A dual action coumarin-camptothecin polymer for light responsive drug release and photodynamic therapy

Abstract

A light-responsive polymer allowing the controlled release of camptothecin and the generation of reactive oxygen species (ROS) is reported. The polymer was prepared by controlled copolymerisation of water-soluble N,N-dimethyl acrylamide with a bromocoumarin methacrylate monomer. The lipophilic chemotherapy agent camptothecin was caged onto the coumarin unit via a photo-cleavable carbonate ester enabling light-triggered cargo release. The polymer showed good biocompatibility in the dark, and high cancer cell killing activity mediated both by the photo-release of camptothecin and ROS generation.

Scheme 1. Synthesis of the bifunctional monomer (CMACPT) containing caged camptothecin and a polymerisable methacrylate unit.

Fig. 1. (a) Evolution over time of the HPLC traces (detection 310 nm) of the monomer CMACPT during 365 nm irradiation in a 50 : 50 mixture of H₂O : acetonitrile t_R (CMACPT) = 5.82 min, t_R (CPT) = 5.02 min; (b) drug release over time under irradiation (365 nm) (SD determined from triplicate measurements); (c) evolution of the absorption spectrum of a solution of ¹O₂ sensor DPBF (50 μM) and CMACPT (5 μM) in acetonitrile upon excitation at 365 nm; (d) evolution of the fluorescence spectrum of a solution of the ROS sensor DHR123 (5 μM) and CMACPT (5 μM) in acetonitrile upon excitation at 365 nm; (e) normalised absorption spectrum of the P(DMA-co-CMACPT) polymer in PBS; (f) kinetic profile of CPT release from the polymer during irradiation (365 nm) in PBS. Values are mean ± SD.

Fig. 2. (a) Cell viability 4 h post-treatment of HeLa cells (MTT assay) following exposure to varying concentrations of P(DMA-co-CMACPT) (6.75–250 μg mL⁻¹, corresponding to equivalent concentrations of camptothecin of 0.375 μM to 15 μM) kept either in the dark or following a 2-minute 365 nm irradiation. Values are mean ± SD, n = 3, ** = p ≤ 0.01, *** = p ≤ 0.001, **** = p ≤ 0.0001. (b) Evolution of the cell viability post-treatment (365 nm illumination, 2 min) of HeLa cells treated with P(DMA-co-CMACPT) (blue circles) or equivalent concentrations of camptothecin (red squares). Values are mean ± SD.