Reactive Oxygen Species Responsive Paclitaxel-PEG Nano-Prodrug for Treatment of Metastatic Breast Cancer

The clinical utility of paclitaxel (PTX) is constrained by its poor water solubility and systemic cytotoxicity. Prodrugs of PTX can markedly enhance solubility and reduce the cytotoxicity of the parent drug. However, their efficacy is often constrained by the linkage bond’s poor suitable cleavability. In this study, PTX was connected with PEG through a peroxyoxalate linkage bond, a responsive chemical bond of hydrogen peroxide (H 2 O 2 ). The obtained PTX prodrug polymer (PTX-PEG) can self-assemble into micelles with PTX acting as a hydrophobic core (PTX-PEG/MCs). Notably, the peroxyoxalate linkage bond employed in this study can facilitate the release of the parent drug upon stimulation by reactive oxygen species (ROS), resulting in the generation of carbon dioxide and water as the only byproducts. With the method of solvent evaporation, PTX-PEG/MCs were prepared, and their particle sizes, zeta potentials, appearance morphology, and in vitro stability were characterized. The results show that PTX-PEG/MCs have a particle size of 70.8 ± 1.5 nm and a spherical surface morphology. Also, in an environment of 5 μM H 2 O 2, PTX-PEG can perform responsive cleavages of peroxyoxalate bonds, producing carbon dioxide and water with no effect on the chemical structure of PTX. In vitro experiments show that PTX-PEG/MCs can be efficiently absorbed by tumor cells within 15 min of drug administration, effectively inhibiting the proliferation of 4T1 cells and promoting their apoptosis. In vivo distribution experiments show that fast passive-targeting accumulation of PTX-PEG/MCs can be achieved in mouse tumor tissues. Furthermore, in vivo antitumor experiments demonstrate the potential of PTX-PEG/MCs in inhibiting tumor growth and metastasis and their relatively high biosafety. These research results described above show that PTX-PEG/MCs present the characteristics of H 2 O 2 -responsive drug release, which provides a strategy for preparing responsive nanodelivery carriers in a ROS microenvironment of tumors.