ROS-responsive camptothecin-linked thioketal drug delivery system based on ring-closing polymerization

This study develops a drug delivery system that is ROS-responsive and can be triggered by endogenous ROS. A polyethylene glycol (PEG) tail end is attached to a ring-closing polymer (PMPSD), which is conjugated to camptothecin (CPT) via a thioketal linker (TK) to produce a TK-CPT-PMPSD conjugate. An in-depth characterization of the TK-CPT-PMPSD is performed using GPC, FTIR, and ¹H NMR. Using DLS, three days of physiological conditions (0 µM H₂O₂) result in a stable size of 69 ± 2.3 nm with 0.31 PDI, which is then validated by TEM, which shows good agreement with DLS. Additionally, TEM research revealed that the TK-CPT-PMPSD particles were spherical in form and assembled in a controlled manner. The observed drug release from TK-CPT-PMPSD is significantly accelerated at 10 µM and 25 µM H₂O₂ in the range of 63% and 80% in a 72-hour time frame, implying that the thioketal linker is ROS-sensitive. Furthermore, MTT tests show that the resulting TK-CPT-PMPSD NPs are harmless to normal cells at a concentration of 250 µg mL⁻¹, while research on cancer cells substantiates a promising anti-tumor characteristic with a 37% apoptosis at a 10 µg mL⁻¹ concentration. Fluorescence imaging studies indicate that TK-CPT-PMPSD has improved anticancer efficacy and efficient nuclei internalization after 12 h of incubation. As far as we are aware, the delivery of CPT-conjugated, thioketal PMPSD using ring-closing metathesis polymerization (RCMP) is a novel concept.