Design, Synthesis And Application Of Highly Branched And Functionalized Peptidic Monodisperse Polyethylene Glycols

Modification of drugs or drug candidates with biomaterials is a widely used method to improve their druggability and therapeutic effecacy.Polyethylene glycols(PEGs)are the most used biomaterials and their ‘‘stealthy'' effect has become the ‘‘gold standard''.However,regular PEGs even with an excellent polydispersity index(PDI)are still complex mixtures of different length oligomers which brings a range of problems during PEGylation,purification,characterization,quality control and regulatory approval,etc.To address the heterogeneity issue of PEGs,we have developed several methods for the synthesis of monodisperse PEGs(M-PEGs).Based on these methods,we developed a convenient strategy for highly branched and functionalized peptidic monodisperse polyethylene glycol,then explored their unique properties and the application as drug carriers:1.We have developed a cyclic sulfate-based strategy for the convenient synthesis of branched M-PEG AAs on a gram-scale and applied them for the synthesis of highly branched peptidic M-PEG ‘‘brushes' '.Through Fmoc-based solid phase peptide synthesis(SPPS),these branched M-PEG AAs could be conveniently assembled into a series of highly branched peptidic M-PEGs.2.To provide the M-PEGs with multiple amino,carboxylic,indolyl,and phenyl groups for drug conjugation,derivatization,and self-assembly,etc.,L-lysine,L-glutamic acid,L-tryptophan,and L-phenylalanine were incorporated in a programable fashion.Their biocompatibility and physicochemical properties were then investigated.It was found that highly branched peptidic M-PEG ‘‘brushes' ' showed high biocompatibility,fine-tunable lipophilicity,improved thermostability and plasma stability.3.The application of peptidic M-PEG as drug carrier was explored.L-cysteines were incorporated into peptidic M-PEG,and the antitumor drugs doxorubicin or paclitaxel was then conjugated to the peptidic M-PEG through a suitable linker in a prodrug way.4.Azides can not only be converted to primary amines but also symmetrical secondary amines through the catalytic hydrogenation.We employed this method for the convenient synthesis of branched M-PEGs.To improve the selectivity of the reaction,we investigated the reduction of mono-azide M-PEG under different conditions.It shows that the reductive dimerization is preferred over normal reduction process under the catalysis of Pd/C(0.2 eq)at room temperature,and employing methanol as the reaction solvent.