Illuminating the future: NIR-II visualizes gas therapy for precision cancer treatment

Abstract

Physiological gas molecules: Initially, gaseous molecules, such as carbon monoxide (CO), hydrogen sulfide (H2S), nitric oxide (NO), and others, were widely believed to be either toxic or biologically inert to humans. However, with the progression of research, it has been discovered that these gases are actually endogenous and play essential roles within the body when present at appropriate concentrations. They have been found to make significant contributions to various biological activities.[1] Further investigations have unveiled the role of these gaseous molecules as messengers, commonly referred to as “gasotransmitters,” participating in biological processes that regulate diverse physiological systems, including the immune, nervous, respiratory, and circulatory systems. An illustrative example is NO, which was identified in 1987 as a relaxation component originating from the human endothelium.[2] Since then, the veil of these interesting gas molecules has gradually been lifted. The primary mode of action for these gasotransmitters is based on their interaction with hemoglobin to facilitate signal transduction. These gas molecules are not only integral to physiological functions but also serve as targets for research into potential therapeutic applications and treatments for various medical conditions. Their intricate roles in cellular signaling and regulation highlight the complexity of physiological processes in living organisms. Gas molecular therapy of cancer: Natural gasotransmitters, including NO, CO, H2S, etc., play significant roles in facilitating growing, proliferation, and metastasis of cancer-associated cells in the tumor microenvironment (TME). According to current studies and reports, there is no significant selective difference observed in the effects of gas molecules on different types of cancer. Although different types of cancers may differ in their development and characterization, their common essence lies in the abnormal proliferation of malignant cells. Gas molecules have been found to firmly attach to different proteins’ haem iron centers, particularly hemoglobin in the mitochondria, to control the bioenergetics of the cell. The action of gas molecules primarily involves energy inhibition, influencing the growth and survival of cancer cells. However, to date, there have been no reports or studies indicating significant selective differences of gas molecules in different types of cancers. This field still requires further research and exploration to gain a better understanding of the relationship between gas molecules and the various types of cancers. Low levels of these gases (below the nM threshold) in the TME modulate the antioxidant, signaling, and beneficial bioenergetic systems that shield cancer cells and promote the growth of tumor cells, expansion, and spread, while high concentrations (over the nM level) of these gasses are harmful to cancerous cells via preventing the respiration of mitochondria. However, potent signaling molecules like NO, CO, and H2S face restricted therapeutic utility owing to their gaseous state, pronounced reactivity, brief half-life, and systemic toxicity.[1] Hence, achieving effective therapeutics necessitates the development of strategies for gasotransmitter administration, affording control over both the site and duration of emission. Inadequate levels of gases in diseased cells or tissues can impede optimal therapeutic outcomes. Ideally, administered gases should target and concentrate at the site of illness rather than dispersing in the bloodstream, maintaining their presence throughout the therapeutic window. The concept of precision gas treatment is expected to gain prominence in such a scenario. A key challenge in precision gas treatment lies in the distribution and monitored release of gases. The three fundamental methods for gas delivery encompass the injection of gas-releasing molecules (GRMs, also known as gas prodrugs and gas donors), oral ingestion of gas, and direct gas inhalation. The central concerns revolve around biosafety and bioavailability. Due to the absence of directed gas suppression and regulated gas discharge, neither direct gas inhibition nor GRM treatment can effectively regulate gas levels in circulation or diseased tissue. The amalgamation of the advantages of sophisticated nanomaterials presents a viable solution to this predicament through the avenue of nanomedicine. Substantial loading of GRMs and gas onto the nanocarrier has the potential to markedly enhance gas transport within cells. As compressed gas is analogous to solid GRMs, nanomedicine constructed with GRMs possesses a considerably larger gas-loading capacity than that built with gas. Given these challenges, scientists have been exploring various concepts and approaches to achieve efficient gas therapy. There are several really ingenious ideas, for example, Liu et al.