Supramolecular PEGylation of Camptothecin for Cancer Therapy

ABSTRACT PEGylated drugs and their self-assembled nanoparticles have been used as a first-line technology in nanomedicines. However, premature disassembly before reaching the lesions under dilute conditions limits their bioavailability. This challenge can be overcome by covalent crosslinking. However, undefined molecular structures of the prodrugs are introduced, which hinder large-scale production and clinical translation. Herein, a supramolecular PEGylated camptothecin nanodrug with a crosslinked architecture and defined molecular drug structure was developed. PEGylated mono-tetraethylenepentamine β-cyclodextrin (mPEG-TEPA-CD) and adamantane modified camptothecin (AD-SS-CPT) were first synthesized. The host-guest coupling of β-cyclodextrin and adamantine moieties between mPEG-TEPA-CD and AD-SS-CPT induced the formation of supramolecular PEGylated camptothecin, which could self-assemble into micelles in the aqueous medium. They were further stabilized by the addition of a diacrylate crosslinker for reaction with the amine groups on mPEG-TEPA-CD, maintaining the unaltered AD-SS-CPT. The nanodrugs can internalize into tumor cells quickly and release free CPT in response to glutathione. They also have prolonged blood circulation time and can accumulate efficiently at tumor sites, thus showing effective anti-tumor activity. This supramolecular drug delivery system provides a new strategy for the design of nanodrugs.