Enhancing the Release Efficiency of a Molecular Chemotherapeutic Prodrug by Photodynamic Therapy

Abstract

Tumor‐specific, hypoxia‐activated prodrugs have been developed to alleviate the side effects of chemotherapy drugs. However, the release efficiency of hypoxia‐activated prodrugs is restricted by the degree of tumor hypoxia, which further leads to poor cancer treatment effects. On the other hand, oxygen is consumed gradually in photodynamic therapy (PDT), which aggravates hypoxia at the tumor site. In this study, we combined hypoxia‐activated prodrugs with PDT agents to promote the prodrugs release, thereby improving their bioavailability and therapeutic effects. As a proof of concept, a mitochondria‐targeted molecular prodrug, CS‐P, was designed and synthesized. It can be selectively activated by tumor hypoxia to release chemotherapeutic drugs and photosensitizers, and then further discharge drugs after light irradiation. The design strategy proposed in this paper provides a new idea for enhancing hypoxia‐activated prodrug release and real‐time monitoring prodrug release.

Photodynamic therapy for cancer: mechanisms, photosensitizers, nanocarriers, and clinical studies

“…designed iRGD‐modified nanoparticles to codeliver the PS ICG and the O 2 ‐depleted prodrug tirapazamine, yielding a synergistic therapeutic effect. In a parallel study, Yuan et al 220 . engineered a photopromoted nanoparticle to release the PS Ce6 and the O 2 ‐depleted autophagic prodrug paclitaxel (PTX2‐Azo), resulting in synergistic cancer therapy.…”

“…Wang et al 213 designed iRGD-modified nanoparticles to codeliver the PS ICG and the O 2 -depleted prodrug tirapazamine, yielding a synergistic therapeutic effect. In a parallel study, Yuan et al 220 engineered a photopromoted nanoparticle to release the PS Ce6 and the O 2 -depleted autophagic prodrug paclitaxel (PTX2-Azo), resulting in synergistic cancer therapy. These findings underscore how PDT-driven reactive O 2 species generation exacerbates cellular hypoxia, consequently enhancing the release of anoxia-activated prodrugs for superior tumor therapy.…”

Enhancing Fractionated Cancer Therapy: A Triple-Anthracene Photosensitizer Unleashes Long-Persistent Photodynamic and Luminous Efficacy

“…Cancer continues to be a significant global health burden and presents challenges for current treatment modalities. − Traditional approaches, such as chemotherapy, radiotherapy, and hyperthermia, are widely used but have limitations, including poor tumor selectivity and severe side effects. − In contrast, photodynamic therapy (PDT) has emerged as a promising alternative due to its precision, noninvasiveness, repeatability, minimal drug resistance, and less side effects. ,− PDT has demonstrated efficacy in preclinical and clinical settings for various cancer types, including skin cancer, early obstructive lung cancer, superficial bladder cancer, bile duct cancer, esophagus cancer, and head and neck cancers. ,− However, there are several challenges hindering the widespread application of PDT. The photosensitizers used in PDT mainly rely on type II photosensitization, involving the exchange of electron spin between the photosensitizer (T 1 ) and oxygen to generate singlet oxygen ( 1 O 2 ). ,− Insufficient production of reactive oxygen species (ROS) may occur if the triplet energy of the photosensitizer is too low or if the tumor environment has limited oxygen. − Additionally, the limited lifetime (approximately 1 ns) and diffusion distance (less than 100 nm) of ROS generated during PDT restrict their reach to targeted areas and impede sustained therapy. − Prolonging the irradiation duration to generate more ROS may result in irreversible vascular damage and rapid depletion of oxygen in the tumor microenvironment …”

Hollow Nanooxidase Enhanced Phototherapy Against Solid Tumors

“…Malignant tumors can cause a decline in body immunity, are easily complicated by infection, and can lead to septic shock and death. − Compared with normal tissues, the tumor microenvironment (TME) exhibits many unique features, including extreme hypoxia, high levels of hydrogen peroxide (H 2 O 2 ) and glutathione (GSH), and a mildly acidic nature. − Aiming at the characteristics of tumor TME, phototherapy (including photothermal therapy and photodynamic therapy) has the advantages of low invasiveness, deep penetration, and high efficiency, and has been popular in anticancer approaches. − Photodynamic therapy (PDT) is usually an oxygen-dependent treatment; however, it is difficult to produce enough free radicals to kill tumor cells under extreme hypoxia in the TME, resulting in unsatisfactory therapeutic effects. − As an oxygen-independent treatment method, photothermal therapy (PTT) mainly uses the local high temperature generated by photothermal therapy agents under near-infrared (NIR) light irradiation to kill tumor cells . However, the heat shock effect, induced in tumor cells, weakens its therapeutic effect .…”