Browsing by Author "Ilchev, Alexander"

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    Amine end-functional poly(N-vinylpyrrolidone) as amMacroinitiator for L-lysine N-carboxyanhydride polymerization - towards the preparation of pH-responsive micelles for drug delivery
    (Stellenbosch : Stellenbosch University, 2015-03) Ilchev, Alexander; Klumperman, Bert; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: Cancer is a notorious affliction that knows no age, gender, ethnic, racial, or species bounds and is responsible for over 14% of annual worldwide human deaths. There is no universal cure and the treatments that exist have poor probabilities of success. Chemotherapy is often considered the staple for cancer treatment as it can enter areas of the body that are unsafe for surgery and can treat tumors that are too small to be detected, even with modern imaging techniques. However, chemotherapy can induce many harmful and fatal side-effects. It can also lose its therapeutic effect if the cancer mutates to become multi-drug resistant. These shortcomings can be linked to the poor selectivity and pharmacokinetics of conventional chemotherapy drugs. Modern research focusses on improving these aspects of existing chemotherapy regimens through the incorporation of drug delivery principles. This dissertation focusses on the development of a novel, polymeric, pHresponsive drug delivery system for chemotherapy that incorporates the chemotherapeutic drug as well as a cell-penetrating peptide in a prodrug formulation. The system was designed to inhibit the release of its components into healthy tissues while selectively accumulating, through the enhanced permeability and retention effect, and releasing its payload, through reversible hydrolysis of imine bonds, within tumor tissues. Poly(L-lysine) was chosen as the cell-penetrating peptide since it is able to form imine bonds through its ε-amine functional groups on its residues. It was prepared by the primary amine-initiated ring-opening polymerization of Nε-(benzyloxycarbonyl)-L-lysine Ncarboxyanhydride at 0 °C and pressures lower than 1 mbar as these conditions allow for a controlled, living polymerization to occur. The benzyloxycarbonyl end-group was removed by acidolysis with HBr in a mixture of dichloromethane and 1,4-dioxane at 0 °C. The initiator used for the ring-opening polymerization was poly(N-vinylpyrrolidone) with a primary amine end-group, prepared by RAFT-mediated polymerization with O-ethyl-S-(phthalimidylmethyl)xanthate. This RAFT agent was shown to display slow pre-equilibrium kinetics which was linked to the lower relative stability of the phthalimidylmethyl radical compared to the poly(N-vinylpyrrolidone) propagating radical. The pre-equilibrium and main equilibrium kinetics of the RAFT polymerization were optimized by performing the polymerization in semi-batch mode. During the semi-batch polymerization, the monomer to RAFT agent ratio could be controlled by adjusting the monomer feed. This ratio was shown to be inversely proportional to the probability of radical transfer from the propagating radical to the phthalimidylmethyl radical. The phthalimide end-group could be converted to a primary amine both by reacting with hydrazine in methanol as well as reduction with sodium borohydride in water followed by hydrolysis in 1 M HCl at 60 °C. Doxorubicin and benzaldehyde could be conjugated, via imine bonds, to the poly(N-vinylpyrrolidone-block-L-lysine) copolymer spontaneously in methanol. Both types of conjugates would self-assemble into micelles when dispersed in water. However, the Doxorubicin conjugates were unstable, precipitating out of solution within 24 hours. The benzaldehyde conjugates were stable in water for over 24 hours. This suggested that a formulation of Doxorubicin and benzaldehyde conjugated to the block copolymer may be sufficiently stable under the physiological conditions of blood plasma.