Cancer Cell-Targeted Photosensitizer and Therapeutic Protein Co-Delivery Nanoplatform Based on a Metal–Organic Framework for Enhanced Synergistic Photodynamic and Protein Therapy

Abstract

Efficient and cancer cell-targeted delivery of photosensitizer (PS) and therapeutic protein has great potentiality for improving the anticancer effects. Herein, zeolitic imidazolate framework-8 (ZIF-8) nanoparticles, one of the most attractive metal–organic framework materials, were used for coencapsulating the chlorin e6 (Ce6, a potent PS) and cytochrome c (Cyt c, a protein apoptosis inducer); then the nanoparticle was subsequently decorated with the hyaluronic acid (HA) shell to form cancer cell-active targeted nanoplatform (Ce6/Cyt c@ZIF-8/HA). The in vitro and in vivo experiments show the cancer cell targeting capability and pH-responsive decomposition and the release behavior of Ce6/Cyt c@ZIF-8/HA. Upon light irradiation, the released Ce6 produced cytotoxic reactive oxygen species for photodynamic therapy. Meanwhile, the released Cyt c-induced programmed cell death for protein therapy. Furthermore, the Cyt c worked normally under hypoxia conditions and could decompose H2O2 to O2 (with peroxidase-/catalase-like activity), resulting in synergistically improved therapeutic efficiency. These small molecules and protein codelivery nanoplatforms would promote the development of complementary and synergetic modes for biomedical applications.

Hypoxia-Responsive Nanoreactors to Amplify Oxidative Damage Through Multiple Cascaded Pathways for Promoting Photodynamic/Ferroptosis-Induced ROS Generation and Simultaneously Disrupting Tumor Antioxidant Defense System

“…The murine hepatoma cell line hepa 1-6 and the mouse embryonic broblast cell line NIH 3T3 were utilized in this study to analyze the in vitro performance of BCFe@SRF. The cultured conditions of cells were according to our previous reports [7]. Notably, to imitate tumor hypoxia environment, the cells were placed in an anaerobic incubator with 2.5% O 2 when co-incubated with the samples.…”

“…Photodynamic therapy (PDT), a typical oxidative therapeutic modality, employs photo-activated photosensitizers (PSs) to transfer the absorbing laser energy to surrounding oxygen molecules and subsequently generate high levels of 1 O 2 to kill cancer cells [5,6]. As is well known, PDT can be operated within a controllably restricted area so that it presents enhanced selectivity and limited side effects [7,8].…”

“…However, the low tumor accumulation of PSs after intravenous injection, limited light penetration and the constant oxygen consumption during PDT make it di cult to produce enough ROS in vivo [7][8][9]. In addition, cancer cells have oxidation defense systems, expressing high concentration of intracellular antioxidant glutathione (GSH), which would hamper the performance of ROS and signi cantly compromise PDT e cacy [10,11].…”

Hypoxia-responsive nanoreactors based on self-enhanced photodynamic sensitization and triggered ferroptosis for cancer synergistic therapy

“…Photodynamic therapy (PDT), a typical oxidative therapeutic modality, employs photo-activated photosensitizers (PSs) to transfer the absorbing laser energy to surrounding oxygen molecules and subsequently generate high levels of 1 O 2 to kill cancer cells [ 5 , 6 ]. As is well known, PDT can be operated within a controllably restricted area so that it presents enhanced selectivity and limited side effects [ 7 , 8 ]. However, the low tumor accumulation of PSs after intravenous injection, limited light penetration and the constant oxygen consumption during PDT make it difficult to produce enough ROS in vivo [ 7 – 9 ].…”

“…As is well known, PDT can be operated within a controllably restricted area so that it presents enhanced selectivity and limited side effects [ 7 , 8 ]. However, the low tumor accumulation of PSs after intravenous injection, limited light penetration and the constant oxygen consumption during PDT make it difficult to produce enough ROS in vivo [ 7 – 9 ]. In addition, cancer cells have oxidation defense systems, expressing high concentration of intracellular antioxidant glutathione (GSH), which would hamper the performance of ROS and significantly compromise PDT efficacy [ 10 , 11 ].…”