Supramolecular Cages for Drug Delivery: RNA Stabilization and Delivery Using MOCs- and MOFs-based Nanostructures

Research output: Book/ReportPh.D. thesis

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Abstract

Porous organometallic structures, including metal-organic cages (MOCs) and metal-organic frameworks (MOFs), are supramolecular entities assembled by metal nodes and organic ligands through coordination, which have been widely applied for a variety of applications over the last decades. Their unique features, including biocompatibility, high cargo loading, and ease of nanofabrication, provide MOCs and MOFs-based nanoparticles with great potential for applications in biological sciences, especially drug delivery. Recent years witnessed that drug delivery applications gradually expanded from small-molecule pharmaceuticals to therapeutic biomacromolecules. Due to the robust gene editing and RNA regulatory properties, miRNA are promising therapeutic agents in disease therapy, especially cancer. However, their therapeutic application is severely limited by their instability in biological environments, resulting from ribonuclease degradation. In addition, their innate negative charge hampers their cell membrane penetration, leading to low therapeutic efficiency. The use of nanoparticle carriers has emerged as a suitable strategy to protect and deliver RNA and several classes of nanomaterials have been applied, including gold nanoparticles, liposomes, silica nanoparticles, etc. By contrast, the studies of miRNA delivery using MOF and MOC nanoparticles are rare. This thesis is focused on the development of MOCs and MOFs for miRNA stabilization and delivery.
In the first project, a cationic metalloporphyrin MOC was developed to bind the miRNA sequences, thus dramatically enhancing the stability of RNA in the presence of metabolic enzymes. A broad array of analytic methods was used allowing good understanding of RNA binding, showing that both π stacking and electrostatic interactions contribute to RNA stabilization. The miRNA was proven to interact with the external surface of MOCs, as the occupation of the cavity of MOC with a preloaded cargo, had a negligible effect on miRNA binding. The bound RNA maintained genetic activity after release in the intracellular acidic environment. Taking advantage of the photodynamic properties of the MOC, the nanosystem showed efficient in vitro cell killing from a synergistic gene and photodynamic effect, providing evidence for its therapeutic potential in breast cancer treatment.
Encouraged by the first work, the water-stable porphyrinic MOF, PCN-224, was investigated for its ability to co-deliver miRNA bound on the exterior surface and doxorubicin encapsulated inside the pore. The miRNA surface binding was found to significantly protect miRNA against the ribonuclease degradation, but also enhance the colloidal stability of the MOFs. Cationic lipids were wrapped around the formulated RNA-bound MOFs nanoparticles, giving further protection. Also, the lipid encapsulation significantly enhanced the cellular uptake. Due to the presence of doxorubicin and the photodynamic property of MOF, the fabricated nanocomplex showed a high therapeutic efficiency through a combination of miRNA gene regulation, chemotherapy and photodynamic therapy.
In the last work, novel positively charged MOCs with luminescent properties and water solubility were designed and synthesized. The organic component tetraphenylethylene, a typical organic ligand showing aggregation-induced-emission, gave the structures outstanding photoluminescent properties in both diluted aqueous solution and aggregated state. Through the post-modification with polyethylene glycol chains and exchange of the anionic by sulfate, the hydrophobic MOC was rendered water-soluble while retaining luminescent properties. Taking inspiration from the first and second works, the obtained cationic MOCs are predicted to bind RNA through relevant non-covalent interactions, hereby having the potential for miRNA stabilization and delivery. In addition, the luminescent properties of the obtained MOCs-delivery system, makes them relevant structures for cellular imaging. Overall, we can foresee that the MOCs can have multiple potential applications in miRNA therapy.
Original languageEnglish
PublisherDTU Chemistry
Number of pages206
Publication statusPublished - 2022

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