Recently, Jun-Long Zhang group from the College of Chemistry and Molecular Engineering, Peking University reported the first case of photoactivated H2O2 enhanced photoimmunotherapy with Nickel(II) Phototheranostics. The study was published in Journal of the American Chemical Society on October 13, 2023 (https://doi.org/10.1021/jacs.3c08181), with the title “Nickel(II) Phototheranostics: A Case Study in Photoactivated H2O2-Enhanced Immunotherapy”. They reported a dual-functional oxygen-independent phototheranostic agent, Ni-2, rationally designed to provide a near-infrared (NIR) photoactivated thermal- and hydroxyl radical (•OH)-enhanced photoimmunotherapeutic anticancer response, which is achieved for firstly “proof-of-concept” of Nickel-based molecular probes in cancer immunotherapy.
Hypoxia is considered a significant feature of the tumor microenvironment, which is caused by the rapid growth of tumor cells and limited neovascularization. As an inherent characteristic of solid tumors, tumor hypoxia is not only an important cause of tumor proliferation, invasion, metastasis, recurrence, and immunosuppression, but also seriously inhibits the therapeutic effect of conventional chemotherapy, radiotherapy and photodynamic therapy. Therefore, the development of efficient theranostics methods for hypoxic tumors has become a major problem in the field of cancer treatment.
In recent years, Jun-Long Zhang group has been perennial concerned about natural tetrapyrrole metal coenzymes to develop new ligands and construct metal diagnosis and treatment probes. The Nickel(II) complex are potential phototheranostics agent, whose 3d electronic structure is rich in excited states and has diverse oxidation-reduction properties and reactivity. However, due to the short-excited state lifetime and large distorted structure of the excited state caused by d-d transition, few efforts have been devoted to exploring 3d transition metal complexes in photoimmunotherapy.
Zhang and his co-workers previously reported the first oranonickel(II) Phototheranostics by introducing a “metal-carbon bond” for photothermal thrombodebolism (J. Am. Chem. Soc., 2022, 144, 7346–7356). In this work, they designed a Nickel(II) tripyrrin, Ni-2, that integrates multiple functions, including photoactivated H2O2-enabled therapy, photothermal therapy (PTT), immune response, and imaging into one molecule and showed it was effective as a multifunctional photosensitizer (Fig. 1).
Fig. 1 Photoactivated H2O2-Enhanced Immunotherapy Mediated by Ni-2. (a) Photophysical properties of Ni-2 and the phototheranostic events that it is expected to trigger upon Near-IR (NIR) photoactivation (S0 = ground singlet state; S1 = excited singlet state). (b) Mechanisms of the thermal and H2O2-enabled photoimmunotherapeutic anticancer response expected upon photoexcitation of Ni-2.
The complexes feature intense NIR absorption bands in the near-infrared (NIR-I and NIR-II) biowindow, demonstrating high photostability and excellent photoacoustic and photothermal effects with a photothermal conversion efficacy of 58.0% (Fig. 2). Additionally, the inherent excited-state dynamics and energy dissipation pathway of 3d metal complexes made them potential photothermal agents. The in-depth study using ultrafast TA spectroscopy supported by theoretical calculations provided that under NIR irradiation, the energy dissipation process in Ni-2 is mainly in the form of non-radiative transition.
Fig. 2 Photophysical properties and excited state dynamics of Nickel (II) complex.
Amazingly, Ni-2 has novel photocatalysis features that allowed the catalytic conversion of H2O2 to •OH upon photooxidation of Ni(II) to Ni(III) and impacts the overall ROS levels by attenuating endogenous antioxidants (i.e., NADH) to modulate the TME and induce oxidative tumor damage (Fig. 3).
Fig. 3 Photochemical properties of Nickel (II) complex.
As a multifunctional phototherapy reagent, Ni-2 was found not only to accurately locate tumor sites through photoacoustic imaging and inhibit tumor growth in a CT26 tumor-bearing mouse model, but also to activate an immune response via a combination of photothermal- and H2O2-induced effects. Upon photoirradiation, it could not only generate heat but also produce cytotoxic •OH, disrupt intracellular redox homeostasis, and promote ICD induction, as reflected in DC maturation, T cell infiltration, and cytokine secretion. Further study revealed that Ni-2@F127-mediated phototherapy induces a systemic immune response and could synergize the effect of aPD-L1 in suppressing tumor immune evasion (Fig. 4). Collectively, the present results provide support for the proposition that Ni-2 or its analogues could emerge as useful tools for photoimmunotherapy, as well as supply a new strategy for the design and application expansion of molecular probes for 3d metal therapy.
Fig. 4 Photoacoustic imaging-guided photoimmunotherapy.
Ruijing Zhang, a Ph.D. student jointly trained by South China University of Technology and Peking University, is the first author of this work. Prof. Jun-Long Zhang from Peking University, Prof. Jing Zhang at University of Chinese Academy of Sciences, and Prof. Jonathan L. Sessler from The University of Texas at Austin are the co-corresponding authors. Other collaborators include Prof. Song Gao from South China University of Technology, Prof. Wenkai Zhang from Beijing Normal University and Guangliu Ran, a postdoc at the Beijing Normal University. This research was found by the National Natural Science Foundation of China, the Beijing National Laboratory for Molecular Sciences.
Original link for the paper: https://pubs.acs.org/doi/10.1021/jacs.3c08181.
