Identification of a pH-Responsive Peptide–Paclitaxel Conjugate as a Novel Drug with Improved Therapeutic Potential

Abstract

A highly sensitive, nontoxic, hydrophilic cell-penetrating peptide (CPP = c[RGDKLAK]) was selected for the construction of an effective peptide-drug conjugate (PDC). A hydrophobic drug paclitaxel (PTX) was successfully conjugated with CPP via ester linkage with succinic acid (SA) as a pH-cleavable linker moiety. The characterization techniques employed in this study indicate the >95% purity of the resulting PDC (CPP-SA-PTX). The <i>in vitro</i> studies show that our proposed PDC exhibits enhanced stability (∼90%) and cytotoxicity (EC₅₀ = 8.32 ± 0.09 nM). Besides the excellent solubility of PDC in water, the PTX effect on positive β-tubulin-III indicates that the drug releases retained pharmacological properties. Additionally, <i>in vivo</i>, therapeutic-dose treatment reveals the prominent tumor-growth inhibitory effects (2.82-3.24-fold) of PDC in tumor mice models. Subsequently, these observations confirmed that our novel-designed PDC (CPP-SA-PTX) adduct may serve as a promising therapeutic agent to treat glioblastoma.