Photodynamic therapy (PDT) has shown great effectiveness in oncotherapy but has not been implemented in broad clinical applications because the limited penetration depth of the light used has been ...unable to reach deep-seated tumors. However, X-rays have been widely used in the clinical field for imaging and radiation therapy due to their excellent tissue penetration depth. Recently, X-rays have been established as an ideal excitation source for PDT, which holds great promise for breaking the depth limitation of traditional PDT for treatment of deep-seated tumors. This review aims to provide an overview of nanoscintillator-mediated X-ray induced PDT (X-PDT) including the concept, the design considerations of nanosensitizers for X-PDT, the modelling of nanosensitizer energy deposition, the putative mechanism by which X-PDT kills cells, and the prospects of future directions. We attempt to summarize the main developments that have occurred over the past decades. Possibilities and challenges for the clinical translation of X-PDT are also discussed.
The use of gold nanoparticles as radiosensitizers is an effective way to boost the killing efficacy of radiotherapy while drastically limiting the received dose and reducing the possible damage to ...normal tissues. Herein, we designed aggregation‐induced emission gold clustoluminogens (AIE‐Au) to achieve efficient low‐dose X‐ray‐induced photodynamic therapy (X‐PDT) with negligible side effects. The aggregates of glutathione‐protected gold clusters (GCs) assembled through a cationic polymer enhanced the X‐ray‐excited luminescence by 5.2‐fold. Under low‐dose X‐ray irradiation, AIE‐Au strongly absorbed X‐rays and efficiently generated hydroxyl radicals, which enhanced the radiotherapy effect. Additionally, X‐ray‐induced luminescence excited the conjugated photosensitizers, resulting in a PDT effect. The in vitro and in vivo experiments demonstrated that AIE‐Au effectively triggered the generation of reactive oxygen species with an order‐of‐magnitude reduction in the X‐ray dose, enabling highly effective cancer treatment.
Cancer‐killing clusters: Aggregation‐induced emission gold clustoluminogens (AIE‐Au) for X‐ray‐induced photodynamic therapy (X‐PDT) were designed. Under low‐dose X‐ray irradiation, AIE‐Au strongly absorbed X‐rays and efficiently generated hydroxyl radicals, which enhanced the radiotherapy effect. Additionally, AIE‐AuX‐ray‐induced luminescence excited the conjugated photosensitizers, resulting in a PDT effect.
The aim of this study was to illustrate the dramatically different anticancer activities between coordinatively saturated polypyridyl (1 a–4 a) and cyclometalated (1 b–4 b) ruthenium(II) complexes. ...The cyclometalated complexes 1 b–4 b function as DNA transcription inhibitors, exhibiting switch‐on cytotoxicity against a 2D cancer cell monolayer, whereas the polypyridyl complexes 1 a–4 a are relatively inactive. Moreover, complexes 1 b–4 b exhibit excellent cytotoxicity against 3D multicellular tumor spheroids (MCTSs), which serve as an intermediate model between in vitro 2D cell monolayers and in vivo 3D solid tumors. The hydrophobicity, efficient cell uptake, and nucleus targeting ability, as well as the high DNA binding affinity of complexes 1 b–4 b, likely contribute to their enhanced anticancer activity. We surmise that cyclometalation could be a universal approach to significantly enhance the anticancer activity of substituted polypyridyl RuII complexes. We also suggest that 3D MCTSs may be a more practical platform for anticancer drug screening than 2D cancer monolayer approaches.
RuC more effective than RuN: A small change in the structure of an RuII complex induces dramatically different anticancer activities (see figure). Cyclometalated RuII complexes 1 b–4 b function as DNA transcription inhibitors and exhibit significantly improved anticancer activities compared with polypyridyl RuII complexes 1 a–4 a.
Ferritin (FRT) is a major iron storage protein found in humans and most living organisms. Each ferritin is composed of 24 subunits, which self-assemble to form a cage-like nanostructure. FRT ...nanocages can be genetically modified to present a peptide sequence on the surface. Recently, we demonstrated that Cys-Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys (RGD4C)-modified ferritin can efficiently home to tumors through RGD–integrin αvβ3 interaction. Though promising, studies on evaluating surface modified ferritin nanocages as drug delivery vehicles have seldom been reported. Herein, we showed that after being precomplexed with Cu(II), doxorubicin can be loaded onto RGD modified apoferritin nanocages with high efficiency (up to 73.49 wt %). When studied on U87MG subcutaneous tumor models, these doxorubicin-loaded ferritin nanocages showed a longer circulation half-life, higher tumor uptake, better tumor growth inhibition, and less cardiotoxicity than free doxorubicin. Such a technology might be extended to load a broad range of therapeutics and holds great potential in clinical translation.
Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha ...(SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.
•Extend the traditional framework of two-sided markets by incorporating the role of matching into network effect.•The improvement of recommender systems (RS) can increase users’ surplus but not ...necessarily benefit advertisers.•Advertisers’ gains from RS improvement depend on the strength of marginal utility of network effect (MUNE) that advertisers obtain from each user.•Social welfare is more likely to increase with RS improvement, if users or advertisers can obtain stronger MUNE from each user.
