Tailoring Renal Clearable Zwitterionic Cyclodextrin for Colorectal Cancer-Selective Drug Delivery

Abstract

Abstract Although cyclodextrin (CD)-based renal-clearable nanocarriers have a high potential for clinical translation in targeted cancer therapy, their optimal designs for enhanced tumor retention and reduced off-target accumulation have rarely been proposed. Herein, we present a delicately tailored structure of a renal-clearable zwitterionic CD, hepatkis-(6-deoxy-6-((phenylboronic acid-tetraethyleneglycol-l-glutamic acid Nα-sulfobetaine)-octaethyleneglycol-caproamide))-β-cyclodextrin (PBA-(ZW)-CD), for colorectal cancer (CRC)-selective drug delivery. Twenty CD derivatives with different charged moieties and spacers are synthesized and screened for colloidal stability. The resulting five candidates are complexed with adamantyl sulfocyanine 7 and evaluated for biodistribution. PBA-(ZW)-CD, the optimized structure, displays a high tumor-to-background ratio of 3.7–4.1. PBA-(ZW)-CD inclusion complexes of doxorubicin and ulixertinib are fabricated, and their enhanced tumor accumulation (vs. free doxorubicin, 2.0-folds; vs. free ulixertinib, 2.1-folds), facilitated elimination (vs. free doxorubicin, 15.2 and 0.0% remaining in the heart and muscles, respectively; vs. free ulixertinib, 17.7 and 7.4% in the liver and kidneys, respectively), and tumor penetration comparable to those of free drugs are verified via mass-spectrometric quantitation and imaging. The improved antitumor efficacy of PBA-(ZW)-CD/drug combination therapy is demonstrated in heterotopic and orthotopic CRC models (vs. free drug combination, tumor size reduction by 52.0 and 76.2%, respectively), suggesting that PBA-(ZW)-CD can be used as a promising CRC-targeted nanoplatform.