Emerging Targets and Bioconjugation Strategies in Photodynamic Cancer Diagnosis and Therapy

Haibo Bing^*
*Correspondence: Haibo Bing, Department of Environmental and Municipal Engineering, Lanzhou Jiaotong University, Lanzhou, China, Email:

Introduction

Photodynamic Diagnosis (PDD) and Photodynamic Therapy (PDT) have emerged as powerful tools in cancer management, offering a minimally invasive approach for tumor detection and treatment. These techniques rely on the use of Photosensitizers (PS) that, upon activation by specific wavelengths of light, generate Reactive Oxygen Species (ROS) capable of inducing selective tumor cell destruction. The effectiveness of PDD and PDT is largely dependent on the choice of molecular targets and bioconjugation strategies, which enhance the specificity, bioavailability, and therapeutic efficacy of the photosensitizers. One of the primary challenges in photodynamic therapy is achieving selective accumulation of the photosensitizer in malignant tissues while minimizing damage to healthy cells. To address this, emerging molecular targets have been identified based on tumor-specific biomarkers, overexpressed receptors, and the unique tumor microenvironment. Cell surface receptors such as Epidermal Growth Factor Receptor (EGFR), Folate Receptor (FR), and integrins have been widely studied for their role in tumor proliferation and are now being exploited for targeted PS delivery. The use of peptide ligands, monoclonal antibodies, and small molecules to direct PS accumulation at these receptors has significantly improved selectivity, leading to more efficient tumor localization and reduced off-target effects.

Description

Hypoxia, a common characteristic of solid tumors, presents another crucial target for PDT enhancement. Since hypoxic conditions can limit ROS generation, strategies that exploit hypoxia-responsive elements or oxygen-independent photochemical reactions have been developed. These include the use of hypoxia-activated prodrugs or the combination of PDT with oxygen-generating agents, such as perfluorocarbons and catalase-loaded nanoparticles. These approaches aim to overcome oxygen limitations, ensuring effective tumor cell apoptosis even under hypoxic stress. The tumor microenvironment, which is often acidic and rich in proteolytic enzymes, provides an opportunity for pH-responsive and enzyme-activated photosensitizers. Acid-sensitive linkers and enzyme-cleavable peptides have been incorporated into PS conjugates to ensure controlled release at the tumor site. Such smart delivery systems enhance the therapeutic index of PDT by minimizing systemic toxicity and ensuring activation occurs predominantly in malignant tissues [1].

Bioconjugation strategies play a pivotal role in improving PS solubility, stability, and targeting capabilities. Covalent attachment of photosensitizers to tumor-targeting ligands is one of the most effective ways to enhance specificity. This can be achieved through click chemistry, amide bond formation, and thiolmaleimide reactions, allowing for stable and biocompatible conjugates. For example, the conjugation of photosensitizers to monoclonal antibodies, known as photoimmunotherapy, has shown great promise in selectively targeting tumor antigens while sparing healthy tissues. This approach is particularly useful in treating cancers that overexpress specific surface markers, such as HER2-positive breast cancer and CD20-positive lymphomas. Nanotechnologybased bioconjugation has further revolutionized PDT by enabling controlled PS delivery, enhanced bioavailability, and improved photophysical properties. Nanocarriers, such as liposomes, polymeric micelles, dendrimers, and inorganic nanoparticles, have been extensively used to encapsulate photosensitizers, ensuring prolonged circulation time and enhanced tumor penetration. These nanoplatforms offer additional benefits such as stimuli-responsive release, where PS activation is triggered by environmental changes specific to tumors, including pH, temperature, and enzymatic activity [2].

Conjugation of PS with carbon-based nanomaterials, such as graphene oxide and carbon dots, has also gained traction in PDT. These materials exhibit high photostability, efficient energy transfer, and excellent biocompatibility. Moreover, they enable multimodal therapy by combining PDT with Photothermal Therapy (PTT) or drug delivery, leading to synergistic anticancer effects. Gold and silver nanoparticles, owing to their plasmonic properties, have been employed to enhance PS absorption and energy transfer efficiency, thereby increasing ROS production and treatment efficacy. Hybrid bioconjugation strategies that combine multiple targeting mechanisms have demonstrated superior performance in PDD and PDT. Dual-targeting approaches, where a PS is conjugated to both a tumor-specific ligand and a nanocarrier, enable precise delivery while reducing premature clearance from circulation. Multifunctional systems that integrate imaging and therapy, often referred to as theranostics, have enabled real-time monitoring of PS accumulation and therapeutic response. Fluorescent-tagged photosensitizers, for example, allow simultaneous tumor imaging and treatment, improving diagnostic accuracy and therapeutic outcomes [3].

Recent advancements in genetic engineering have introduced innovative bioconjugation strategies, including the use of engineered protein scaffolds and synthetic peptides for PS targeting. Fusion proteins that combine a tumortargeting domain with a PS-binding moiety have shown remarkable selectivity and efficacy. In addition, Cell-Penetrating Peptides (CPPs) have been explored for intracellular PS delivery, facilitating deeper tumor penetration and improved subcellular localization. Despite these advancements, several challenges remain in optimizing PDD and PDT for clinical applications. One major hurdle is the potential for immunogenicity and off-target effects associated with bioconjugates. While targeted delivery improves specificity, immune recognition of conjugated molecules can sometimes lead to adverse reactions. Strategies to minimize immunogenicity, such as PEGylation and biomimetic coatings, are being explored to improve biocompatibility and circulation time [4,5].

Conclusion

Another limitation is the heterogeneity of tumors, which can affect PS uptake and treatment response. Personalized approaches, guided by molecular profiling and patient-specific tumor characteristics, are essential to maximize therapeutic benefits. The integration of artificial intelligence and machine learning in PDD has shown promise in enhancing tumor detection accuracy and predicting PDT outcomes based on imaging and biomarker data. The future of photodynamic therapy lies in the development of next-generation photosensitizers with enhanced photophysical and pharmacokinetic properties. Novel PS molecules with high quantum yield, near-infrared absorption, and reduced phototoxicity are being investigated to improve tissue penetration and selectivity. Additionally, the combination of PDT with immune checkpoint inhibitors and other immunotherapies is emerging as a promising strategy to induce systemic anti-tumor immunity, potentially overcoming tumor recurrence and metastasis. Overall, emerging targets and bioconjugation strategies have significantly advanced the field of photodynamic cancer diagnosis and therapy. By leveraging molecular specificity, smart drug delivery systems, and innovative nanotechnologies, researchers are developing more effective and personalized approaches to cancer treatment. While challenges remain, continued advancements in this field hold great promise for improving patient outcomes and establishing PDT as a mainstream modality in oncology.

Acknowledgment

None.

Conflict of Interest

None.

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