This Review covers recent progress on near-infrared fluorescence imaging for preclinical animal studies and clinical diagnostics and interventions.

Near-infrared fluorophores for biomedical imaging

Photodynamic therapy (PDT) was discovered more than 100 years ago, and has since become a well-studied therapy for cancer and various non-malignant diseases including infections. PDT uses photosensitizers (PSs, non-toxic dyes) that are activated by absorption of visible light to initially form the excited singlet state, followed by transition to the long-lived excited triplet state. This triplet state can undergo photochemical reactions in the presence of oxygen to form reactive oxygen species (including singlet oxygen) that can destroy cancer cells, pathogenic microbes and unwanted tissue. The dual-specificity of PDT relies on accumulation of the PS in diseased tissue and also on localized light delivery. Tetrapyrrole structures such as porphyrins, chlorins, bacteriochlorins and phthalocyanines with appropriate functionalization have been widely investigated in PDT, and several compounds have received clinical approval. Other molecular structures including the synthetic dyes classes as phenothiazinium, squaraine and BODIPY (boron-dipyrromethene), transition metal complexes, and natural products such as hypericin, riboflavin and curcumin have been investigated. Targeted PDT uses PSs conjugated to antibodies, peptides, proteins and other ligands with specific cellular receptors. Nanotechnology has made a significant contribution to PDT, giving rise to approaches such as nanoparticle delivery, fullerene-based PSs, titania photocatalysis, and the use of upconverting nanoparticles to increase light penetration into tissue. Future directions include photochemical internalization, genetically encoded protein PSs, theranostics, two-photon absorption PDT, and sonodynamic therapy using ultrasound.

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New photosensitizers for photodynamic therapy

The reactive oxygen species (ROS)-mediated mechanism is the major cause underlying the efficacy of photodynamic therapy (PDT). The PDT procedure is based on the cascade of synergistic effects between light, a photosensitizer (PS) and oxygen, which greatly favors the spatiotemporal control of the treatment. This procedure has also evoked several unresolved challenges at different levels including (i) the limited penetration depth of light, which restricts traditional PDT to superficial tumours; (ii) oxygen reliance does not allow PDT treatment of hypoxic tumours; (iii) light can complicate the phototherapeutic outcomes because of the concurrent heat generation; (iv) specific delivery of PSs to sub-cellular organelles for exerting effective toxicity remains an issue; and (v) side effects from undesirable white-light activation and self-catalysation of traditional PSs. Recent advances in nanotechnology and nanomedicine have provided new opportunities to develop ROS-generating systems through photodynamic or non-photodynamic procedures while tackling the challenges of the current PDT approaches. In this review, we summarize the current status and discuss the possible opportunities for ROS generation for cancer therapy. We hope this review will spur pre-clinical research and clinical practice for ROS-mediated tumour treatments.

Reactive oxygen species generating systems meeting challenges of photodynamic cancer therapy

Reactive oxygen species (ROS) play an essential role in regulating various physiological functions of living organisms. The intrinsic biochemical properties of ROS, which underlie the mechanisms ne...

Reactive Oxygen Species (ROS)-Based Nanomedicine.

The complexity, diversity, and heterogeneity of tumors seriously undermine the therapeutic potential of treatment. Therefore, the current trend in clinical research has gradually shifted from a focus on monotherapy to combination therapy for enhanced treatment efficacy. More importantly, the cooperative enhancement interactions between several types of monotherapy contribute to the naissance of multimodal synergistic therapy, which results in remarkable superadditive (namely “1 + 1 > 2”) effects, stronger than any single therapy or their theoretical combination. In this review, state-of-the-art studies concerning recent advances in nanotechnology-mediated multimodal synergistic therapy will be systematically discussed, with an emphasis on the construction of multifunctional nanomaterials for realizing bimodal and trimodal synergistic therapy as well as the intensive exploration of the underlying synergistic mechanisms for explaining the significant improvements in synergistic therapeutic outcome. Furtherm...

