A polycaprolactone-based nanocarrier containing thioketal linkers and charge conversion capabilities for doxorubicin delivery

Abstract

Reactive oxygen species (ROS) are found in higher concentrations near cancerous and inflammatory cells, making ROS-responsive nanocarriers a promising avenue for cancer drug delivery. In this research, we developed novel biodegradable nanoparticles (BnOH-(PCL-co-DMMCL)-TK-mPEG NPs) composed of poly (ethylene glycol)-block-poly caprolactone polymer. These nanoparticles incorporate a ROS-sensitive thioketal-linker and a pH-sensitive charge-conversional component to improve cellular uptake and facilitate drug release in the tumor microenvironment (TME). The pH-sensitive charge-conversional feature was achieved using an acid-labile β-carboxylic amide group. Under acidic TME conditions, the nanoparticles exhibited a swift transition from negative to positive surface charge, with in vitro studies confirming enhanced cellular internalization. Additionally, the thioketal ROS-responsive linkers in the nanoparticles preferentially broke down in the presence of 10 mM H₂O₂ under mildly acidic conditions (pH 6.2), simulating the ROS environment of TME. This degradation was evidenced by rapid changes in nanoparticle size after 6 hours. Doxorubicin hydrochloride (DOX) release rates increased significantly, reaching 72% after 24 hours in the presence of 10 mM H₂O₂ at pH 7.4, and 82% at pH 6.2 over the same period. MTT assays demonstrated the high biocompatibility of the synthesized copolymer. The DOX-loaded nanoparticles showed strong cell internalization capabilities and effective intracellular release of DOX.