Multi-stimuli responsive polymeric prodrug micelles for combined chemotherapy and photodynamic therapy†
Nowadays, cancer therapy faces severe challenges regarding boosting therapeutic efficiency and reducing the side effects of drugs. To overcome these challenges, herein multifunctional polymeric prodrug micelles combining chemotherapy and photodynamic therapy are put forward; the multifunctional polymeric prodrug micelles are prepared through self-assembly of amphipathic copolymer and photosensitizer Chlorin e6 (Ce6). These therapeutic prodrug micelles have better intracellular uptake and deeper tumor infiltration through charge reversal and smaller size changes, respectively. The polymeric prodrug micelles have fast disassembly and release Ce6 in the case of cathepsin B existence in the lysosome. Under light irradiation at 660 nm, Ce6 can efficiently generate singlet oxygen and accelerate the release of gemcitabine (GEM) by destroying the bis-(alkylthio) alkene functional group, which is the singlet-oxygen responsive linker, to achieve the combination of chemotherapy and photodynamic therapy (PDT). Under light irradiation at 660 nm, the singlet oxygen can also efficiently destroy mitochondrial functions to activate mitochondria apoptosis pathways, including increased reactive oxygen species (ROS) levels and swollen mitochondria. Further, employing 4T1-bearing BALB/c mice as a model, the anticancer effect of the therapeutic prodrug micelles is systematically investigated in vivo. The therapeutic prodrug micelles show an efficient tumor growth inhibition in vivo after light irradiation. Meanwhile, therapeutic prodrug micelles can significantly reduce adverse effects compared with the free drug, exhibiting better biocompatibility. Therefore, this prodrug micelle with a triple sensitivity response and synergistic chemo–photodynamic therapy functions is expected to offer promising applications in efficient antitumor therapy.