[3] designed and developed a polymeric vesicle (DOX•HCl and IR780 coloaded nanoparticles, NPSD-IR) that remotely modulates the release of NO via near-infrared (NIR) light. This vesicle can be selectively concentrated at the tumor site through the enhanced permeability and retention effect. It achieves NO release and drug delivery under low pH and glutathione (GSH) reduction conditions in tumor cells. Transiently, a high concentration of NO is released by NIR irradiation. The elevated NO concentration (1.0 μM–1.0 mM) inhibits the growth of tumor cells through mechanisms such as DNA damage, enzyme nitration, nitrosation, etc. Meanwhile, reactive oxygen species generated by photodynamic therapy and heat generated by photothermal therapy further kill the tumor cells and ultimately achieve multi-mode combination therapy for the effective treatment of drug-resistant tumors (Figure 1A). Wang et al.[4] designed functional nanostructures with NaGdF4:Yb, Tm/g-C3N4/CusP composites as cores and surface-coated folic acid-modified zeolitic imidazolate framework-8 shells, which could be targeted and enriched to the tumor region, and then the shells, zeolitic imidazolate framework-8, collapsed under the acidic conditions of TME. The cores were exposed to 980 nm laser irradiation to realize the photothermal conversion and generate reactive oxygen species.Figure 1: Typical examples of gas molecules against cancer.Note: (A) The application of NPSD-IR for NO therapy. Reprinted from Liu et al.[ 3 ] Copyright 2021, with permission from Elsevier Ltd. (B) Synthetic route and schematic diagram of NaGdF4:Yb,Tm/g-C3N4/Cu3P composites for H2 therapy. Reprinted with permission from Wang et al.[ 4 ] Copyright 2021 American Chemical Society. (C) Illustrating the application of mPEG(CO) for CO therapy. Reprinted from Ma et al.[ 5 ] Copyright 2022 Wiley–VCH GmbH. Reproduced with permission. CO: Carbon monoxide; H2: hydrogen; mPEG(CO): polyethyleneglycol(carbon monoxide); NO: nitric oxide; NPSD-IR: DOX•HCl and IR780 co-loaded nanoparticles.At the same time, the hydrogen oxide (H2O) in TME to hydrogen (H2), this nanosystem achieves combined H2 therapy under laser irradiation (Figure 1B). Ma et al.[5] synthesized a novel amphiphilic therapeutic gas carrier material (mPEG(CO)) using carbonyl iron and constructed a TME-triggered aggregation-induced emission nano drug-carrying system by co-assembling it with an aggregation-induced emission polymeric photothermal material. When the nano-bomb meets with overexpressed hydrogen peroxide in the TME, CO gas is rapidly released, and the resulting CO gas can inhibit the rapid proliferation of tumor cells to a certain extent (Figure 1C). However, current nano-gas therapies are mainly facing the following significant limitations: i) a lack of uniformity in the stability and safety of inorganic nano-gas systems, ii) the heightened risk of leakage and safety hazards associated with unstable inorganic self-assembled gas agents, iii) the difficulty in constructing stable and biologically safe organic molecular nanogas platforms, and iv) the ongoing challenge of visualizing precision-targeted gas molecular therapies. Based on the distinctive features of NIR-II visualization gas therapy, this treatment is suitable for addressing metastatic, deep-seated, or refractory tumors, including lung, liver, and pancreatic cancers. These types of tumors are typically located deep within the body and often pose challenges in accurately determining their boundaries. Targeted gas delivery enables precise diagnosis and treatment, effectively localizing and addressing these specific areas of concern. The utilization of NIR-II technology in visualizing gas therapy results in precise treatment outcomes. By precisely directing gas delivery to the targeted sites, therapeutic agents can directly target tumor cells, leading to enhanced efficacy. Moreover, the low toxicity of the gas molecules minimizes their impact on the overall health of living organisms, distinguishing this approach from traditional treatment methods. As a result, this therapeutic approach holds significant potential in reducing the risk of tumor recurrence and metastasis while ensuring the well-being of the patients. Nevertheless, despite the numerous theoretical advantages of NIR-II visualized gas therapy, the practical feasibility and efficacy of its implementation require further investigation through extensive research and clinical trials. Scientists and medical professionals will continue to delve into this field, seeking additional insights into NIR-II visualization gas therapy and striving for continual enhancements in treatment methodologies. NIR-II visualizes gas therapy for cancer treatment: The paramount challenge in gas therapy resides in the precise distribution of these gas molecules to the afflicted area. Therefore, the combination of imaging technology with gas therapy, enabling real-time observation of the therapeutic process and the distribution of gas nanoparticles, becomes crucial in addressing challenges like widespread dispersion and uncertain aggregation time in gas therapy. Fluorescence imaging has garnered significant attention in the biomedical and life sciences due to its heightened sensitivity, resolution, and operational simplicity. The evolution of optical imaging techniques has progressively broadened the bioimaging spectrum from the visible region (400–700 nm) to the NIR-I (700–900 nm) and NIR-II (1000–1700 nm) regions. NIR, characterized by lower tissue absorption, scattering, and enhanced penetration depth compared to visible light, has led to advancements in imaging.