Synthesis, Characterization And Biological Evaluation Of Low Molecular Weight Poly(Ethylene Glycol)-Paclitaxel Prodrugs

Paclitaxel (PTX) is an antitumor drug extensively used against a variety of human cancers including ovarian, breast, non-small cell lung tumors, etc. However, its clinical use is significantly limited because of its low aqueous solubility. The currently used clinical form of paclitaxel (Taxol(?)), is dissolved in a mixture of Cremophor EL (poly-oxyethylated caster oil) and ethanol (1:1, v/v) injection. However, Cremophor EL has been associated with a number of serious side effects and could result in hypersensitivity reactions. To overcome these problems, many efforts have been put to look for a safe drug delivery system with a high PTX solubility and favorable antitumor activity.Chemically conjugated PEG-PTX prodrugs have been studied extensively and many progresses have been achieved during the passed few years. This type of prodrugs have a number of advantages, such as stable chemical structure, easy preparation of nanopaticles, relatively high drug loading and reduced side effects. However, most of the reported PEG-PTX prodrugs use high molecular weight PEG, which has led to significantly low PTX loading and may possibly decrease the therapeutic effect. In this project, aiming to develop a promising PEG-PTX prodrug with improved solubility and increased drug loading, we synthesized four different PEG-PTX prodrugs modified by light PEG, and evaluated their physical, chemical and biological characters with a series of assays.In this study, we firstly synthesized PEG550-PTX and PEG1900-PTX by conjugating light PEG to the2’-OH of PTX. Interestingly, we found that PEG molecular weight needs to reach certain value so that the conjugated prodrug could self-assemble into nanoparticles. Moreover, these directly conjugated prodrugs could significantly improve PTX’s solubility and drug loading. However, they might be quickly cleared from the blood and be difficult to accumulate in tumor tissue, because they easely released free PTX in physiological conditions (pH7.4) while the release process was quite slow in acid environment. In order to overcome the above drawback of quick release of free PTX from directly conjugated PTX prodrug, we further synthesized PEG1900-SA-PTX and PEG1900-EBMB-PTX by spacers between light PEG and PTX. Our data indicated that different spacers significantly affected the biological properties of prodrugs. For example, PEG1900-SA-PTX with succinic acid as spacer could not improve PTX’ pharmacokinetic characters. However, PEG1900-EBMB-PTX with4-methyl bromide benzoic acid ethyl ester as spacer released free PTX slowly in pH7.4, which might contribute to its longer blood circulation time. Further biodistribution study indicated that much more PEG1900-EBMB-PTX was accumulated in tumor tissue in comparison with free PTX while much less of this prodrug was taken by endothelial devour system. Therefore, PEG1900-EBMB-PTX may have promising in vivo anti-tumor activity, and deserves further investigation.