NIR-Triggered On-Demand Nitric Oxide Release for Enhanced Synergistic Phototherapy of Hypoxic Tumor.

Hypoxia of tumor microenvironments is a major factor restricting tumor treatment, which causes progression and metastasis of tumor. The hypoxic tumor microenvironment not only makes the traditional treatment method, such as chemotherapy, ineffective but also hinders the O2-dependent treatments, such as photodynamic therapy (PDT). Recently, stimuli-responsive nitric oxide (NO) donors have attracted extensive research interest in hypoxic tumor treatment because the NO release process is O2-independent. Besides, NO can distribute more uniformly than drug molecules and more widely than the PDT-generated active species due to its strong diffusion ability (200 µm in cells) and long lifetime (2 s in cells). Encouraged by these advantages, a near infrared light-triggered NO release polymeric nanoplatform (P1-CapNO NPs) was constructed by a thermally sensitive NO release unit, a photothermal unit, and a hydrophilic polyethylene glycol unit. P1-CapNO NPs possess strong absorption in the NIR region (the wavelength of maximal absorption peak was 790 nm with a molar absorption coefficient of 2.4 × 105 M-1 cm-1), great photothermal conversion efficiency (23.8%), and NO release ability (the released NO concentration can reach 1.3 µM) under 808 nm laser irradiation. Owing to these advantages, the great synergistic antitumor effect can be achieved in vitro and in vivo even under the hypoxic environment. The synergistic therapeutic strategy in this work could bypass the obstacles caused by hypoxia in tumor treatment and provide a reference for building a NO-involved therapeutic platform.

Overcoming Tumor Hypoxia through Multiple Pathways Using an All-in-One Polymeric Therapeutic Agent to Enhance Synergistic Cancer Photo/Chemotherapy Effects.

Hypoxia is a significant characteristic of tumors, which causes aggressive tumor growth and strong therapy resistance. Inspired by the improved therapeutic efficacy of synergistic treatment, herein, an all-in-one polymeric therapeutic agent was developed, which could overcome tumor hypoxia through multiple pathways. Multiple therapeutic agents were incorporated into the polymer, including the singlet oxygen (1O2) carrier unit to store cytotoxic reactive oxygen species, the photosensitized and photothermal unit to trigger the capture and release of 1O2, and the hypoxia-responsive prodrug unit to maintain a long-term tumor inhibition. In addition, the hydrophilic polyethylene glycol unit was also introduced to improve water-solubility and biocompatibility. Importantly, this study achieved the capture and controllable release of 1O2 just by regulating the power of an 808 nm laser for the first time, which is more convenient and flexible than previous works. As expected, the as-prepared copolymer displayed reduced oxygen dependence, accompanied with promising synergistic anti-tumor and anti-recurrence efficacies under hypoxic in vitro and in vivo environments. Consequently, this synergistic anti-hypoxia strategy may open up new avenues in the design of all-in-one therapeutic platforms for promoting the development of accurate, efficient, and long-acting treatment in clinical studies.