Drug-Loaded Star-Shaped pH-Responsive Monomolecular Copolymer Nanocarriers for Tumor Targeting and Cancer Therapy

Tumor targeting and controlled drug release at the target are the key problems for cancer pharmacotherapy. A simply structured pH-responsive nanocarrier was prepared to achieve the above aims in this study. A four-armed star copolymer, tetra-(methoxy-poly(ethylene glycol)-poly(2-(N,N-diethylamino)ethyl methacrylate)-poly(ε-caprolactone) pentaerythritol ((mPEG-pDEA-PCL)₄-PET, PDCP), was synthesized via the ring-opening polymerization, atom transfer radical polymerization and click chemistry, which formed a monomolecular nanocarrier in water. Its size and zeta potential were strongly pH-dependent from 71 nm and 2.1 mV at pH 8 to 127.5 nm and 25.4 mV at pH 5. The morphological change of pDEA chains was the basic reason. The chains were protonated at lower pH so as to freely extend to the aqueous media, though they were hydrophobic at higher pH to coat on the surface of hydrophobic cores. The star-shaped PDCP had a large hydrophobic core to load hydrophobic drugs (e.g., paclitaxel). High effective drug entrapment in the blood circulation and rapid drug release at the tumor tissues was achieved in PDCP due to its pH-responsive function. The MCF-7 cytotoxicity of the paclitaxel-loaded PDCP nanocarriers at pH 6.5 was similar to free paclitaxel. And the PDCP nanocarriers were well internalized by the MCF-7 cells according to the flow cytometry and laser confocal microscopy. The paclitaxel-loaded PDCP nanocarriers showed the comparable in vivo anticancer effect to the paclitaxel solution (Taxol) although the former's toxicity was much lower than the latter. The star-shaped pH-responsive monomolecular PDCP nanocarriers are suitable to deliver hydrophobic anticancer drugs for cancer therapy with tumor targeting and controlled drug release.