Introduction: In the past decades, polymer therapeutics have emerged as a promising technology in the area of drug design and delivery. In this work, we synthesized and characterized polymer-drug conjugates consisting of... [ view full abstract ]
Introduction: In the past decades, polymer therapeutics have emerged as a promising technology in the area of drug design and delivery. In this work, we synthesized and characterized polymer-drug conjugates consisting of dendritic polyglycerol (dPG) as carrier, either sulfated or non-sulfated, and the highly potent drug monomethyl auristatin E (MMAE). Dendritic polyglycerols are based on a spherical polyether polyol scaffold with many hydroxy groups on the surface that results in good water solubility. Furthermore, they are known to be highly biocompatible and therefore studied extensively for biomedical applications. It was demonstrated recently that sulfation leads to polyanionic derivatives which exhibit high binding affinities to positively charged protein motifs resulting in strong anti-inflammatory properties due to interaction with P- and L-selectin in particular. In connection with these findings we currently study the utility for tumor targeting. Monomethyl auristatin E is a highly potent antiproliferative drug, which hitherto is only known from receptor-mediated antibody-drug conjugates, while polymer-MMAE conjugates have not been reported so far. Therefore, we suggest that by coupling MMAE to dendritic polyglycerol using a similar linker strategy, we obtain potent polymer-drug conjugates which can be used even more generally against several tumor cell lines.
Methods: We determined drug-to-polymer ratios by HPLC and examined the conjugates’ cell viability by cell proliferation cytotoxicity assay. In addition, after dye labeling, we performed cellular uptake studies using confocal microscopy and flow cytometry.
Results: We successfully synthesized sulfated and non-sulfated dendritic polyglycerol monomethyl auristatin E conjugates using a self-immolative disulfide linker (dPG-SS-MMAE and dPGS-SS-MMAE) which has already been used in a similar manner for reductively cleavable antibody-auristatin conjugates. Accordingly, our polymer-drug conjugates should be cleaved in tumor cells and release the drug.
Discussion: Our results show that the non-sulfated conjugates are less taken up by cells, hence are less toxic in comparison to the sulfated conjugates, which are cytotoxic with nanomolar efficacy.
