Design, synthesis, and analysis of crosslinked polymeric nanoparticles for drug delivery applications
File(s)
Author(s)
Blagojevic, Luka
Type
Thesis
Abstract
Polymeric nanoparticles are versatile carriers of a range of therapeutic entities and enable the controlled release of these therapies in an increasingly specific spatiotemporal manner. The miniaturisation of clinically advanced degradable polymers such as poly(lactic-co-glycolic) acid allowed the establishment of polyester nanoparticles as highly biocompatible golden standards for biomedical applications. Comparatively, synthetic chemistry approaches allow access to crosslinked polymeric nanoparticles via the chemical manipulation of small polymerisable molecules and in doing so, offer the prospect of precise control over drug encapsulation and drug release properties.
The research described in this thesis concerns the synthesis of novel crosslinked polymeric nanoparticles via the radical polymerisation of structurally well-defined building blocks designed around the chemistry of degradable chemical motifs. Firstly, a library of polymerisable oligoesters inspired by sequenced poly(lactic-co-glycolic acid) was successfully prepared by stepwise synthesis. Secondly, these polymerisable oligoesters were reacted to form crosslinked polymeric nanoparticles via an unprecedented methodology that enables radical polymerisation and nanoparticle formation processes to occur simultaneously in one pot. Thirdly, the encapsulation of the small-molecule drug dexamethasone was achieved within these novel nanoparticles via a single-step procedure, generating drug-loaded NPs which were found to be stable in the presence of proteins, can be stored as aqueous suspensions at room temperature, and are able to release a fraction of the encapsulated drug in vitro. Finally, a disulphide-containing monomer inspired by the chemistry of polymerisable oligoesters is synthesised and reacted to form nanoparticles which are responsive to the presence of glutathione, setting the foundations for the further advancement of the platform towards stimuli-responsive drug delivery systems.
The research described in this thesis concerns the synthesis of novel crosslinked polymeric nanoparticles via the radical polymerisation of structurally well-defined building blocks designed around the chemistry of degradable chemical motifs. Firstly, a library of polymerisable oligoesters inspired by sequenced poly(lactic-co-glycolic acid) was successfully prepared by stepwise synthesis. Secondly, these polymerisable oligoesters were reacted to form crosslinked polymeric nanoparticles via an unprecedented methodology that enables radical polymerisation and nanoparticle formation processes to occur simultaneously in one pot. Thirdly, the encapsulation of the small-molecule drug dexamethasone was achieved within these novel nanoparticles via a single-step procedure, generating drug-loaded NPs which were found to be stable in the presence of proteins, can be stored as aqueous suspensions at room temperature, and are able to release a fraction of the encapsulated drug in vitro. Finally, a disulphide-containing monomer inspired by the chemistry of polymerisable oligoesters is synthesised and reacted to form nanoparticles which are responsive to the presence of glutathione, setting the foundations for the further advancement of the platform towards stimuli-responsive drug delivery systems.
Version
Open Access
Date Issued
2023-10-10
Date Awarded
01/11/2023
License URL
Advisor
Kamaly, Nazila
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)