Preparation and In Vitro Validation of a Cucurbit[7]uril-Peptide Conjugate Targeting the LDL Receptor

Here we report the coupling of a cyclic peptide (VH4127)targetingthe low density lipoprotein (LDL) receptor (LDLR) noncompetitively to cucurbit[7]uril (CB[7]) to develop a new kind of drug deliverysystem (DDS), namely, CB[7]-VH4127, with maintained binding affinityto the LDLR. To evaluate the uptake potential of this bismacrocycliccompound, another conjugate was prepared comprising a high-affinitygroup for CB[7] (adamantyl(Ada)-amine) coupled to the fluorescenttracker Alexa680 (A680). The resulting A680-Ada & BULL;CB[7]-VH4127supramolecular complex demonstrated conserved LDLR-binding potentialand improved LDLR-mediated endocytosis and intracellular accumulationpotential in LDLR-expressing cells. The combination of two technologies,namely, monofunctionalized CB[7] and the VH4127 LDLR-targeting peptide,opens new avenues in terms of targeting and intracellular deliveryto LDLR-expressing tissues or tumors. The versatile transport capacityof CB[7], known to bind a large spectrum of bioactive or functionalcompounds, makes this new DDS suitable for a wide range of therapeuticor imaging applications.

Automated summary

In this study, a cyclic peptide (VH4127) targeting the LDL receptor (LDLR) was noncompetitively coupled to cucurbit[7]uril (CB[7] ) to develop a new drug delivery system (DDS) named CB[7]-VH4127, which maintained its binding affinity to LDLR. The resulting supramolecular complex A680-Ada & BULL;CB[7]-VH4127 demonstrated conserved LDLR-binding potential and improved LDLR-mediated endocytosis and intracellular accumulation in LDLR-expressing cells. This new DDS opens up new possibilities for targeting and intracellular delivery to LDLR-expressing tissues or tumors.