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Browsing by Subject "Targeted Drug Delivery"

Now showing 1 - 3 of 3
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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.
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    Targeted delivery of polymer vesicles functionalized with fibronectin mimetic peptides to cancer cells
    (2012-09) Pangburn, Todd Owen
    Polymersomes, polymeric vesicles that self-assemble in aqueous solutions from block copolymers, have been avidly investigated in recent years as potential drug delivery agents. In this work, the feasibility of chemical conjugation of fibronectin mimetic targeting peptides (GRGDSP and PR_b) onto the surface of polymersomes is investigated, and the efficacy of these peptide functionalized polymersomes to achieve targeted delivery to cancer cells is studied. The diblock copolymer poly(ethylene oxide)-b-poly(1,2-butadiene) was synthesized and self-assembled to form polymersomes, which were subsequently functionalized with peptides using a ―click‖ conjugation reaction. Delivery efficacy of these peptide functionalized polymersomes loaded with fluorescent iii Abstract Polymersomes, polymeric vesicles that self-assemble in aqueous solutions from block copolymers, have been avidly investigated in recent years as potential drug delivery agents. In this work, the feasibility of chemical conjugation of fibronectin mimetic targeting peptides (GRGDSP and PR_b) onto the surface of polymersomes is investigated, and the efficacy of these peptide functionalized polymersomes to achieve targeted delivery to cancer cells is studied. The diblock copolymer poly(ethylene oxide)-b-poly(1,2-butadiene) was synthesized and self-assembled to form polymersomes, which were subsequently functionalized with peptides using a ―click‖ conjugation reaction. Delivery efficacy of these peptide functionalized polymersomes loaded with fluorescent markers, a chemotherapeutic (doxorubicin), or siRNA was assessed and compared. Both the efficacy and the process of delivery and internalization of peptide functionalized polymersomes were investigated for colon and breast cancer cells. PR_b functionalized polymersomes were found in all cases to significantly outperform both GRGDSP and non-functionalized polymersomes, in terms of promoting cell binding, internalization, specificity, and effective delivery. This work highlights peptide functionalized polymersomes in general, and PR_b functionalized polymersomes in specific, as a highly promising targeted delivery system.
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    Targeted drug delivery and enhanced intracellular release using functionalized liposomes.
    (2009-12) Garg, Ashish
    The ability to target cancer cells using an appropriate drug delivery system can significantly reduce the associated side effects from cancer therapies and can help in improving the overall quality of life, post cancer survival. Integrin a5b1 is expressed on several types of cancer cells, including colon cancer and plays an important role in tumor growth and metastasis. Thus, the ability to target the integrin a5b1 using an appropriate drug delivery nano-vector can significantly help in inhibiting tumor growth and reducing tumor metastasis. The work in this thesis focuses on designing and optimizing, functionalized stealth liposomes (liposomes covered with polyethylene glycol (PEG)) that specifically target the integrin a5b1. The PEG provides a steric barrier allowing the liposomes to circulate in the blood for longer duration and the functionalizing moiety, PR_b peptide specifically recognizes and binds to integrin a5b1 expressing cells. The work demonstrates that by optimizing the amount of PEG and PR_b on the liposomal interface, nano-vectors can be engineered that bind to CT26.WT colon cancer cells in a specific manner and internalize through a5b1-mediated endocytosis. To further improve the efficacy of the system, PR_b functionalized pH-sensitive stealth liposomes that exhibit triggered release under mild acidic conditions present in endocytotic vesicles were designed. The study showed that PR_b functionalized pH-sensitive stealth liposomes, undergo destabilization under mildly acidic conditions and incorporation of the PR_b peptide does not significantly affect the pH-sensitivity of the liposomes. PR_b functionalized pH-sensitive stealth liposomes bind to CT26.WT colon carcinoma cells that express integrin a5b1, undergo cellular internalization, and release their load intracellularly in a short period of time as compared to other formulations. PR_b-targeted pH-sensitive stealth liposomes encapsulating 5-fluorouracil (5-FU) show significantly higher cytotoxicity than the PR_b-targeted inert stealth liposomes and the non-targeted stealth liposomes (both pH-sensitive and inert). The studies demonstrated that optimized PR_b functionalized pH sensitive liposomes have the potential to deliver a payload, such as chemotherapeutic agents, directly to colon cancer cells in an efficient and specific manner.