A Novel Formulation of Docetaxel-Containing Micelle Surface Modified with Metronidazole to Target Tumor Hypoxia

Chemistry Medicinal Chemistry Bioengineering Oncology Life Sciences Medicine
tumor hypoxia metronidazole active targeting micelle docetaxel

Background Introduction

Cancer is one of the leading causes of death globally, and despite significant progress in treatment, the complexity of tumors, particularly tumor hypoxia, remains a major obstacle to successful therapy. Hypoxic regions are prevalent in solid tumors, where oxygen concentrations are significantly lower than in normal tissues due to vascular abnormalities and insufficient blood supply. Hypoxia not only promotes rapid tumor growth but also reduces the efficacy of chemotherapy and radiotherapy. Therefore, effectively targeting hypoxic regions in tumors has become a critical issue in cancer treatment.

In recent years, the application of nanotechnology in tumor therapy has provided new insights. Nanocarriers (such as polymers, liposomes, and inorganic nanoparticles) can deliver drugs more effectively to tumor sites. Among them, micelles, as small colloidal dispersion systems, have become a research hotspot due to their small size (typically between 5-100 nm) and controllable drug release properties. The core-shell structure of micelles enables them to stably carry hydrophobic drugs and achieve targeted delivery through surface modification.

Metronidazole (Met), a 5-nitroimidazole derivative, exhibits both antimicrobial and antitumor properties. Its antitumor effects primarily stem from its affinity for hypoxic tumors, allowing it to accumulate and exert therapeutic effects in hypoxic environments. Therefore, modifying micelles with metronidazole may serve as an effective strategy for targeting hypoxic regions in tumors.

Source of the Paper

This research paper was completed by a team from Mashhad University of Medical Sciences in Iran, with key authors including Mehdi Faal Maleki, Leila Farhoudi, Maryam Ebrahimi Nik, and others. The study was published in 2025 in the journal Bionanoscience, titled A Novel Formulation of Docetaxel-Containing Micelle Surface Modified with Metronidazole to Target Tumor Hypoxia.

Research Process and Results

1. Synthesis and Characterization of Metronidazole-C18

The study first synthesized Metronidazole-C18 (Met-C18), a compound that combines metronidazole with an octadecyl (C18) tail. The synthesis was achieved through a single-step nucleophilic substitution reaction under solvent-free conditions. The final product was characterized using nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS). The results confirmed the successful synthesis of Met-C18, with characteristic absorption peaks for the nitro (-NO₂) and hydroxyl (-OH) groups appearing at 1537 cm⁻¹ and 3221.6 cm⁻¹, respectively.

2. Preparation of Docetaxel-Loaded Micelles

The research team prepared docetaxel (DTX)-loaded micelles and modified their surfaces with varying concentrations of Met-C18 (0%, 2.5%, 5%, and 7.5%). The micelles were prepared using the thin-film method and characterized using dynamic light scattering (DLS) and transmission electron microscopy (TEM). The results showed that all micelles had sizes ranging from 63 to 95 nm, with a polydispersity index (PDI) below 0.4, indicating uniform size distribution. TEM images further confirmed the spherical structure of the micelles.

3. Drug Release Study

Drug release studies were conducted in phosphate-buffered saline (PBS, pH 7.4). The results showed that all micelles exhibited a burst release within the first 8 hours, followed by a plateau in the release rate. Among them, the 7.5% Met-C18-modified micelles showed the lowest release rate, with only about 24% of DTX released within 24 hours, indicating the highest stability.

4. Cytotoxicity Study

The research team evaluated the cytotoxicity of the micelles under normoxic and hypoxic conditions using the MTT assay. The results showed that as the concentration of Met-C18 increased, the cytotoxicity of the micelles also increased. Under hypoxic conditions, the 7.5% Met-C18-modified micelles exhibited the highest cytotoxicity, with IC50 values significantly lower than other groups. This indicates that Met-C18-modified micelles can effectively target hypoxic tumor cells.

5. In Vivo Biodistribution Study

To assess the distribution of micelles in vivo, the research team conducted biodistribution experiments using radioactive iodine (¹²⁵I)-labeled DTX. The results showed that the 7.5% Met-C18-modified micelles had significantly higher accumulation in tumors compared to other groups, demonstrating excellent targeting ability.

6. In Vivo Antitumor Experiment

In the C26 colon carcinoma mouse model, antitumor experiments showed that the 7.5% Met-C18-modified micelles significantly delayed tumor growth and improved survival rates. Compared to the control group, the median survival time (MST) of mice in the 7.5% group was extended to 35.5 days, indicating significant antitumor efficacy.

Conclusion and Significance

This study successfully developed a novel metronidazole-modified nanomicelle that effectively targets hypoxic regions in tumors and delivers docetaxel. The results demonstrate that the 7.5% Met-C18-modified micelles exhibit optimal stability, cytotoxicity, and antitumor efficacy. This discovery provides a new strategy for targeting tumor hypoxia and holds significant scientific and practical value.

Research Highlights

  1. Targeting Tumor Hypoxia: Through metronidazole modification, the micelles can specifically accumulate in hypoxic tumor regions, significantly improving drug targeting and therapeutic efficacy.
  2. Optimization of Nanomicelles: By adjusting the concentration of Met-C18, the research team optimized the stability and drug release properties of the micelles, offering new insights into nanocarrier design.
  3. In Vitro and In Vivo Validation: The study comprehensively validated the antitumor efficacy of the micelles through in vitro cell experiments and in vivo animal models, laying the foundation for clinical applications.

Other Valuable Information

The research team also noted that while metronidazole shows promise in targeting tumor hypoxia, its potential carcinogenicity requires further investigation. Future studies should focus on the effects of metronidazole-modified micelles on tumor angiogenesis, metastasis, immune response, and drug resistance to fully assess their clinical potential.

This research not only provides new insights into targeting tumor hypoxia but also demonstrates the immense potential of nanotechnology in cancer treatment. With further research and optimization, this technology may offer more effective treatment options for cancer patients.