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

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 in vitro 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, in vivo, 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.