Light activatable nanosystems for drug delivery
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Date
21/06/2023Item status
Restricted AccessEmbargo end date
21/06/2024Author
Shaw, Paige Amber
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Abstract
Polymers are showing great promise in advancing the field of “Smart Medicines”, the area on which this PhD thesis is focused. The contents of this thesis explore the versatility of light in combination with polymeric systems to achieve selective drug delivery in three ways: using light to monitor cell uptake, the release of drugs from a polymeric backbone, and drug release via nanoparticle cleavage.
The first project includes the modification of RAFT agents to enable the controlled synthesis of size-defined monodisperse polymers with defined end-groups. Here, modifications included fluorophores and lysine-based cell-penetrating peptides. The modified RAFT agents then allowed for the synthesis of polymer chains that were fluorescently “tagged” and demonstrated enhanced cell uptake due to the cell penetrating peptide attached. The polymers showed high biocompatibility and were found to be localised inside endosomes within cells. This work demonstrates the first use of RAFT agents modified with both a fluorophore and cell-penetrating peptide, which endows both a tracking ability and high cell uptake. It allowed for polymer uptake to be measured quantitatively using fluorescence to compare the cellular uptake abilities of three different length cell-penetrating peptides.
The second route explored within the PhD thesis was light-mediated drug release. Here two approaches were taken:
(i). Drug attachment along a polymeric backbone with drug release facilitated by
photo-cleavage. Here, the water insoluble chemotherapy agent camptothecin was conjugated to a coumarin methacrylate monomer via a light cleavable bond, rendering the camptothecin 'inactive'. The coumarin camptothecin monomer was then co-polymerised with the water soluble N,N-dimethyl acrylamide (DMA) to yield a water soluble, light cleavable, camptothecin containing polymer. The light sensitivity of the polymer under 365 nm light was validated in solution and in vitro. Biological testing showed high biocompatibility of the polymer under dark conditions, with the polymer showing high levels of toxicity following irradiation. This work demonstrates the versatility of polymers to be used for selective cell-killing, but also their ability to enhance the water solubility of typically ‘difficult to formulate’ chemotherapy drugs.
(ii). Integrating a light responsive coumarin
moiety containing two orthogonal
functional groups in between the two blocks of an amphiphilic block copolymer
comprised of polyethylene glycol (PEG) and poly-L-lactide (PLA). Such photocleavable amphiphilic polymers were used to form light-sensitive nanoparticles, with the ability to encapsulate drugs within their core. Here the chemotherapy drug doxorubicin was encapsulated and consequently liberated by illumination under 365 nm light. Nanoparticles were found to release over 60 % of encapsulated drug after only 2 minutes of light irradiation. In vitro results validated the novel strategy, showing high biocompatibility under dark conditions and selective toxicity upon irradiation.
In summary the developed polymer systems showed promise as drug delivery agents by demonstrating good biocompatibility, trackability, high cell uptake, improved drug solubility, controlled drug activation, and selective drug delivery.
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