Multicompartmental Carriers for Medical Applications.

Abstract

Targeted particulate carrier based therapies have the potential to vastly improve current treatment modalities in medicine by concentrating a therapeutic at its desired target, and lowering its distribution in other locations, effectively increasing its therapeutic index. However, particulate carriers have yet to realize this potential, in part due to barriers resulting from their interactions with physiological processes. In this dissertation, multicompartmental carriers comprised of multiple materials, allowing for multiple functionalities within a single carrier, are manufactured by electrohydrodynamic (EHD) co-jetting. A number of carriers systems fabricated by EHD co-jetting are developed, and their potential therapeutic applications are demonstrated. In particular, endosome-sensing carriers are developed for cytosolic delivery, using existing commercially available pH-sensitive polymers, polyethyleneimine (PEI) and glycol chitosan (GC), as well as novel polymers, based on dextran and ascorbic acid. Gene silencing is achieved by delivery of siRNA to GFP expressing MDA-MB-231 cells using both PEI and GC based carriers. Additionally, we show that the PEI based carriers can be surface immobilized with AMD3100 by incorporation of a functionalized polylactide. Such carriers demonstrate binding affinity to triple negative breast cancers in vitro, and we demonstrate increased silencing efficacy from AMD3100 immobilized, siRNA-loaded carriers. In addition to carriers with targeting to specific cancers, virus-mimicking particles are fabricated that can selectively bind to cell membranes. It is also shown how EHD co-jetted carriers may be selectively surface modified with poly(ethylene glycol) (PEG) and CD47 to avoid uptake by Raw264.7 cells. Finally, GC based carriers capable of both siRNA delivery and live imaging are developed and their behaviors in vivo are explored.