Effect Of Peg Composition On The Dissociation Rate Of Camptothecin-Peg Conjugates

Abstract

Camptothecin (CPT) is an anti-cancer drug that inhibits the enzyme DNA Topoisomerase 1, leading to the apoptosis of cancerous cells. Although several analogs of CPT have been synthesized as chemotherapy agents, a number issues remain that hinder its success including lack of stability of the active form, poor solubility and limited circulation time. To overcome these challenges, conjugation of the CPT drug to polymers such as polyethylene glycol (PEG), has been shown to improve CPT solubility and circulation time, thus leading to an increase in drug bioavailabity. However there is still limited understanding of how the properties of the polymer influence the dissociation of the drug from the drug-polymer complex. In this study, PEG polymers of varying molecular weights (MW) and polydispersities were conjugated to CPT and characterized via 1H NMR and mass spectrometry (MS). The extent of CPT dissociation from the CPT-PEG conjugate was monitored via liquid chromatography over two days at a variety of temperatures and pH. The data acquired from these studies showed distinct molecular weight effects on CPT-PEG dissociation rates. In addition, we also observed an increase in the rate and extent of dissociation as a function of hydroxide ion concentration. Future areas of investigation will include performing the dissociation studies with additional PEGs of different MW to further confirm the observed MW dependency as well as using PEGs with different end groups to study possible end group effects. The results of this work should lay the foundation for developing controlled-release CPT-PEG conjugates for a wide variety of drug delivery applications.