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Recurrence of glioblastoma (GBM) mostly occurs in close vicinity to the resection cavity. Therefore, our group has previously designed an implant to locally apply repetitive photodynamic therapy to mitigate tumor recurrence. The penetration depths of different wavelengths in brain tissue were exhaustively studied before. However, the PDT-induced biological effects of 5-ALA-based PDT against GBM cells at different depths have not been evaluated yet. Therefore, a synthetic brain substitute material of 1-10 mm thickness and with optical properties comparable to the white or gray matter of pig brain was developed. Tumor cell viability was assessed in spheroids from six GBM cell lines using disks of varying thickness prepared from pig brain substitute material to mimic in vivo radiation attenuation. Using an artificial brain tissue optical model based on material science, we have established a relationship between the PDT-induced effect of our PDT implant and the distance of migrating GBM cells from the resection cavity wall. This model may be helpful to aid optimization of the irradiation doses and fractionation required to attain the maximal therapeutic effect by long-term PDT applications.

A limitation of photodynamic therapy (PDT) is the depth of penetration of visible light needed for activation of the photosensitizers, restricting treatment to tumors on or just under the skin’s surface or those lining internal organs and cavities. Niagara Muhammad Idris and colleagues have addressed this issue by developing upconversion fluorescent nanoparticles (UNCs) that convert deeper penetrating near-infrared light to visible wavelengths without sacrificing efficacy for singlet oxygen (1O2) production. The group tested the UNCs in vivo in a subcutaneous mouse tumor model using a dual-sensitizer approach for greater PDT efficacy. Conventional photodynamic therapy (PDT) is limited by the penetration depth of visible light needed for its activation. Here we used mesoporous-silica–coated upconversion fluorescent nanoparticles (UCNs) as a nanotransducer to convert deeply penetrating near-infrared light to visible wavelengths and a carrier of photosensitizers. We also used the multicolor-emission capability of the UCNs at a single excitation wavelength for simultaneous activation of two photosensitizers for enhanced PDT. We showed a greater PDT efficacy with the dual-photosensitizer approach compared to approaches using a single photosensitizer, as determined by enhanced generation of singlet oxygen and reduced cell viability. In vivo studies also showed tumor growth inhibition in PDT-treated mice by direct injection of UCNs into melanoma tumors or intravenous injection of UCNs conjugated with a tumor-targeting agent into tumor-bearing mice. As the first demonstration, to the best of our knowledge, of the photosensitizer-loaded UCN as an in vivo –targeted PDT agent, this finding may serve as a platform for future noninvasive deep-cancer therapy.

Drug delivery systems (DDSs) based on nanomaterials have shown a promise for cancer chemotherapy; however, it remains a great challenge to localize on-demand release of anticancer drugs in tumor tissues to improve therapeutic effects and minimize the side effects. In this regard, photoresponsive DDSs that employ light as an external stimulus can offer a precise spatiotemporal control of drug release at desired sites of interest. Most photoresponsive DDSs are only responsive to ultraviolet-visible light that shows phototoxicity and/or shallow tissue penetration depth, and thereby their applications are greatly restricted. To address these issues, near-infrared (NIR) photoresponsive DDSs have been developed. In this review, the development of NIR photoresponsive DDSs in last several years for cancer photo-chemotherapy are summarized. They can achieve on-demand release of drugs into tumors of living animals through photothermal, photodynamic, and photoconversion mechanisms, affording obviously amplified therapeutic effects in synergy with phototherapy. Finally, the existing challenges and further perspectives on the development of NIR photoresponsive DDSs and their clinical translation are discussed.

