Date of Award

2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biotechnology Science and Engineering

Committee Chair

Carmen Scholz

Committee Member

Sharifa Love-Rutledge

Committee Member

Krishnan Chittur

Committee Member

Jon Hakkila

Committee Member

Emanuel Waddell

Subject(s)

Nanoparticles -- Therapeutic use., Nanomedicine -- Methods.

Abstract

Nanomaterials-based hybrid nano therapy is gaining attraction as a promising way to treat intracellular bacterial infections. Gold-based nanomaterials have been widely used for biomedical applications such as photothermal therapy (PTT). This thesis discusses the development of a combination therapeutic approach that kills intracellular bacteria in conjunction with photothermal and antibiotic therapy using gold nanorod (GNR) based nano-assembly. This NIR laser-activated nano-assembly delivers antibiotics to the site of infection and offers PTT. The synergistic application of both therapies increases the efficacy of treatment. The protected delivery of antibiotics and their release in the proximity of the bacterial surface decreases off-target toxicity and drug dosage. The core of the nano-assembly is composed of GNRs coated with a mesoporous silica shell (MS). The MS shell serves as a carrier for the anti-tuberculosis drug bedaquiline. The core-shell nanoparticle is encapsulated within a thermo-sensitive liposome (TSL). The TSL layer is further conjugated to the mycobacteria-targeting peptide NZX. NZX mediates the adhesion of the final nano-assembly onto the mycobacterial surface. Upon NIR laser irradiation GNRs convert the photon energy of the laser to localized heat, which melts the TSL, triggering the release of bedaquiline. The antibacterial activity of the final nano-assembly against Mycobacterium smegmatis (Msmeg) was 20 folds more efficacious than the free drug equivalent. Mtb can alter immune defense mechanisms exerted by the host macrophage. Hence, host-targeted nano-assemblies (HTNs) were fabricated by conjugating host targeting ligands (β-Glucan) onto the nano-assembly. The binding of β-Glucan conjugated HTNs to the dectin-1 receptor present on macrophages increases the free radical production and cellular uptake of HTNs. An NIR laser triggers the photothermally induced structural disruption of the nano-assembly, releasing the drug at the targeted sites. The released bedaquiline within the macrophage promotes phagosome acidification and phagolysosome formation, effectively killing 99% of intracellular bacteria. Similar nano-assemblies were developed for dual-targeted drug delivery against lung carcinoma and proved to be 20 fold more effective than the anticancer drug alone. Finally, a simple and rapid diagnostic test was developed for detecting mycobacteria within a minute using lectin conjugated multi-core silica-coated magnetic nanoparticles.

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