Advanced Mesoporous Particles for Colon-targeted Delivery: Insights into Enhanced Delivery of Proteolysis-targeting Chimeras

Abstract

Proteolysis-targeting Chimeras (PROTACs) are revolutionary molecules that induce target protein degradation and, therefore, are suited for intractable drug targets. However, they challenge traditional delivery methods for small molecules via the oral route due to their complex physiochemical properties. Delivery using mesoporous carriers emerge as an advanced strategy that could address PROTACs challenges and aid their delivery to target sites. The colon is one such site with promise for oral delivery of these molecules due to low degradative capacity and efflux compared to other regions. This thesis aims to engineer a novel mesoporous carrier to enhance the delivery of small and mid-sized molecules to the colon. The work investigated the effects of different atomisation nozzles and process parameters on physical properties of the novel carrier. This was followed by assessment of its ability to accommodate complex molecules like PROTACs and loading characterisation. Finally, colonic targeting of loaded carrier with different molecules was investigated. Optimising atomisation and spray drying parameters led to carrier particles which retained their porosity and solubility-enhancing function but acquired spherical, non-deflated morphology with uniform size distribution. The poorly soluble model PROTAC, MZ1, was loaded into the engineered carrier leading to significant dissolution enhancement. However, imaging techniques revealed the loaded drug was mainly located within the larger pores near the periphery of the carrier, possibly due to difficulty to diffuse deeper. The carrier was also tested for its targeted colonic release using a capping material incorporated within Felodipine-loaded and MZ1-loaded formulations, respectively. In vitro dissolution tests in simulated media demonstrated selective colonic release upon exposure to colonic enzymes. This work demonstrated the capability of mesoporous carriers to improve the dissolution profile and simultaneously deliver drugs, like PROTACs, into colonic environment where absorption could occur. The work paves the way for translation of challenging molecules into oral dosage forms.