Nanotechnology for Multimodal Synergistic Cancer Therapy

BODIPY dyes tend to be highly fluorescent, but their emissions can be attenuated by adding substituents with appropriate oxidation potentials. Substituents like these have electrons to feed into photoexcited BODIPYs, quenching their fluorescence, thereby generating relatively long-lived triplet states. Singlet oxygen is formed when these triplet states interact with 3O2. In tissues, this causes cell damage in regions that are illuminated, and this is the basis of photodynamic therapy (PDT). The PDT agents that are currently approved for clinical use do not feature BODIPYs, but there are many reasons to believe that this situation will change. This review summarizes the attributes of BODIPY dyes for PDT, and in some related areas.

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BODIPY dyes in photodynamic therapy.

Achieving effective treatment of deep-seated tumors is a major challenge for traditional photodynamic therapy (PDT) due to difficulties in delivering light into the subsurface. Thanks to their great tissue penetration, X-rays hold the potential to become an ideal excitation source for activating photosensitizers (PS) that accumulate in deep tumor tissue. Recently, a wide variety of nanoparticles have been developed for this purpose. The nanoparticles are designed as carriers for loading various kinds of PSs and can facilitate the activation process by transferring energy harvested from X-ray irradiation to the loaded PS. In this review, we focus on recent developments of nanoscintillators with high energy transfer efficiency, their rational designs, as well as potential applications in next-generation PDT. Treatment of deep-seated tumors by using radioisotopes as an internal light source will also be discussed.

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Scintillating Nanoparticles as Energy Mediators for Enhanced Photodynamic Therapy

BODIPYs are photosensitizers activatable by light to generate highly reactive singlet oxygen (1O2) from molecular oxygen, leading to tissue damage in the photoirradiated region. Despite their extraordinary photophysical characteristics, they are not featured in clinical photodynamic therapy. This review discusses the recent advances in the design and/or modifications of BODIPYs since 2013, to improve their potential in photodynamic cancer therapy and related areas.

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Recent strategies to improve boron dipyrromethene (BODIPY) for photodynamic cancer therapy: an updated review

Traditional photodynamic therapy (PDT) requires external light to activate photosensitizers for therapeutic purposes. However, the limited tissue penetration of light is still a major challenge for this method. To overcome this limitation, we report an optimized system that uses Cerenkov radiation for PDT by using radionuclides to activate a well-known photosensitizer (chlorin e6, Ce6). By taking advantage of hollow mesoporous silica nanoparticles (HMSNs) that can intrinsically radiolabel an oxophilic zirconium-89 (89Zr, t1/2 = 78.4 h) radionuclide, as well as possess great drug loading capacity, Ce6 can be activated by Cerenkov radiation from 89Zr in the same nanoconstruct. In vitro cell viability experiments demonstrated dose-dependent cell deconstruction as a function of the concentration of Ce6 and 89Zr. In vivo studies show inhibition of tumor growth when mice were subcutaneously injected with [89Zr]HMSN-Ce6, and histological analysis of the tumor section showed damage to tumor tissues, implying that...

Cerenkov Radiation Induced Photodynamic Therapy Using Chlorin e6-Loaded Hollow Mesoporous Silica Nanoparticles.

For the purpose of this review, active targeting in cancer research encompasses strategies wherein a ligand for a cell surface receptor expressed on tumor cells is used to deliver a cytotoxic or imaging cargo. This area of research is more than two decades old, but in those 20 and more years, how many receptors have been studied extensively? What kinds of the ligands are used for active targeting? Are they mostly naturally occurring molecules such as folic acid, or synthetic substances developed in campaigns for medicinal chemistry efforts? This review outlines the most important receptor or ligand combinations that have been used in active targeting to answer these questions, and therefore to address the most important one of all: is research in active targeting affording diminishing returns, or is this an area for which the potential far exceeds progress made so far?

Anyanee Kamkaew

Papers

BODIPY dyes in photodynamic therapy.

Scintillating Nanoparticles as Energy Mediators for Enhanced Photodynamic Therapy

Recent strategies to improve boron dipyrromethene (BODIPY) for photodynamic cancer therapy: an updated review

Cerenkov Radiation Induced Photodynamic Therapy Using Chlorin e6-Loaded Hollow Mesoporous Silica Nanoparticles.

Small Molecules for Active Targeting in Cancer.