Shaping Dendrimers for Active Oxygen Delivery: An Emerging Strategy for Targeting Tumor Microenvironments.

Reactive oxygen species (ROS) have been identified as one of the critical factors in cancer development. ROS have been linked to cancer at all stages, and their applications in cancer treatment have gained attention due to their concentration-dependent implications: (1) low to moderate levels as fundamental signaling molecules, and (2) higher levels in cancer cells as a unique characteristic of cancer and cytotoxic agents. However, resistance and off-target effects are the main barriers that can hinder and limit the therapeutic efficacy of chemotherapies. The main reason for that is the complex tumor microenvironment such as hypoxia. Developing drug nanocarriers that can target ROS represents a potential delivery platform to overcome these barriers. For instance, doxorubicin-encapsulated ROS (nitric oxide) micelles accumulated 6.7-fold more drug in PC3-Luc cancer cells than when using this drug alone. Regrettably, the past studies have merely discussed the micelle alone as a nanocarrier for the delivery of ROS-based therapy in cancer without exploring dendrimers. Instead, this review examines the structural design of dendrimers tailored for oxygen transport, their conjugation with ROS-generating therapies, and therapeutic applications in photodynamic therapy, radiotherapy, and chemotherapy. Besides, it also discusses the translational challenges and future perspectives for ROS-based dendrimers. For the first time, this work also critically compares various dendrimer types and generations, oxygen-delivery strategies, drug loading properties, in vitro/in vivo outcomes, and toxicity data. A dedicated section discussing biodistribution, clearance, biocompatibility, and regulatory considerations of dendrimers was also explored in this study. Finally, this review concludes that the dendrimers can be engineered to carry and deliver active oxygen by using the following delivery strategies: (1) addition of oxygen carriers, (2) enzyme functionalization, (3) the incorporation of photosensitizers and metal ions, and (4) surface alterations.