Godwin, Antony Robert; (2001) The synthesis and conjugation chemistry of polymeric precursors for medicine. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis is concerned with the development of physiologically soluble polymers for drug conjugation. As for any medicine, there is a need for polymer-drug conjugates to be structurally defined especially in terms of molecular weight (MW) and molecular weight distribution (MWD). To develop polymeric precursors for the synthesis of polymer-drug conjugates possessing better optimised MW profiles and expedient conjugation chemistry, a first strategy involved the preparation of novel A,0-acetal protected N-(2-hydroxypropyl)methacrylamide (HPMA) monomers for anionic polymerisation. However, these monomers exhibited poor stability and anionic polymerisation was not achieved (other uses for these monomers are described based on free radical polymerisation). A second more versatile strategy was adopted that utilised Atom Transfer Radical Polymerisation procedures to prepare a narrow MWD active ester homopolymer (Mw/Mn = 1.1 to 1.3,= 2,000 to 50,000 g-mol-1), and believed to be the first such example. Using the known active ester monomer, N-methacryloxysuccinimide, the reaction conditions had to be carefully controlled to ensure a successful polymerisation. The conjugation chemistry (aminolysis) of the homopolymer was systematically evaluated and could be monitored using infra-red spectroscopy. The utility of this strategy was exemplified by the preparation of (1) model copolymer- drug conjugates with tailored drug loading and solubilising pendent chains and (2) methacrylic acid (co)polymers with incremental differences in structure for a cytokine and chemokine release study. A propensity for competitive hydrolysis and imide formation during conjugation was identified and experimental conditions were found to minimise/eliminate this problem. It was concluded that such a narrow MWD active ester homopolymer has improved versatility over current precursors for the preclinical preparation and development of methacrylamide based polymer-drug conjugates and other methacrylamide speciality polymers for medicine.

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