Introduction
Cancer remains one of the leading causes of death worldwide, with 19.3 million new cases and 10 million deaths reported in 2022 alone. Traditional chemotherapy, although effective, often lacks selectivity for cancer cells, leading to severe side effects. Enzymatic therapy has emerged as a promising strategy by leveraging the catalytic efficiency and biodegradability of enzymes to deplete nutrients vital for tumor growth, degrade the extracellular matrix of tumors, or activate prodrugs.
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Glucose oxidase (GOx) stands out due to its ability to oxidize β-d-glucose into gluconic acid and H2O2, effectively cutting off the energy supply to tumor cells and inducing cytotoxic effects through oxidative stress. Despite its potential, GOx's clinical use is limited by issues such as immunogenicity, poor in vivo stability, short half-life, and systemic toxicity. With advancements in nanotechnology, nanocarriers can address these challenges by enhancing the stability, circulating half-life, and tumor accumulation, and reducing the toxicity of GOx.
Mechanism of GOx-Based Nanocarriers for Tumor Therapy
Starvation Therapy
Cancer cells rely heavily on glucose for energy production, a phenomenon known as the Warburg effect. This dependence makes them vulnerable to glucose depletion. GOx-based nanocarriers can exploit this vulnerability by converting glucose to gluconic acid and H2O2, inducing nutrient starvation and oxidative stress in tumor cells.
Vesicle-based nanocarriers have shown promise in encapsulating GOx for effective delivery to tumor sites. For instance, studies have demonstrated that vesicle-encapsulated GOx can specifically deplete glucose in cancer cells more effectively than in normal cells. The combination of GOx with chemotherapeutic agents can further enhance the anti-tumor effects. For example, Huo et al. used ZIF-based nanoparticles to deliver GOx and doxorubicin (DOX), resulting in boosted chemotherapy efficacy through mitochondrial disruption and antioxidant system damage.
Oxidative Therapy
Oxidative therapy aims to increase oxidative stress within cancer cells to a toxic threshold. Reactive oxygen species (ROS) such as H2O2, produced by GOx oxidation of glucose, play a critical role in this strategy. Zhao et al. developed a GOx-polymer nanogel that not only enhanced the oxidative stress but also reduced GOx's side effects by localizing its action to tumor sites.
Further advancements have focused on enhancing the enzymatic processes of GOx to increase oxidative stress. For example, Li et al. developed polymeric nanoreactors that reduced glutathione (GSH)-mediated ROS scavenging, amplifying the oxidative stress and leading to cancer cell death and tumor elimination.
Fig. 1 Mechanism of GOx-based nanocarriers enhanced tumor therapy (Li S., et al. 2023).
GOx-Based Nanocarriers for Tumor Target Therapeutic
Passive Targeting
Passive targeting relies on the unique physiological characteristics of tumors, particularly the enhanced permeability and retention (EPR) effect. Tumor tissues are known for their leaky vasculature and poor lymphatic drainage, which facilitate the accumulation of nanoparticles within the tumor microenvironment. This phenomenon was first elucidated by Maeda in 1986 and has since been a cornerstone in the development of nanomedicine for cancer therapy.
Researchers have explored various approaches to leverage the EPR effect for enhanced drug delivery using GOx-based nanocarriers. For instance, Ren et al. developed bioreactor cascades using FeS-GOx nanodots that effectively penetrate tumor tissues and release therapeutic payloads such as paclitaxel (PTX). These nanodots capitalize on the EPR effect to accumulate selectively in tumors, thereby improving treatment outcomes.
While the EPR effect offers promising benefits, its variability across different tumor types and patient populations presents challenges. To address this, researchers are investigating strategies to augment the EPR effect. For example, nanoparticles designed to release nitric oxide (NO) have been shown to improve blood flow and vascular permeability, thereby enhancing the accumulation of nanocarriers in tumor tissues.
Active Targeting
Mechanisms of Active Targeting
Active targeting involves the functionalization of nanocarriers with ligands that specifically bind to receptors overexpressed on cancer cells or respond to external stimuli present in the tumor microenvironment. This approach aims to improve the specificity and efficacy of drug delivery while reducing off-target effects. There are two primary mechanisms for active targeting: ligand-directed and physically-directed targeting.