[6] The NIR-I fluorescent probe indocyanine green has received approval from the U.S. Food and Drug Administration for in vivo applications and clinical diagnostics. Commercially available indocyanine green probes are commonly utilized for lymph node tracking in breast and gastric cancers. Nevertheless, the increasing demand for high-precision imaging necessitates fluorescence imaging with improved penetration capabilities and higher resolution. In contrast to NIR-I fluorescence imaging, NIR-II fluorescence imaging, with its longer excitation and emission wavelengths, demonstrates superior performance in imaging depth and spatiotemporal resolution. Moreover, the seamless integration of NIR-II fluorescence imaging with cancer diagnosis and phototherapy holds great potential for enhancing the efficiency and accuracy of cancer treatment. This advancement is anticipated to significantly contribute to the precise identification and localization of cancerous cells.[7] As previously indicated, the future of precision gas therapy lies in the integration of imaging advantages. In line with this, our research team has recently pioneered the development of NIR-II fluorescence imaging-guided diagnostic platforms for activatable molecular phototherapeutics, namely IR-FEP-RGD-S-S-S-Fc and FTEB-TBFc. These platforms are designed for active tumor targeting and H2S-enhanced combined chemokinetic-cryo-photothermal therapy.[7,8] IR-FEP-RGD-S-S-S-Fc, incorporating the Cyclic-RGDfk peptide segment, exhibits a tumor-targeting effect, facilitating the endocytosis of nanoparticles. The elevated concentration of GSH in the TME triggers the separation of fluorescent molecules from ferrocene via GSH-sensitive trisulfide bonds, releasing H2S gas molecules. In this process, photothermal therapy in the NIR-II region elevates the TME temperature, instigating the endogenous Fenton reaction and boosting the production of •OH radicals. The released H2S effectively inhibits mitochondrial cytochrome coxidase peroxidase activity, inducing mitochondrial dysfunction and intensified oxidative stress. The diminished expression of cytochrome coxidase and mitochondrial dysfunction further curtails adenosine triphosphate synthesis, inhibiting heat shock protein expression and augmenting the efficiency of hypothermal photothermal therapy. Additionally, the accumulation of H2S expedites the conversion of Fe3+ to Fe2+, promoting more •OH generation from the Fenton-reaction cycle. During oxidative stress reactions, •OH attacks lipid molecules, generating more harmful lipid peroxides. Furthermore, the FTEB-TBFc organic platform harnesses H2S production through trisulfide bond breaking, concomitant with GSH depletion in the TME. This molecularly engineered photothermal nanoplatform generates heat, fluorescence, and singlet oxygen under 808 nm irradiation, enhancing photodynamic treatment and chemodynamic therapy at a biosafe laser power of 0.33 W/cm2. Both of these works represent unique instances of precision anticancer gas therapy utilizing the NIR-II organic molecule. Conclusion and future prospects: In summary, from a cellular bioenergetic standpoint, cancer cells exhibit a preference for energy consumption through the glycolysis pathway, as opposed to the aerobic respiration commonly observed in normal cells. NO, CO, and H2S play roles in regulating and maintaining bioenergetic homeostasis by impeding the survival pathway of cancer cells while safeguarding normal cells, which is related to the fact that NO, CO, and H2S gaseous transmitters are firmly bound to hemoglobin centers in various proteins, especially in mitochondria, in order to regulate cellular bioenergetics, and that the gas molecules show concentration-dependent anticancer effects. Therefore, the key challenge remains in precisely targeting the diffuse gas molecules in the cancerous tissue. Within the current research landscape, while inorganic nanoplatforms have shown promise in providing precise gas-based creative reports, the importance of biocompatible organic nanoplatforms cannot be overstated, especially in terms of their potential for clinical translation. It is widely acknowledged that most gas molecules result from chemical changes. In contrast to the ion-based gas generation of inorganic nanoplatforms, emerging organic nanoplatforms hinge on chemical bonding alterations. This therapeutic strategy, which involves the release of gaseous substances through sensitive chemical bonding in the TME, aligns perfectly with the future theme of precision medicine in the fight against cancer. The focal point of gas therapy will revolve around integration with visualization techniques, with the NIR-II imaging technology standing as the core technology for materializing this concept. The existing body of research in this domain is relatively limited, signifying substantial room for future exploration and advancement (Figure 2).Figure 2: NIR-II imaging guide for precise gas anticancer therapy in the future.Note: Created with Autodesk 3ds Max. CO2: Carbon dioxide; H2: hydrogen; H2S: hydrogen sulfide; NIR-II: near-infrared II (1000–1700 nm); NO: nitric oxide; SO2: sulfur dioxide.

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