| Description |
Colorectal cancer (CRC) is one of the most lethal malignancies, ranking second to lung cancer in males and breasts cancer in females. Its death rate has not significantly changed over the past 20 years in spite of surgical procedures that have vastly improved in the same period. This is likely due to the late stage at which CRC is diagnosed, and the intrinsically high, nonspecific toxicity that conventional chemotherapeutic treatments suffer from. Novel drug delivery strategies can be implemented to reduce the nonspecific toxicities of conventional chemotherapeutics. In such a strategy, a two-pronged approach to deliver therapeutic agents both locally and systemically may lead to a shift in the paradigm on the current treatment of CRC. For the first approach, a colon-specific drug delivery system based on biodegradable hydrogels and novel linear polymeric carriers was designed. The second approach exploits the benefits of systemic delivery by utilizing a targeted polymeric carrier. For colon-specific drug delivery, interpenetrating network (IPN) hydrogels composed of pH-sensitive, aromatic azo group-containing hydrogels as one of its components, and a hydrolyzable network as the other were synthesized. The properties of IPNs were investigated with the aim of identification of structures suitable as colon- specific drug delivery systems. The swelling kinetics for hydrogels with different compositions were determined at conditions mimicking the gastrointestinal tract. Also, iv physical properties of degradability and the modulus of elasticity in compression were used to characterize the properties of the IPN hydrogels. In the second study, three derivatives of the cyclic constrained nonapeptide specific to CRC, namely YW-KPIEDRPME (RPM1), methacryloylglycylglycine-6- aminohexanoyl-8-amino-3,6-dioxaoctanoyl-8-amino-3,6-dioxaoctanoyl-8-amino-3,6- dioxaoctanoyl-YW-KPIEDRPME (RPM2), and K(fluorescein)-KPIEDRPME (RPM3), were synthesized. RPM1 and RPM2 were incorporated into the water-soluble N-(2- hydroxypropyl)methacrylamide (HPMA) copolymer. For the final study, two novel, linear polymeric systems were designed, one for systemic and the other for local delivery. The former system was a carrier composed of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, 9-aminocamptothecin (9-AC), and biorecognizable cyclic nonapeptide. In the latter system, a copolymer of HPMA and 9-aminocamptothecin bound via an aromatic azo bond and a self-elimination spacer was synthesized. Therapeutic efficiency of a systemic versus local approach was evaluated in vivo using a noninvasive orthotopic tumor model. |