Ligand-Directed Active Targeting
RGD peptides are widely used ligands that target αvβ3 integrins, which are overexpressed on the surface of tumor cells. Researchers have developed smart nanodrugs incorporating Metformin (Met) and GOx within RGD peptide-functionalized carriers. These nanodrugs exhibit enhanced tumor cell uptake and therapeutic efficacy through mechanisms such as glycolysis suppression and starvation therapy.
Hyaluronic acid (HA) is another popular ligand for active targeting due to its ability to bind CD44 receptors overexpressed on various cancer cells. Nanocarriers functionalized with HA have been employed to co-deliver therapeutic agents such as Artesunate (AS) and GOx, demonstrating effective tumor suppression through ROS-mediated oxidative damage and metabolic intervention.
Folate receptors are commonly overexpressed in cancer cells, making them attractive targets for drug delivery. Nanostructures modified with folate have been utilized to deliver GOx and chemotherapeutic agents like camptothecin (CPT) directly to folate receptor-positive tumors, leading to improved therapeutic outcomes and reduced systemic toxicity.
Physically-Directed Active Targeting
Physically-directed targeting employs external stimuli such as light, ultrasound, or magnetic fields to guide the delivery of nanocarriers to tumors.
Photodynamic therapy (PDT) utilizes photosensitizers and light to generate reactive oxygen species (ROS) within tumors, leading to cell death. GOx-based nanocarriers coated with photosensitizers have been developed to enhance PDT efficacy by combining ROS generation with tumor-specific oxygen depletion, thereby improving treatment outcomes.
Sonodynamic therapy (SDT) employs ultrasound to activate sonosensitizers and induce ROS production within tumors. GOx-loaded nanocarriers designed for SDT have demonstrated deeper tissue penetration and enhanced therapeutic efficacy compared to traditional PDT, highlighting their potential for treating deep-seated tumors.
Magnetic targeting utilizes external magnetic fields to guide nanocarriers to specific tumor sites, enhancing treatment precision. Autocatalytic Fenton nanosystems incorporating GOx have been developed for magnetic targeting, leveraging glucose metabolism to induce hydroxyl radical production and enhance anticancer efficacy in targeted regions.
Conclusion
GOx-based tumor therapy offers significant promise due to its ability to induce tumor starvation and oxidative stress. However, challenges such as systemic toxicity, poor stability, and limited oxygen availability must be addressed to realize its full potential. Nanocarriers offer a viable solution by enhancing the stability, targeting, and efficacy of GOx.
Future research should focus on optimizing GOx nanocarriers for clinical translation. Key areas include improving the oxygen supply to enhance GOx catalytic activity, developing biodegradable and biocompatible nanocarriers, and employing advanced technologies such as microfluidics and AI to streamline nanocarrier design and synthesis. Additionally, exploring combinatorial therapies and refining targeting strategies will be crucial.
By addressing these challenges and leveraging advancements in nanotechnology, GOx-based nanocarriers hold the potential to revolutionize cancer therapy, providing more effective and specific treatment options with fewer side effects.
References
- Li S., et al. Recent advances in glucose oxidase-based nanocarriers for tumor targeting therapy. Heliyon. 2023.
- Ren H., et al. Self-assembled FeS-based cascade bioreactor with enhanced tumor penetration and synergistic treatments to trigger robust cancer immunotherapy. Acta Pharmaceutica Sinica B. 2021, 11(10): 3244-3261.
- Huo T., et al. Mitochondrial dysfunction and antioxidation dyshomeostasis-enhanced tumor starvation synergistic chemotherapy achieved using a metal–organic framework-based nano-enzyme reactor. ACS Applied Materials & Interfaces. 2022, 14(3): 3675-3684.
- Zhao W., et al. Glucose oxidase–polymer nanogels for synergistic cancer-starving and oxidation therapy. ACS Applied Materials & Interfaces. 2017, 9(28): 23528-23535.
- Li J., et al. Therapeutic vesicular nanoreactors with tumor‐specific activation and self‐destruction for synergistic tumor ablation. Angewandte Chemie. 2017, 129(45): 14213-14218.
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