Upconversion nanoparticles (UCNs) have the extraordinary ability to emit light with UV-visible wavelengths on illumination in the near IR region. This protocol describes the preparation of UCNs with potential therapeutic applications. Photoactivation is a process in which light is used to 'activate' photolabile therapeutics. As a therapeutic strategy, its advantages are that it is noninvasive and that a high degree of spatial and temporal control is possible. However, conventional photoactivation techniques are hampered by the limited penetration depth of the UV and visible lights to which the photosensitive compounds are responsive. Here we describe a protocol for the use of upconversion nanoparticles (UCNs) as light transducers to convert deeply penetrating near-infrared (NIR) light to UV-visible wavelengths matching that of the absorption spectrum of photosensitive therapeutics. This allows the use of deep-penetrating and biologically friendly NIR light instead of low-penetrating and/or toxic visible or UV lights for photoactivation. In this protocol, we focus on two photoactivation applications: photodynamic therapy (PDT) and photoactivated control of gene expression. We describe how to prepare and characterize the UCNs, as well as how to check their function in biochemical assays and in cells. For both applications, the UCNs are coated with mesoporous silica for easy loading of the therapeutics. For PDT, the UCNs are coated with polyethylene glycol (PEG) for stabilization and folic acid for tumor targeting and then loaded with photosensitizers that would be expected to kill cells by singlet oxygen production; the nanoparticles are injected intravenously. For photoactivated control of gene expression, knockdown of essential tumor genes is achieved using UCNs loaded with caged nucleic acids, which are injected intratumorally. The whole process from nanoparticle synthesis to animal studies takes ∼36 d.

Persistent luminescence nanoparticles (PLNPs) are unique optical materials that emit afterglow luminescence after ceasing excitation. They exhibit unexpected advantages for in vivo optical imaging of tumors, such as autofluorescence-free, high sensitivity, high penetration depth, and multiple excitation sources (UV light, LED, NIR laser, X-ray, and radiopharmaceuticals). Besides, by incorporating other functional molecules, such as photosensitizers, photothermal agents, or therapeutic drugs, PLNPs are also widely used in persistent luminescence (PersL) imaging-guided tumor therapy. In this review, we first summarize the recent developments in the synthesis and surface functionalization of PLNPs, as well as their toxicity studies. We then discuss the in vivo PersL imaging and multimodal imaging from different excitation sources. Furthermore, we highlight PLNPs-based cancer theranostics applications, such as fluorescence-guided surgery, photothermal therapy, photodynamic therapy, drug/gene delivery and combined therapy. Finally, future prospects and challenges of PLNPs in the research of translational medicine are also discussed.

In vivo, molecular imaging is prevalent for biology research and therapeutic practice. Among advanced imaging technologies, photoacoustic (PA) imaging and sensing is gaining interest around the globe due its exciting features like high resolution and good (~ few cm) penetration depth. PA imaging is a recent development in ultrasonic technology that generates acoustic waves by absorbing optical energy. However, poor light penetration through tissue continues to be the key obstacle in the field. The NPs as contrast agents can assist in overcoming tissue penetration depth as NPs can produce high signal to noise (SNR) PA signal which aids reconstruction of high resolution of the PA images in deep tissue sights. Subsequently, NPs are very effective in PA based targeted and precise theranostic applications. This article detail about various NPs (organic, inorganic and hybrid) used in PA imaging and spectroscopy applications including various disease diagnosis, therapy and theranostic. It also features optical property, advantages and limitations of various NPs utilised in PA techniques which would comprehend readers about the potential of NPs in evolving PA technique from laboratory to clinical modality in future.Graphical abstract

Photodynamic therapy (PDT) agents activated by near-infrared (NIR) light have demonstrated effectiveness in animal studies. However, clinical trials in humans are lacking due to biocompatibility concerns. We evaluate the feasibility of NIR-PDT using newly developed upconversion nanoparticles-quantum dots-Rose Bengal (UCQRs) through Monte Carlo simulations. Surgery, the primary treatment mode for breast cancer, often reduces the quality of life due to scarring, necessitating a less invasive alternative. Herein, we propose an NIR-PDT approach using UCQRs to treat patients with early-stage breast cancer. The treatment can be performed on patients in the prone position using light irradiation alone, significantly reducing the burden on patients. In NIR-PDT using UCQR, a treatment depth of 3 to 4 cm can be expected based on the penetration depth of the 808-nm excitation light. We created 150 digital breast phantoms by reconstructing breast slice images from breast computed tomography scans. These phantoms were classified by breast density and tumor depth, and simulations were performed on representative models. The therapeutic effect of NIR-PDT was assessed based on the amount of singlet oxygen generated, calculated from the fluence in the tumor voxels. The simulations indicated that tumor depth had a greater impact on the therapeutic outcomes compared with breast contour or structure. In all phantoms where tumors with a 7-mm diameter were embedded at depths of 15 to 25 mm, the generated singlet oxygen exceeded the cell death threshold across all tumor voxels. Shallow tumors between 15 and 20 mm can be treated with 15 or fewer irradiations, whereas deep tumors between 20 and 25 mm are estimated to require up to 45 irradiations. This virtual clinical trial using 150 digital phantoms suggests that NIR-PDT with UCQRs offers a promising, minimally invasive alternative for treating breast cancer.

