Anti-miRNA Delivery Systems Based on Self-assembled Nanostructure
thesisposted on 2018-02-18, 00:00 authored by Yu Zhang
Nanomedicine has been one of the focuses of drug delivery field, especially when it comes to cancer therapy, due to the unprecedented potential benefits it could bring, such as specificity and high cargo loading. Standing on the advantages of nanoscale delivery vehicle, gene delivery targets the root of a disease instead of the product of the disease pathology, striving to achieve specificity on an even higher hierarchy. The discovery of miRNAs might be the critical piece of the cancer research puzzle since one miRNAs can regulate a broad network of genes involved in different signaling pathways. The overall objective of this dissertation is to test the hypothesis that systematic study of the assembly and disassembly process of delivery carrier will provide guidance for the development of more efficacious anti-miRNA delivery technologies. Surface properties of methoxy-poly(ethylene glycol-b-lactide-b-arginine) micelles were varied by controlling the oligoarginine block length and conjugation density. Depending upon the oligoarginine length and density, micelles exhibited anti-miRNA loading capacity directly related to the presentation of charged groups on the surface. The unpackaging of nucleic acid from micelleplexes requires thoughtful design considerations because the release of nucleic acids payloads from carrier in cytoplasm is a necessary step for effective nucleic acids delivery. Redox responsive feature was found to contribute significantly to anti-miRNA dissociation from the micelleplex and lead to higher delivery efficiency, indicating the necessity of including self-disassembly function in anti-miRNA delivery carrier. Stability issue has been plaguing the systematic administration of micelle-based nanoparticles. For the first time, it was demonstrated that micelles and micelleplexes have significantly better stability in cerebrospinal fluid (CSF) than in human plasma, indicating the advantage of applying micelle-based nanoparticles for CNS disease.