Engineered Bacteriophages for Radiotherapy Applications : Applications of Engineered Bacteriophages in Targeted Radiotherapy, 2/5

Applications of Engineered Bacteriophages in Targeted Radiotherapy

Radiotherapy remains one of the central pillars of cancer treatment, used in approximately 50–60% of all cancer patients during the course of their disease. Despite continuous technological progress, including intensity-modulated radiotherapy and image-guided approaches, a fundamental limitation persists: ionizing radiation inevitably damages healthy tissues surrounding the tumor. This constraint restricts dose escalation, contributes to acute and chronic toxicities, and limits therapeutic efficacy in radioresistant or anatomically complex tumors. In this context, targeted radiotherapy strategies have emerged as a major research focus, aiming to deliver cytotoxic radiation selectively to malignant cells while sparing normal tissue. Among the emerging vectors explored for this purpose, engineered bacteriophages represent a novel and conceptually disruptive platform.

Bacteriophages, viruses that naturally infect bacteria, possess a unique combination of properties that make them attractive for biomedical repurposing. They are biologically inert toward human cells, structurally robust, genetically programmable, and amenable to large-scale production. When modified to function as targeting vectors rather than infectious agents, phages can be exploited as nanoscale carriers capable of delivering therapeutic payloads, including radioactive isotopes, directly to cancer cells. Their application in targeted radiotherapy reflects a broader shift toward molecularly guided radiation delivery.

                                      

Rationale for Phage-Based Radiotherapy

The central concept of phage-mediated radiotherapy is to transform radiation from a spatially defined physical treatment into a biologically targeted molecular therapy. Conventional external beam radiotherapy irradiates both malignant and normal tissues within the treatment field, while even advanced techniques remain constrained by organ motion, tissue heterogeneity, and dose tolerance of surrounding structures. In contrast, vectorized radiotherapy aims to concentrate radioactive decay events within or immediately adjacent to tumor cells.

Engineered bacteriophages can be functionalized to recognize tumor-associated molecular markers, enabling selective accumulation in malignant tissues. When loaded with radionuclides, these vectors act as carriers that localize radiation at the cellular or subcellular level. This approach aligns conceptually with radioimmunotherapy, but differs in several important aspects: phages offer higher structural stability, lower production costs, greater surface modularity, and the ability to carry high radionuclide payloads without loss of targeting capability.

The nanoscale dimensions of bacteriophages, typically ranging from 50 to 200 nm depending on the phage family, facilitate penetration into tumor interstitium, including poorly vascularized regions. This property is particularly relevant for solid tumors, where hypoxia and heterogeneous perfusion limit the effectiveness of conventional radiotherapy.

Types of Radiotherapeutic Applications

One of the primary envisioned applications of phage-based radiotherapy is the treatment of solid tumors. In this setting, phages engineered to recognize tumor-specific receptors can accumulate preferentially within malignant tissue. Once localized, the decay of attached radionuclides induces DNA damage through direct ionization and generation of reactive oxygen species. Preclinical models suggest that highly localized radiation delivery can produce tumor control with substantially lower total administered activity compared to systemic radionuclide therapies.

Phage-mediated radiotherapy is also being explored for disseminated disease and micrometastatic cancer. Small metastatic lesions and residual tumor cell clusters often evade detection and are difficult to treat with localized external irradiation. Targeted phage vectors circulating systemically could, in principle, seek out and irradiate these microscopic disease sites, addressing a major cause of cancer relapse. This application is particularly attractive for malignancies such as ovarian cancer, melanoma, and certain hematological cancers with solid-phase involvement.

Another promising application lies in adjuvant radiotherapy following surgery or conventional irradiation. After tumor resection, microscopic residual disease frequently persists at the margins. Phage-based vectors could be administered postoperatively to selectively irradiate remaining malignant cells without affecting wound healing or surrounding normal tissues.

Choice of Radiation Modality

The therapeutic profile of phage-based radiotherapy is strongly influenced by the type of radionuclide employed. Alpha-emitting isotopes, such as actinium-225 or astatine-211, are particularly attractive due to their high linear energy transfer (LET), typically in the range of 50–230 keV/µm. Alpha particles induce dense clusters of DNA double-strand breaks, leading to cell death that is largely independent of oxygenation or cell cycle status. Their very short tissue range, usually less than 100 µm, minimizes collateral damage to neighboring healthy cells.

Beta emitters, including lutetium-177 and yttrium-90, offer a longer tissue penetration range, from several hundred micrometers to a few millimeters. This “cross-fire” effect can be advantageous in heterogeneous tumors where not all cells express the target receptor uniformly. Phage-based delivery systems may exploit this property to compensate for incomplete targeting coverage.

Gamma-emitting radionuclides are primarily used for imaging rather than therapy, but their integration into phage vectors enables theranostic applications. In such systems, the same phage construct can be used to visualize biodistribution and tumor uptake before delivering therapeutic radiation, allowing patient-specific dosimetry and treatment planning.

Theranostics and Personalized Medicine

One of the most transformative implications of phage-based radiotherapy is its compatibility with theranostic strategies. By labeling phages with diagnostic radionuclides for positron emission tomography or single-photon emission computed tomography, clinicians could directly visualize targeting efficiency, tumor penetration, and off-target accumulation. This information would enable real-time optimization of therapeutic dosing and selection of patients most likely to benefit.

Such an approach aligns with the principles of personalized medicine, moving away from uniform radiation protocols toward biologically informed treatment decisions. In the long term, phage libraries could be customized to individual tumor molecular profiles, enabling truly patient-specific radiotherapy vectors.

Safety and Toxicity Considerations

Although phage-based radiotherapy aims to reduce toxicity, safety remains a critical concern. Ionizing radiation is inherently damaging, and even highly targeted systems carry some risk of off-target effects. However, theoretical and experimental evidence suggests that localized radionuclide delivery via phages could significantly lower radiation exposure to healthy tissues compared with conventional radiotherapy.

Biodistribution studies indicate that phages are primarily cleared by the reticuloendothelial system, with accumulation in the liver and spleen. While this raises concerns about organ toxicity, the use of short-range alpha emitters and optimized dosing may mitigate these risks. Importantly, bacteriophages do not replicate in human tissues, limiting long-term persistence.

Immunogenicity is another consideration, as repeated administration may elicit neutralizing antibodies. Strategies such as transient dosing, surface modification, or use of less immunogenic phage platforms are being investigated to address this limitation.

In summary, engineered bacteriophages represent a novel and versatile platform for targeted radiotherapy. By combining molecular specificity with localized radiation delivery, they have the potential to overcome long-standing limitations of conventional radiotherapy. While significant challenges remain, continued advances in synthetic biology, radiochemistry, and cancer biology suggest that phage-based radiotherapy could become a valuable component of future oncologic treatment paradigms.

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