Identification of a pH-Responsive Peptide–Paclitaxel Conjugate as a Novel Drug with Improved Therapeutic Potential
Syed Faheem Askari Rizvi, Nadir Abbas, Haixia Zhang, Quan Fang
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 in vitro studies show that our proposed PDC exhibits enhanced stability (∼90%) and cytotoxicity (EC 50 = 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.