Aljuffali, NHA; (2015) Nanoparticle Mediated Delivery of RNA Oligonucleotides for Lung Cancer Therapy. Doctoral thesis , UCL (University College London).

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Abstract

Despite the global burden of lung cancer, current treatment regimens are marred by low efficacy and dose-related toxicity. Accordingly, novel therapeutic strategies are highly warranted. RNA interference and RNA aptamer platforms hold great therapeutic potential for regulating aberrant proteins implicated in lung cancer pathogenesis. Clinical translation, however, has been hampered by the lack of safe and efficacious delivery vectors. Due to their unique quantum properties and tunable design, nanoparticles are materializing as potent gene carriers. This thesis focused on the engineering and characterization of two nanoparticle constructs for the delivery of siRNA and RNA aptamer oligonucleotides. The first nanocarrier was comprised of a gold core and an organic shell, consisting of alternating hydrophilic and hydrophobic domains. This “striped” conformation enabled energy-independent cell membrane penetration and endosomal evasion. When conjugated to anti-sense oligonucleotides, these nanoparticles retained their penetrating capacities. However when conjugated to siRNA, nanoparticles lost their cell- penetrating capabilities and entered cells through energy-driven endocytic routes, compromising their gene silencing efficiency. The second nanocarrier consisted of a detonation nanodiamond core with a shell of RNA oligonucleotides. Nanodiamond-siRNA constructs were found to be biocompatible, to exhibit robust cellular internalization, and to downregulate mRNA and protein expression in two gene models. Knockdown potential, however, was limited by endosomal sequestration and slow siRNA release. In future, nanodiamonds would benefit from the attachment of acid-buffering polymers to enable endosomal escape and more potent gene silencing effects. Nanodiamonds were additionally functionalized with RNA aptamers for cancer cell targeting and therapeutic EGFR blockade. These chimeras were found to enhance binding affinities to EGFR targets relative to unfunctionalized aptamers, and to selectively induce cell apoptosis in EGFR-expressing lung cancer cell lines. As these aptamers were able to target both wild-type and mutant EGF receptors, they can potentially serve as adjuncts to TK inhibitors and anti-EGFR monoclonal antibodies in the clinic, thus expanding the scope of EGFR therapies. The work in this thesis accentuates the importance supra-molecular assembly in the context of biointerfacial interactions and proposes design schemas for those endeavoring to develop nanoparticle carriers for oligonucleotide delivery and cancer therapy.

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