Browsing by Subject "Amphiphile"

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    Development and characterization of aptamer-amphiphiles against fractalkine for targeted drug delivery
    (2013-12) Waybrant, Brett M.
    A foundation of modern diagnostics and therapeutics is the ability to non-covalently bind to a molecule of interest. These affinity molecules are behind a broad array of products ranging from therapeutics to HIV tests. Currently, antibodies are used as the affinity molecule. Despite the success of antibodies, alternatives are needed due to high development and production costs, and issues with stability. Aptamers are an exciting alternative to antibodies. Aptamers are short sequences of single stranded DNA or RNA that bind molecular targets with high affinity and specificity. Aptamers are inexpensive to produce, are very stable, have long shelf lives, and could potentially replace antibodies in a number of applications. One potential application of aptamers is targeted drug delivery. The goal of targeted drug delivery is to selectively deliver a therapeutic payload to the site of action thereby increasing efficacy and decreasing side effects. Fractalkine is a cell surface protein expressed at sites of inflammation. It is expressed on several types of cancerous tissues and it is involved in the patheogenisis of arthritis, asthma, and atherosclerosis. This work describes the development and characterization of an aptamer that binds fractalkine with high affinity. The aptamer was modified with a hydrophobic tail, creating an aptamer-amphiphile, for use in a model drug delivery vesicle called a liposome. The aptamer-amphiphile was optimized for a high affinity interaction with fractalkine by adding a spacer molecule between the aptamer headgroup and the hydrophobic tail. The optimized amphiphile had high affinity for fractalkine and self-assembled into micelles and an interesting nanotape morphology. Finally, as a proof of concept, the optimized aptamer-amphiphile was incorporated into a liposome and targeted to fractalkine expressing cells. This work highlights the development of aptamers as affinity ligands, and demonstrates their use as potential drug delivery agents.
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    Self-Assembled Single Stranded DNA-Amphiphiles for Targeted Drug Delivery
    (2018-06) Harris, Michael
    The use of targeted drug delivery has significantly improved the field of medicine in the last 30 years. At the same time, the field of DNA nanotechnology has allowed for the design nanoparticles with exact nanoscale precision. This thesis combines the two fields by using single-stranded DNA amphiphiles, a novel class of biomaterials, to create new targeted drug delivery vehicles. DNA aptamers are a sub-class of single stranded DNA molecules whose three-dimensional structure allows them to bind to one molecule with high affinity. ssDNA-amphiphile micelles were created from a ssDNA aptamer sequence to create a targeted ssDNA micelle for cancer therapies. These targeted micelles were shown to internalize only to cells expressing the aptamer target and release into the cytosol over 24 h. In vivo studies showed that although tumor accumulation of ssDNA-amphiphile micelles is independent of their targeting capability, internalization of the micelles requires the aptamer sequence. DNA-amphiphiles have also been shown to form nanotubes when in aqueous solution, dependent on the exact DNA sequence and lipid tail structure used. One ssDNA-amphiphile that forms nanotubes was used for delivery to mouse glioblastoma cells. The nanotubes were shown to internalize to the glioblastoma cells, but not to healthy mouse astrocytes. When delivered directly to both hemispheres of the brains of mice with tumors in the right hemisphere, retention was observed only in the tumor hemisphere and not in the healthy hemisphere. This observation was conserved when the nanotubes were delivered systemically. The nanotubes were then used for an initial in vitro chemotherapy experiment. When mixed with the chemotherapeutic doxorubicin, the nanotubes released little chemotherapeutic over the course of two weeks, with no significant change in the nanotube structure over this time. When delivered to mouse glioblastoma cells, the doxorubicin – nanotube mixture showed better cell toxicity compared to free doxorubicin. This is a promising result for chemotherapeutic delivery of the nanotubes.