Functional Nanomaterials for Phototherapies of Cancer

A review of NIR dyes in cancer targeting and imaging.

Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the cell and mitochondrial membrane potentials, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this Review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes, and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

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Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Over the last decade, organic photothermal therapy (PTT) agents have attracted increasing attention as a potential complement for, or alternative to, classical drugs and sensitizers involving inorganic nanomaterials. In this tutorial review, we provide a structured description of the main classes of organic photothermal agents and their characteristics. Representative agents that have been studied in the context of photothermal therapy since 2000 are summarized and recent advances in using PTT agents to address various cancers indications are highlighted.

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Organic molecule-based photothermal agents: an expanding photothermal therapy universe

Surgical resection of solid tumors is currently the gold standard and preferred therapeutic strategy for cancer. Chemotherapy drugs also make a significant contribution by inhibiting the rapid growth of tumor cells and these two approaches are often combined to enhance treatment efficacy. However, surgery and chemotherapy inevitably lead to severe side effects and high systemic toxicity, which in turn results in poor prognosis. Precision medicine has promoted the development of treatment modalities that are developed to specifically target and kill tumor cells. Advances in in vivo medical imaging for visualizing tumor lesions can aid diagnosis, facilitate surgical resection, investigate therapeutic efficacy, and improve prognosis. In particular, the modality of fluorescence imaging has high specificity and sensitivity and has been utilized for medical imaging. Therefore, there are great opportunities for chemists and physicians to conceive, synthesize, and exploit new chemical probes that can image tumors and release chemotherapy drugs in vivo. This review focuses on small molecular ligand-targeted fluorescent imaging probes and fluorescent theranostics, including their design strategies and applications in clinical tumor treatment. The progress in chemical probes described here suggests that fluorescence imaging is a vital and rapidly developing field for interventional surgical imaging, as well as tumor diagnosis and therapy.

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Fluorescent chemical probes for accurate tumor diagnosis and targeting therapy

A near-infrared fluorescent heptamethine indocyanine dye with preferential tumor accumulation for in vivo imaging.

Mitochondria are recognized as the ideal target for cancer treatment because they play a central role in oxidative metabolism and apoptosis. In this work, a mitochondria-targeted near-infrared (NIR) photosensitizer (PS) for synchronous cancer photodynamic therapy (PDT) and photothermal therapy (PTT) is synthesized. This multifunctional small-molecule PS is developed from a variety of synthesized heptamethine cyanine dyes, which are modified with various N-alkyl side chains on the lipophilic cationic heptamethine core. It is demonstrated to preferentially accumulate in cancer cells by organic-anion transporting polypeptide mediated active transport and retain in mitochondria by its lipophilic cationic property. As mitochondria are susceptible to hyperthermia and excessive reactive oxygen species, this new PS integrating PTT and PDT treatment exhibits highly efficient phototherapy in multiple cancer cells and animal xenograft models. Furthermore, this targeted PS with NIR imaging property also enables tumors and their margins clearly visualized, providing the potential for precisely imaging-guided phototherapy and treatment monitoring. This is the first report that a small-molecule PS integrates both cancer PTT and PDT treatment by targeting mitochondria, significantly increasing the photosensitization. This work may also present a practicable strategy to develop small-molecule-based cancer theranostic agents for simultaneous cancer targeting, imaging, and therapy.

Mitochondria‐Targeted Small‐Molecule Fluorophores for Dual Modal Cancer Phototherapy

Preferential accumulation of the near infrared heptamethine dye IR-780 in the mitochondria of drug-resistant lung cancer cells.

The endoplasmic reticulum (ER) stress signaling or unfolded protein response (UPR) is a common feature of many human diseases, including cancer. Excessive activation of ER stress directly induces cell death, holding a new promising strategy for the therapeutic intervention of cancer. Current ER-stress-inducing agents mainly target UPR components or proteasomes, which exert limited treatment efficacy and undesired side effects due to unselective ER stress and poor tumor-specific distribution. In this study, a unique near-infrared (NIR) fluorophore, IR-34, is synthesized and identified to selectively and efficiently trigger tumoricidal ER stress by targeting the mitochondrial protein NDUFS1. IR-34 is demonstrated to specifically accumulate in living cancer cells for tumor NIR imaging and drastically inhibit tumor growth and recurrence without causing apparent toxicity. Thus, this multifunctional NIR fluorophore may represent a novel theranostic agent for tumor imaging-guided treatment and also strengthens the idea that mitochondria could be a useful target for therapeutic ER stress in cancer cells.

Tao Liu

Papers

A near-infrared fluorescent heptamethine indocyanine dye with preferential tumor accumulation for in vivo imaging.

Mitochondria‐Targeted Small‐Molecule Fluorophores for Dual Modal Cancer Phototherapy

Preferential accumulation of the near infrared heptamethine dye IR-780 in the mitochondria of drug-resistant lung cancer cells.

An NIR-Fluorophore-Based Therapeutic Endoplasmic Reticulum Stress Inducer.

The immunosuppressive properties of non-cultured dermal-derived mesenchymal stromal cells and the control of graft-versus-host disease