The folate receptor (FR) has emerged asan attractive target for selective delivery of folate coupled therapeuticagents. We describe the construction and assessment of a folate conjugatesynthesized using a monodisperse, FMOC protected PEG building block. The PEGspacer serves to ensure water solubility and optimal ligand-receptorinteraction. Assembly was achieved using FMOC solid phase synthesis to build afolate PEG cysteinyl construct, which was further reacted with pyridyldithioethyl carbonate camptothecin. The conjugatedemonstrated an IC50 value of approximately 6 nM in an FR+ KB cancer cell line,and its activity was blocked when assessed in the presence of a 1000 foldexcess of free folic acid. Moreover, the conjugate yielded a relative bindingaffinity and serum binding comparable to previously synthesized constructs withpeptide spacers. Together, these studies demonstrate the utility of newlyavailable, monodisperse, FMOC PEG building blocks for the synthesis of targetedtherapeutic agents.

Synthesis of a folate targeted camptothecin prodrug using a monodisperse PEG spacer

242nd National Meeting (2011)

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