Background Photodynamic therapy (PDT) features high biocompatibility and high spatiotemporal selectivity, showing a great potential in glioblastoma (GBM) treatment. However, its application was restricted by the poor therapeutic efficacy and side effect. Results In this study, a therapeutic nanoplatform (UCNPs@Ce6/3HBQ@CM) with combination of PDT and CO therapy was constructed, in which a photoCORM and a photosensitizer were loaded onto the surface of upconversion nanoparticles (UCNPs) functioning as photon transducer. Benefitting from NIR excitation and multicolor emission of UCNPs, the penetration depth of excitation light is enhanced and meanwhile simultaneous generation of CO and ROS in tumor site can be achieved. The as-prepared nanocomposite possessed an elevated therapeutic efficiency with the assistance of CO through influencing mitochondrial respiration and depleting ATP, accompanying with the reduced inflammatory responses. By wrapping a homologous cell membrane, the nanocomposite can target GBM and accumulate in the tumor site, affording a powerful tool for precise and efficient treatment of GBM. Conclusion This therapeutic nanoplatform UCNPs@Ce6/3HBQ@CM, which combines PDT and CO therapy enables precise and efficient treatment of refractory glioblastoma.

Electromagnetic radiation-triggered therapeutic effect has attracted a great interest over the last 50 years. However, translation to clinical applications of photoactive molecular systems developed to date is dramatically limited, mainly because their activation requires excitation by low-energy photons from the ultraviolet to near infra-red range, preventing any activation deeper than few millimetres under the skin. Herein we conceive a strategy for photosensitive-system activation potentially adapted to biological tissues without any restriction in depth. High-energy stimuli, such as those employed for radiotherapy, are used to carry energy while molecular activation is provided by local energy conversion. This concept is applied to azobenzene, one of the most established photoswitches, to build a radioswitch. The radiation-responsive molecular system developed is used to trigger cytotoxic effect on cancer cells upon gamma-ray irradiation. This breakthrough activation concept is expected to expand the scope of applications of photosensitive systems and paves the way towards the development of original therapeutic approaches. Triggered therapeutics are of interest but currently suffer from limited penetration depth of light sources. Here, the authors report on the development of a system, called radioswitch, that uses ionising irradiation to switch an azobenzene modified drug to an active form for deep tissue triggered therapeutic application.

Photodynamic therapy (PDT) is a promising alternative to conventional cancer treatment methods. Nonetheless, improvement of in vivo light penetration and cancer cell-targeting efficiency remain major challenges in clinical photodynamic therapy. This study aimed to develop multifunctional magnetic nanoparticles conjugated with a photosensitizer (PS) and cancer-targeting molecules via a simple surface modification process for PDT. To selectively target cancer cells and PDT functionality, core magnetic (Fe3O4) nanoparticles were covalently bound with chlorin e6 (Ce6) as a PS and folic acid (FA). When irradiated with a 660-nm long-wavelength light source, the Fe3O4-Ce6-FA nanoparticles with good biocompatibility exerted marked anticancer effects via apoptosis, as confirmed by analyzing the translocation of the plasma membrane, nuclear fragmentation, activities of caspase-3/7 in prostate (PC-3) and breast (MCF-7) cancer cells. Ce6, used herein as a PS, is thus more useful for PDT because of its ability to produce a high singlet oxygen quantum yield, which is owed to deep penetration by virtue of its long-wavelength absorption band; however, further in vivo studies are required to verify its biological effects for clinical applications.