Protein-functionalized and intrinsically radiolabeled 188Re oxide nanoparticles: advancing cancer therapy through concurrent radio-photothermal effects

Nanoscience Chemistry Medicinal Chemistry Medicine Materials Chemistry Oncology Medical Imaging
protein-functionalized 188Re radiotherapy photothermal therapy tumor treatment nanoparticles dual-modality imaging

Protein-Functionalized and Intrinsically Radiolabeled [188Re]ReOx Nanoparticles: Breakthrough Application in Multimodal Synergistic Cancer Therapy

Cancer remains one of the leading causes of death globally, despite significant progress in medical science over the past few decades. However, early detection and treatment methods still face significant challenges. According to the Globocan 2024 report, approximately 20 million new cancer cases and 9.7 million cancer-related deaths were recorded worldwide in 2022. These numbers underscore the urgent need for effective cancer treatment strategies. Against this backdrop, nanomedicine has become a significant frontier in cancer research due to its advantages in precise drug delivery, targeted therapy, and molecular imaging.

Propelled by advancements in nanotechnology, functionalized nanoparticles (NPs) have shown unique potential to target cancer cells with minimal toxicity effectively. Recently, advanced combined treatment strategies such as radiotherapy (RT) and photothermal therapy (PTT) have gained significant attention. These two modalities complement each other: RT induces DNA damage in tumor cells through ionizing radiation, while PTT selectively heats tumor tissues by converting near-infrared (NIR) light into thermal energy, inducing cell death. Yet, limitations of single-modality treatments persist, such as radiation resistance, hypoxic tumor microenvironments, and limited responsiveness of certain cancer cells to thermal therapy. Thus, enhancing treatment synergy has become increasingly critical.

Recently, a research team comprising scientists from the Bhabha Atomic Research Centre and Homi Bhabha National Institute, led by Dr. Rubel Chakravarty, developed a novel nanomedicine for cancer therapy: [188Re]ReOx-HSA nanoparticles. This innovative nanoparticle integrates intrinsically radiolabeled rhenium oxide with biocompatible human serum albumin (HSA) and is capable of performing both RT and PTT simultaneously. Their breakthrough findings were published in the European Journal of Nuclear Medicine and Molecular Imaging.

Research Background and Objectives

The authors aimed to develop a novel theranostic nanoparticle platform by integrating the highly promising radionuclide rhenium-188 (188Re) with HSA. 188Re is a well-established medical radionuclide known for its therapeutic efficacy via β radiation and its suitability for single-photon emission computed tomography (SPECT) imaging via its 155 keV γ radiation. This study seeks to optimize cancer treatment outcomes by delivering this radiolabeled formulation effectively to cancer cells, while also reducing the side effects associated with traditional cancer treatments.

Research Process

The study was conducted in several key phases, showcasing both scientific rigor and technological innovation:

1. Synthesis and Characterization of Nanoparticles

The research team synthesized HSA-coated rhenium oxide nanoparticles (ReOx-HSA NPs) by reducing ammonium perrhenate (NH4ReO4) with sodium borohydride (NaBH4) under aqueous conditions. The mixture was stirred at room temperature for 2 hours, leading to the formation of a dark brown solution indicative of nanoparticle formation.

Key Characterization Results:
- Using high-resolution transmission electron microscopy (HR-TEM), the particles were determined to have a size range of 4–6 nm.
- Dynamic light scattering (DLS) analysis revealed a hydrodynamic diameter of 15.6 ± 0.8 nm, consistent with TEM measurements.
- The nanoparticles remained stable in physiological conditions for at least 10 days without significant size changes, as confirmed by DLS and relaxation time measurements.
- Thermogravimetric analysis (TGA) indicated that approximately 50% of the nanoparticle mass consisted of HSA coating.

Additional analyses, including Raman spectroscopy and X-ray photoelectron spectroscopy (XPS), verified the oxidation states and chemical interactions involved in the nanoparticle formulation.

2. Photothermal Performance Testing

Due to the localized surface plasmon resonance (LSPR) exhibited by rhenium oxide (ReOx), the photothermal performance of ReOx-HSA NPs was evaluated using an 808 nm NIR laser. Results showed a rapid temperature increase within 5 minutes of irradiation. At a concentration of 1 mg/mL, the nanoparticles achieved a temperature increase of 28°C, while the control (deionized water) increased by only 2.3°C. Furthermore, the nanoparticles maintained stable photothermal performance during multiple irradiation cycles.

3. Radiolabeling and Stability Assessment

Intrinsically radiolabeled [188Re]ReOx-HSA NPs were synthesized by introducing 188ReO4- into the reaction mixture. The radiolabeled nanoparticles were purified through size-exclusion chromatography, yielding a high-purity product. Tests confirmed over 92% stability in both phosphate-buffered saline (PBS) and mouse serum media for at least 48 hours.

4. In Vitro Cytotoxicity and Combination Therapy Evaluation

The anticancer efficacy and biocompatibility of [188Re]ReOx-HSA NPs were assessed using melanoma B16F10 cell lines:
- MTT assays revealed minimal cytotoxicity of the non-radioactive nanoparticles even at high concentrations (91% cell viability at 500 µg/mL).
- RT and PTT individually led to 37% and 30% cancer cell death, respectively. However, the combination therapy (RT + PTT) dramatically enhanced efficacy, resulting in 87% cancer cell death.

5. In Vivo Imaging and Treatment Experiments

SPECT/CT imaging and in vivo studies were conducted using melanoma-bearing C57BL/6 mice:
- Imaging Results: The nanoparticles were uniformly distributed in the tumor after intratumoral administration, with no significant leakage to other organs after 48 hours.
- Therapeutic Effects: Combination therapy effectively inhibited tumor growth. Compared to single-modality treatments, lower RT doses combined with PTT significantly reduced tumor size while minimizing radiation toxicity.

Research Findings and Significance

Key Conclusions

This study demonstrates the first successful development of HSA-coated [188Re]ReOx-HSA NPs capable of dual-modality imaging and combined RT/PTT cancer therapy. Core benefits include:
1. Exceptional biocompatibility and photothermal efficiency.
2. Highly stable intrinsic radiolabeling enabling precise pre- and post-treatment imaging.
3. Lightweight, multifunctional, and potentially biodegradable properties that reduce treatment toxicity.

Research Highlights

  • Innovation: First use of intrinsic radiolabeling to incorporate 188Re directly into NPs, avoiding instability associated with external chemical modifications.
  • Multifunctionality: Enables simultaneous radiotherapy, photothermal therapy, and high-contrast imaging.
  • Safety: Treatment resulted in no significant adverse effects, as evidenced by hematological and biochemical tests, as well as histopathology.

Future Prospects and Clinical Applications

The unique properties of [188Re]ReOx-HSA NPs offer significant potential for precise cancer diagnosis and personalized treatment. This study addresses limitations of single-modality therapies, providing a new perspective on combined treatment strategies. Future work should focus on long-term toxicity studies, biodegradability verification, and enhancements for targeting metastatic tumors to facilitate clinical translation.

This research not only highlights the immense potential of nanotechnology in cancer therapy but also provides innovative solutions to improve therapeutic outcomes and the quality of life for cancer patients.