As digital technologies improve and platforms have access to more user data, platforms can use recommender systems (RSs) to discover users’ interests and make better matches. The literature on platforms (two-sided markets) focuses mainly on the number of users and less on the effects of matching. We build a new theoretical framework to reconcile this gap. Users can enjoy a greater network effect (NE) from better matching if platforms invest more in RSs improvement. The results indicate the following. (1) The improvement of RSs can increase users’ surplus but does not necessarily benefit advertisers. Advertisers’ gains from RSs improvement depend on both the strength of the marginal utility of the network effect in advertisers (MUNE-A) and the extent to which platforms subsidize users. (2) Platforms’ investment level in RSs not only relies on the marginal cost but also relates to the strength of the MUNE-A. If the latter becomes too strong, then it is optimal for platforms to reduce their level of investment in RSs due to heavy user subsidies. (3) Social welfare is more likely to increase with RSs improvement if users or advertisers can obtain stronger MUNE from each user.
Photodynamic therapy is an emerging treatment modality that is under intensive preclinical and clinical investigations for many types of disease including cancer. Despite the promise, there is a lack ...of a reliable drug delivery vehicle that can transport photosensitizers (PSs) to tumors in a site-specific manner. Previous efforts have been focused on polymer- or liposome-based nanocarriers, which are usually associated with a suboptimal PS loading rate and a large particle size. We report herein that a RGD4C-modified ferritin (RFRT), a protein-based nanoparticle, can serve as a safe and efficient PS vehicle. Zinc hexadecafluorophthalocyanine (ZnF16Pc), a potent PS with a high 1O2 quantum yield but poor water solubility, can be encapsulated into RFRTs with a loading rate as high as ∼60 wt % (i.e., 1.5 mg of ZnF16Pc can be loaded on 1 mg of RFRTs), which far exceeds those reported previously. Despite the high loading, the ZnF16Pc-loaded RFRTs (P-RFRTs) show an overall particle size of 18.6 ± 2.6 nm, which is significantly smaller than other PS–nanocarrier conjugates. When tested on U87MG subcutaneous tumor models, P-RFRTs showed a high tumor accumulation rate (tumor-to-normal tissue ratio of 26.82 ± 4.07 at 24 h), a good tumor inhibition rate (83.64% on day 12), as well as minimal toxicity to the skin and other major organs. This technology can be extended to deliver other metal-containing PSs and holds great clinical translation potential.
Light-mediated therapy has many unique merits but monotherapy strategies rarely completely inhibit tumor growth because resistance often develops. Combination therapy is a promising strategy in ...oncology and has demonstrated superior safety and efficacy over monotherapy. Here, we conjugated a scintillator complex and gold nanorod nanosensitizer for dual-modal image-guided photothermal and X-ray-induced photodynamic therapy (PDT). Lanthanide complexes were successfully conjugated and offer excellent X-ray-excited optical luminescence for PDT effects. The strong near-infrared (NIR) light and X-ray absorption abilities of gold nanorods make the nanosensitizer function as both a photothermal agent for photothermal therapy and a radiosensitizer for enhanced radiotherapy. The studies in vitro and in vivo demonstrated that the nanosensitizer offers good dual-modal imaging capability and significantly suppresses tumor progression under NIR light and X-ray irradiation. This work shows the great potential of conjugating scintillator lanthanide complexes and gold nanosensitizers for multimodal image-guided therapy of deep-seated tumors.
Macrophages hold great potential in cancer drug delivery because they can sense chemotactic cues and home to tumors with high efficiency. However, it remains a challenge to load large amounts of ...therapeutics into macrophages without compromising cell functions. This study reports a silica‐based drug nanocapsule approach to solve this issue. The nanocapsule consists of a drug–silica complex filling and a solid silica sheath, and it is designed to minimally release drug molecules in the early hours of cell entry. While taken up by macrophages at high rates, the nanocapsules minimally affect cell migration in the first 6–12 h, buying time for macrophages to home to tumors and release drugs in situ. In particular, it is shown that doxorubicin (Dox) as a representative drug can be loaded into macrophages up to 16.6 pg per cell using this approach. When tested in a U87MG xenograft model, intravenously (i.v.) injected Dox‐laden macrophages show comparable tumor accumulation as untreated macrophages. Therapy leads to efficient tumor growth suppression, while causing little systematic toxicity. This study suggests a new cell platform for selective drug delivery, which can be readily extended to the treatment of other types of diseases.
Macrophages are exploited as a vehicle to deliver therapeutics to tumors. This is achieved by a silica‐based nanocapsule that can be engulfed by macrophages by large quantities but minimally release its payloads in the early hours of cell entry. This property buys time for macrophages to migrate to tumors to selectively kill cancer cells while causing minimal systemic toxicity.
Abstract
X-ray-induced photodynamic therapy utilizes penetrating X-rays to activate reactive oxygen species in deep tissues for cancer treatment, which combines the advantages of photodynamic therapy ...and radiotherapy. Conventional therapy usually requires heavy-metal-containing inorganic scintillators and organic photosensitizers to generate singlet oxygen. Here, we report a more convenient strategy for X-ray-induced photodynamic therapy based on a class of organic phosphorescence nanoscintillators, that act in a dual capacity as scintillators and photosensitizers. The resulting low dose of 0.4 Gy and negligible adverse effects demonstrate the great potential for the treatment of deep tumours. These findings provide an optional route that leverages the optical properties of purely organic scintillators for deep-tissue photodynamic therapy. Furthermore, these organic nanoscintillators offer an opportunity to expand applications in the fields of biomaterials and nanobiotechnology.
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