Smart polymeric carriers :|targeted delivery of therapeutic agents

Abstract

In cancer research, studies about polymer drug conjugates and targeted delivery of chemotherapy agents are gaining great attention due to their ability to enhance biodistribution profiles and improve efficacy of chemotherapy agents. In the scope of this thesis four different polymer drug conjugates were synthesized using acrylate based carriers. In each case, drug molecules were covalently attached to the polymeric carrier through biodegradable linkers. These polymeric carriers aim to accumulate the active drug in the tumor via passive and active targeting. Each carrier, due its size, has the capacity to take advantage of enhanced permeation and retention (EPR) effect. Along with the size, active targeting via small molecule targeting units are also utilized. As such, in the first project, anti-angiogenic drug Combretastatin A4 (CA4) was conjugated to polymer backbone through a hydrolyzable ester linker. A second drug, alendronate (ALN) was also conjugated to the system as a bone targeting agent aiming to accumulate the conjugate in bone tissue. For the next three studies, anti-neoplastic agent Docetaxel (DTX) and 5-Fluorouracil (5-FU) derivatives were used as the active drug moiety. These constructs were ornamented further to accumulate in breast and ovarian tumors. In each case, different linkers were utilized in order to affect the release profile of the abovementioned drug molecules. In vitro studies were undertaken to demonstrate the effect of the active agents on a variety of the cell lines.