Chlorins are important chromophores commonly used in photodynamic therapy. According to the review, their in vivo performance can be constrained by several interrelated problems. In aqueous environments chlorins tend to undergo aggregation, which impairs their photophysical behavior. In addition, many chlorin platforms show nonoptimal biodistribution, and there is often insufficient control over intracellular localization. Finally, local microenvironmental conditions in biological tissues can reduce photochemical efficiency, limiting therapeutic utility.
These limitations affect both the delivery and the photochemical effectiveness of chlorin-based photosensitizers. The review positions these barriers as targets for chemical and formulation strategies that can preserve or enhance photophysical properties while improving biological performance.
The review frames heteroatom engineering—the deliberate incorporation of non-carbon atoms into chlorin structures—as a route to integrate photophysical tuning with delivery and targeting functions. By modifying molecular features such as charge, polarity, and capacity for noncovalent interactions, heteroatom substituents can address aggregation, influence solubility and biodistribution, and modulate interactions with biological targets and environments.
The authors focus on phosphorus- and sulfur-containing modifications as modular and complementary tools. These heteroatoms provide distinct chemical handles: phosphorus derivatives can alter hydrophilicity and introduce targeting moieties, while sulfur-based groups can influence spectral properties and enable responsiveness to redox conditions.
Phosphorus motifs are discussed in two principal functional contexts. First, phosphorus-containing groups can act as degradable hydrophilizing handles. In this role, phosphorus motifs are used to increase aqueous compatibility and formulation stability, countering the tendency of chlorins to aggregate in water. Improved hydrophilicity through degradable links may allow better dispersion and controlled release in biological media, contributing to more favorable biodistribution.
Second, phosphorus chemistry enables attachment of targeting tags such as triphenylphosphonium. These lipophilic cationic tags are noted in the review for their ability to bias accumulation toward mitochondria, a subcellular organelle relevant to photodynamic mechanisms of cell damage. In this application phosphorus-based attachments combine a targeting function with the underlying photophysical properties of the chlorin core.
Both applications position phosphorus as a modular tool that can be incorporated to tune pharmacokinetic and subcellular localization characteristics without sacrificing the core chromophore properties.
The review highlights sulfur-based substituents and linkers for two complementary roles. One is spectral tuning: sulfur atoms and sulfur-containing groups can influence the absorption and emission characteristics of chlorins, which may permit optimization of light absorption for specific wavelengths used in therapy.
The second role is redox-responsive activation. Sulfur-based linkers and substituents can provide chemical moieties that respond to redox conditions present in biological tissues, enabling activation or enhanced activity in specific microenvironments. This redox responsiveness can potentially increase targeting and selectivity in complex biological media by favoring activation in diseased or otherwise distinct microenvironments.
Together, these sulfur strategies offer routes to both improve photophysical match to clinical light sources and to introduce conditional activation that may reduce off-target effects.
Throughout the review the authors emphasize the modular nature of heteroatom modifications as a way to couple photophysical tuning with delivery and targeting strategies. By regulating charge, polarity, and noncovalent interactions through heteroatom incorporation, researchers can influence formulation stability, biodistribution, and subcellular localization.
Phosphorus- and sulfur-containing approaches are presented as complementary: phosphorus motifs primarily address hydrophilicity and mitochondrial targeting, while sulfur motifs offer spectral control and redox responsiveness. Together these approaches aim to mitigate the principal limitations of chlorin platforms in vivo, improving both the effective delivery of photosensitizer molecules and their selective photochemical action in target tissues.
The review concludes by positioning heteroatom engineering—specifically phosphorus- and sulfur-containing modifications—as promising modular strategies to enhance the targeting and selectivity of chlorin photosensitizers. By integrating chemical tuning with delivery and targeting functions, these modifications have the potential to improve formulation stability, direct subcellular accumulation, and enable environment-responsive activation, all of which address the core limitations identified for chlorin systems in photodynamic therapy.
The PubMed abstract summarizes the conceptual framework and main emphases of the review. Specific experimental examples, comparative data, synthetic methods, and quantitative outcomes are provided in the full text of the review and are not detailed in the abstract itself.
Conflict of interest: The authors declare no known competing financial interests or personal relationships that could have influenced the reported work.