical properties through a suite of available surface chemistries, and show a complete biocompatible degradation pathway in vivo.
Objectives:
The overarching goal of “MIRNANO†is to develop innovative microRNA-targeted nanoscale devices with advanced functionality for biomedical applications. With regard to the initial OUTGOING PHASE of the action, the main objectives are: 1) The development of novel cancer therapeutics for precision nanomedicine leveraging silencing of oncogenic microRNAs. This is planned to be achieved by using biodegradable porous silicon nanoparticles loaded with specific anti-miR artificial oligonucleotides and decorated with tumor-targeting ligands; 2) The development of innovative hybrid technologies allowing for detection and imaging of target microRNAs in real time. This can be obtained by integrating miRNA-responsive, dynamic DNA nanodevices into porous silicon-based delivery platforms.
Work performed
We developed novel cancer therapeutics that leverage silencing of oncomiRs. We focused on ovarian cancer, which is the most lethal gynecologic malignancy and one of the leading causes of cancer mortality among women, and set out to target miR-21, which is associated with cell proliferation, multidrug resistance, and tumor invasion. We engineered tumor-targeting, anti-miR nanotherapeutics that provided anticancer activity in a mouse model of ovarian cancer. Porous silicon nanoparticles are loaded with an artificial oligonucleotide, a locked nucleic acid (LNA), targeting miR-21, and decorated with a tumor-homing peptide that allows for enhanced accumulation in the tumor microenvironment. After evaluation in multiple ovarian cancer cell lines in vitro, we translated our nanoformulation in vivo and tested its anticancer activity in a xenograft mouse model of ovarian cancer developed from human COV-318 cells. We were able to silence miR-21 in the tumor and achieved complete inhibition of tumor growth with no side effects. We observed no increase of tumor volume over the course of a 10-day treatment, whereas control saline-injected mice showed a 10-fold tumor volume expansion.
Final results
The highly effective anti-miR approach demonstrated here for the treatment of ovarian cancer suggests that porous silicon nanoparticles might serve as an effective platform for delivery of microRNA-silencing therapeutics in other diseases.
Additionally, we showed that nucleic acid-loaded pSiNPs can be incorporated in multiscale technologies that allow for sensing of miRNA markers in situ and in real time by combining miRNA-responsive DNA nanodevices with hybrid polymer/porous silicon tissue engineering scaffolds. We demonstrated long-term release of the engineered DNA payload with retention of specificity and functionality over 20 days. This suggests that extracellular miRNA markers may be detected in cell culture over several weeks, providing a new means for real-time monitoring of disease conditions.
Website & more info
More info: http://www.francescoriccilab.com.