Strategic Design of Conquering Hypoxia in Tumor for Advanced Photodynamic Therapy

Abstract

Photodynamic therapy (PDT), with its advantages of high targeting, minimally invasive, and low toxicity side effects, has been widely used in the clinical therapy of various tumors, especially superficial tumors. However, the tumor microenvironment (TME) presents hypoxia due to the low oxygen (O2) supply caused by abnormal vascularization in neoplastic tissues and high O2 consumption induced by the rapid proliferation of tumor cells. The efficacy of oxygen‐consumping PDT can be hampered by a hypoxic TME. To address this problem, researchers have been developing advanced nanoplatforms and strategies to enhance the therapeutic effect of PDT in tumor treatment. This review summarizes recent advanced PDT therapeutic strategies to against the hypoxic TME, thus enhancing PDT efficacy, including increasing O2 content in TME through delivering O2 to the tumors and in situ generations of O2; decreasing the O2 consumption during PDT by design of type I photosensitizers. Moreover, recent synergistically combined therapy of PDT and other therapeutic methods such as chemotherapy, photothermal therapy, immunotherapy, and gas therapy is accounted for by addressing the challenging problems of mono PDT in hypoxic environments, including tumor resistance, proliferation, and metastasis. Finally, perspectives of the opportunities and challenges of PDT in future clinical research and translations are provided.

“Click” for precise photodynamic therapy

“…For the activatable photosensitisers, the molecular design also needs to be further advanced to enable them to respond in the tissue-penetrating near-infrared region, giving a high turn-on ratio, and to click in a more efficient manner and exhibit higher stability under the physiological conditions. Apart from facilitating PDT as mentioned, the highly versatile bioorthogonal chemistry may also be utilised concurrently to achieve “on-demand” release of other therapeutic agents for dual therapy, 83 for promoting the PDT efficacy by ameliorating the tumour hypoxic environment 84 and for modulating the cell-death pathways with a view to inducing immunogenic cell death. 85 It is envisaged that these research areas will continue to blossom.…”

Mitochondrial-Targeting Nanotrapper Captured Copper Ions to Alleviate Tumor Hypoxia for Amplified Photoimmunotherapy in Breast Cancer

“…Hypoxia also plays a significant role in promoting tumor cell resistance to various anticancer therapies such as photodynamic therapy (PDT). − The main principle of PDT relies on the use of photosensitizers to convert O 2 into a large amount of reactive oxygen species (ROS) upon light exposure. ,, Therefore, the effectiveness of PDT highly depends on O 2 . The hypoxic microenvironment significantly restricts the generation of ROS in PDT, consequently weakening the ROS-dependent endoplasmic reticulum (ER) stress and immunogenetic cell death (ICD) effects, thereby impacting the therapeutic efficacy of PDT. − Thus, alleviating tumor hypoxia could augment the efficacy of PDT and amplify PDT-induced ICD effects through improved immunogenicity. − Moreover, tumor hypoxia alleviation could suppress the expression of hypoxia inducible factor-1 (HIF-1α), which is related to the regulatory T cells (Treg)-mediated tumor immune suppression in tumor microenvironment, thus improving the photoimmunotherapy …”

Cascade-Catalyzed Nanogel for Amplifying Starvation Therapy by Nitric Oxide-Mediated Hypoxia Alleviation

“…Although catalysis-mediated tumor therapy has achieved remarkable progress in tumor treatment, the aberrant tumor microenvironment (TME) remains a major hindrance to the maximal potency of antitumor therapies. − In recent years, starvation-based synergistic therapies have aroused widespread interest in alleviating the abnormal TME of neoplasms and boosting the antitumor effects. Researchers utilize perfluorocarbon vesicles or red blood cell membranes to directly deliver both Gox and O 2 to tumors; however, the low loading efficiency (LE) and inevitable cargo leakage critically limit their application. − Considering that H 2 O 2 is substantially elevated in tumor tissues over normal tissues and can be further generated by Gox, exploiting catalase (CAT) or Fenton’s reagents to catabolize excessive H 2 O 2 may be a novel strategy. − Despite the vigorous glucose catabolism of Gox, the potential systemic toxic effects caused by Gox-based treatments during systemic circulation remain inevitable. , Orthotopic injection may be a better approach to mitigate systemic toxicity compared with intravenous administration. Moreover, further deterioration of hypoxia TME may induce tumor metastasis. , Consequently, it is imminent to develop a reliable Gox delivery nanoplatform for efficient starvation therapy.…”