Drug conjugates and polymeric micelles for targeted delivery of kinase inhibitors

Abstract

A variety of diseases is associated with dysregulation of kinase signaling pathways and kinase inhibitors are hence being considered as potent drugs for the treatment of cancer and inherited diseases such as polycystic kidney disease. Although kinase inhibitors are considered as quite specific drugs that are molecularly targeted, side effects significantly limit their therapeutic applications. Moreover, their specific action also infers that the efficacy of kinase inhibitors is limited by drug resistance. In this thesis, we have explored the development of drug delivery systems such as small molecule-drug conjugates (SMDCs) and polymeric micelles for kinase inhibitors, which eventually can be used to overcome these problems. An SMDC typically is composed of a targeting ligand, a drug payload and a spacer which infers a cleavable linkage with the drug (see Figure 3, Chapter 1). SMDCs have attracted tremendous interest in the pharmaceutical field because they have several advantageous features. Firstly, the small size (as can be deduced from their low molecular weight) of SMDCs enables them to accumulate and penetrate in solid tumors very efficiently. Secondly, the synthesis strategy of SMDCs is versatile and controllable. Polymeric micelles are colloidal nanoparticles with a diameter size around 10 - 200 nm and have a core-shell structure that is formed by self-assembling of amphiphilic block copolymers in aqueous media. The hydrophilic block of the copolymers forms the shell of polymeric micelles to ensure their colloidal stability while the hydrophobic block forms the core of polymeric micelles. Hydrophobic drugs can be loaded in the core by physical entrapment or -preferably, in view of stable drug retention- by chemical crosslinking to the core. The physicochemical properties of polymeric micelles can be controlled by adjusting the components of polymers and drugs. The relatively small size of polymeric micelles -although much larger than SMDCs- enables them to passively accumulate and subsequently penetrate into tumours via the enhanced permeability and retention (EPR) effect. The loaded drug can subsequently be released in the tumor microenvironment. In addition to passive targeting, the surface of polymeric micelles can be decorated with targeting ligands which can facilitate active receptor mediated uptake by cancer cells. This thesis is focused on the development of novel SMDCs and polymeric micelles exploiting platinum coordination chemistry for conjugation of the drug to the delivery system. As discussed below, we have explored and optimized the reaction conditions to form drug conjugates and drug loaded micelles primarily with the kinase inhibitor dactolisib, which is a potent inhibitor of signaling pathways involved in cancer and polycystic kidney disease. In conclusion, small molecule-drug conjugates and polymeric micelles exploiting platinum coordination chemistry described in this thesis can target deliver kinase inhibitors to the diseased cells and, potentially, exert cellular kinase inhibitory effect. The promising results from this thesis encourage the further application of these novel drug delivery systems for preclinical and clinical studies.