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Localised On-Demand Delivery of Nucleic Acid Therapeutics

thesis
posted on 11.03.2022, 16:01 by Catherine SirafimCatherine Sirafim

The body naturally orchestrates response to injuries by producing a variety of bioactive cues at precisely coordinated times. However, when this response is hindered –as it is in many diseased states –this results in a lack of healing. Localised on-demand delivery of therapeutic cues that mimic natural signalling profiles can help overcome this and can be achieved by encapsulation of therapeutics in ultrasound-responsive biomaterials. Moreover, housing this delivery system within a regenerative template can further enhance efficacy. This thesis demonstrates the development of a pocketed collagen-based scaffold for the on-demand release of therapeutic nucleic acid-based nanoparticles from alginate hydrogels by application of ultrasound. As multiple therapeutics can be sequentially delivered, this platform can be adapted for applications requiring multi-stage treatments such as osteosarcoma, breast cancer bone metastasis and diabetic foot ulcers. PEI-pdna nanoparticles (for regeneration) and DNA origami nanostructures (cancer treatment), were encapsulated in ionically crosslinked hydrogels and released on-demand with ultrasound (Chapter 2). A mathematical model was developed to simulate the release of PEI-pdnananoparticles, DNA origami nanostructures and mitoxantrone (chemotherapeutic) from alginate hydrogels (Chapter 3), and it was employed to evaluate processes governing drug/hydrogel mass transport and to simulate various ultrasound regimens. Ultrasound-released DNA origami nanostructures, functionalized with doxorubicin, exhibited a therapeutic effect against breast cancer cells (Chapter 4), while the nanostructures remained structurally stable in cell culture media for 4 days. PEI-pdna ultrasound-released nanoparticles remained bioactive and transfected cells; however, protein levels were very low (Chapter 5). Investigations into the effects of the hydrogels on the polyplexes revealed de-stabilization of the PEI-pdna nanoparticles. In Chapter 6, on-demand release of Horse nanostructures from injectable alginate hydrogels embedded in pocketed scaffolds was achieved, and released structures maintained their bioactivity. This work demonstrated the development of a regenerative platform capable of releasing bioactive therapeutic nanoparticles on-demand by application of ultrasound.

Funding

RCSI StAR

History

First Supervisor

Dr. Cathal Kearney

Second Supervisor

Dr. Niamh Connolly

Third Supervisor

Prof. Fergal J. O'Brien

Fourth Supervisor

Dr. Caroline Curtin

Comments

Submitted for the Award of Doctor of Philosophy to the Royal College of Surgeons in Ireland, 2021.

Published Citation

Sirafim C. Localised On-Demand Delivery of Nucleic Acid Therapeutics [PhD Thesis] Dublin: Royal College of Surgeons in Ireland; 2021

Degree Name

Doctor of Philosophy (PhD)

Date of award

31/05/2021

Programme

  • Doctor of Philosophy (PhD)

Research Area

  • Biomaterials and Regenerative Medicine