Synthesis of polymer-bound small-molecule kinase inhibitors as anti-tumour agents

Taleli, Lebusetsa (2017-12)

Thesis (PhD)--Stellenbosch University, 2017.

Thesis

ENGLISH ABSTRACT: Inhibition of kinase activities using small molecules for the treatment of various diseases, including lung cancer, is one of the most pursued therapeutic targets. Molecularly targeted therapy aimed at the inhibition of specific protein kinase signalling activities, e.g. epidermal growth factor receptor (EGFR), has changed the treatment landscape of clinical oncology into personalised medicine. Today, lung cancer patients are stratified according to tumour genetic mutations and are further profiled into kinase inhibitor treatment options. The 4-anilinoquinazoline class of small molecules are EGFR kinase inhibitors, used for the treatment of adenocarcinoma NSCLC. Therapeutic challenges affecting the efficacy of these molecules include low bioavailability, off-target reactive toxicities, and acquired drug resistance. The core objective of this study was to investigate the formulation of 4-anilinoquinazoline small molecules into polymer-drug conjugates. These conjugates were intended for use in a micellar drug delivery mechanism using poly(N-vinylpyrrolidone) (PVP) and pHresponsive linker groups. The 4-anilinoquinazoline anti-tumour agents carrying Michael acceptor electrophiles (acrylamide and acrylates) were synthesised by assembling various quinazolin-4(3H)-one derivatives. The preparation of a PVP delivery carrier was achieved by means of triazole-based RAFT/MADIX polymerisation. The ɷ-end group transformation of PVP into a thiol functionality was realised by aminolysis and the polymer-drug conjugates were then developed by 1,4-conjugated Michael addition reaction. The conjugates were allowed to self-organise into characteristic micelles in aqueous solutions. Assessments of the drug release profiles under variable pH conditions showed that release is favoured in the acidic tumour microenvironment. Furthermore, the in vitro anti-tumour efficacy of the amide-linked conjugate was demonstrated to match the Gefitinib ATP-competitive EGFR kinase inhibitor against EGFR wild-type and EGFR L858R/T790M mutant. The overall anti-tumour efficacy suggests that the mode of EGFR kinase inhibition is a critical determinant of anti-tumour efficacy. Further developments related to the present formulation are however necessary to enhance bioactivities of the conjugates.

AFRIKAANSE OPSOMMING: Verskeie siektes, insluitend longkanker, word behandel deur die kinase-aktiwiteite te inhibeer met behulp van klein molekules en is daarom een van die mees gefokusde terapeutiese teikens. Molekulêr-geteikende terapie wat gefokus is op die inhibering van spesifieke proteïenkinase seinaktiwiteite, bv EGFR, het die manier waarop hierdie siektes behandel word verbeter. Pasiënte met longkanker word huidiglikglik geklassifiseer op grond van die genetiese mutasie van hul tumor en word verder gegroepeer in die behandeling wat beskikbaar is om die spesifieke kinase te inhibeer. 4-anilinoquinazoline is ‘n klas van klein molekules wat EGFR kinase inhibeer en word gebruik om adenokarsinoom nie-klein selkanker te behandel. Lae bio-beskikbaarheid, niegeteikende reaktiewe toksisiteite en die verworwe geneesmiddelweerstand is nog terpeutiese uitdagings wat die effektiwiteit van hierdie molekules beïnvloed. Die doel van hierdie studie was om die formulering van 4-anilinoquinazolin klein molekules in polimeer-dwelmkonjugate te ondersoek. Hierdie was bedoel vir 'n misellige geneesmiddelleweringsmeganisme wat PVP-polimeer en pH-sensitiewe verbindende groepe gebruik. Die 4-anilinoquinazoline anti-tumor middels wat die Michael-akseptor elektrofiele (akrielamied en akrelaat) vervoer, was gesintetiseer deur verskillende quinazolin-4 (3H)-oon derivate te verbind. Triasool-gebaseerde RAFT/MADIX-polimerisasie is gebruik om die PVP-vervoer draer te berei. Aminolise is verder gebruik om die ɷ-eindgroepe van PVP om te skakel na die terminale tiol groepe waarna die polimeer-dwelmkonjugate ontwikkel was deur middel van ‘n 1,4- gekonjugeerde Michael-addisie reaksie. Hierdie konjugate vorm kenmerkende miselle in waterige oplossings. Evaluering van die geneesmiddel-vrystelling-profiel onder verskillende pHkondisies demonstreer dat die tumor mikro-omgewing verkies ‘n suur omgewing. Verder het ons gedemonstreer dat die in vitro anti-tumor effektiwiteit van die amiedverbindende konjugate ooreenstem met die Gefitinib ATP kompeterende EGFR kinase inhibeerder teen EGFR wilde-tipe en EGFR L858R/T790M mutant. Die algehele antitumor effektiwiteit diu daarop dat die metode van EGFR kinase inhibisie ‘n bepalende faktor is in die anti-tumor effektiwiteit. Verdere ontwikkelings op die huidige formulering is egter nodig om die bioaktiwiteite van die konjugate te verbeter.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/102579
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