[Rapamycin and HPPH Co-Loaded Nanodrug Delivered via Dissolvable Microneedles to Treat Port-Wine Stains]. / å ±è½½é›·å¸•éœ‰ç´ å’Œå ‰å ‹æ´›çš„çº³ç±³è¯ç‰©å¤åˆå¯æº¶è§£å¾®é’ˆæ²»ç–—é²œçº¢æ–‘ç—£çš„å®žéªŒç ”ç©¶.

Objective: Port-wine stains are a kind of dermatological disease of congenital capillary malformation. Based on the biological characteristics of port-wine stains and the advantages of microneedle transdermal administration, we intend to construct a nanodrug co-loaded with rapamycin (RPM), an anti-angiogenesis drug, and photochlor (HPPH), a photosensitizer, and integrate the nanodrug with dissolvable microneedles (MN) to achieve anti-angiogenesis and photodynamic combination therapy for port-wine stains. Methods: First, RPM and HPPH co-loaded nanoparticles (RPM-HPPH NP) were prepared by the emulsification solvent-volatilization method, and its ability to generate reactive oxygen species (ROS) was investigated under 660 nm laser irradiation. Mouse hemangioendothelioma endothelial cells (EOMA) were used as the subjects of the study. The cellular uptake behaviors were examined by fluorescence microscopy and flow cytometry. The cytotoxicity effects of RPM-HPPH NP with or without 660 nm laser irradiation on EOMA cells were examined by MTT assays (with free RPM serving as the control). Then, hyaluronic acid (HA) dissolvable microneedles loaded with RPM-HPPH NP (RPM-HPPH NP@HA MN) were obtained by compounding the nanodrug with HA dissolvable microneedle system through the molding method. The morphological characteristics and mechanical properties of RPM-HPPH NP@HA MN were investigated by scanning electron microscope and electronic universal testing machine. The penetration ability of RPM-HPPH NP@HA MN on the skin of nude mice was evaluated by trypan blue staining and H&E staining experiment. Results: The RPM-HPPH NP prepared in the study had a particle size of 150 nm and generated large amounts of ROS under laser irradiation. At the cellular level, RPM-HPPH NP was taken up by EOMA cells in a time-dependent manner. The cytotoxicity of RPM-HPPH NP was higher than that of free RPM with or without laser irradiation. Under laser irradiation, RPM-HPPH NP exhibited stronger cytotoxic effects and the difference was statistically significant (P<0.05). The height of the needle tip of RPM-HPPH NP@HA MN was 600 µm and the mechanical property of a single needle was 0.75048 N. Trypan blue staining and HE staining showed that pressing on the microneedles could produce pores on the skin surface and penetration of the stratum corneum. Conclusion: RPM-HPPH NP@HA MN can deliver RPM-HPPH NP percutaneously to the lesion tissue and realize the synergistic treatment of port-wine stains with anti-angiogenic therapy and photodynamic therapy, providing a new strategy for the construction of nanodrug-loaded microneedle delivery system and the clinical treatment of port-wine stains.

Plum-blossom needle tapping enhances the efficacy of ALA photodynamic therapy for facial actinic keratosis in Chinese population: a randomized, multicenter, prospective, and observer-blind study.

BACKGROUND: Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) is a reliable treatment for actinic keratosis (AK), but its effect needs to be enhanced in thick lesions. Plum-blossom needle is a traditional Chinese cost-effective instrument for enhancing the transdermal delivery of ALA. However, whether it could improve the efficacy of AK treatment has not yet been investigated. OBJECTIVE: To compare the efficacy and safety of plum-blossom needle-assisted PDT in facial AK in the Chinese population. METHODS: In this multicenter, prospective study, a total of 142 patients with AKs (grades I-III) were randomized into the plum-blossom needle-assisted PDT group (P-PDT) and control PDT group (C-PDT). In the P-PDT group, each AK lesion was tapped vertically by a plum-blossom needle before the application of 10% ALA cream. In the C-PDT group, each lesion was only wiped with regular saline before ALA cream incubation. Then, 3 hours later, all the lesions were irradiated with light-emitting diode (LED) at a wavelength of 630 nm. PDT was performed once every 2 weeks until all lesion patients achieved complete remission or completed six sessions. The efficacy (lesion response) and safety (pain scale and adverse events) in both groups were evaluated before each treatment and at every follow-up visit at 3-month intervals until 12 months. RESULTS: In the P-PDT and C-PDT groups, the clearance rates for all AK lesions after the first treatment were 57.9% and 48.0%, respectively (P < 0.05). For grade I AK lesions, the clearance rates were 56.5% and 50.4%, respectively (P = 0.34). For grade II AK lesions, the clearance rates were 58.0% and 48.9%, respectively (P = 0.1). For grade III AK lesions, the clearance rates were 59.0% and 44.2%, respectively (P < 0.05). Moreover, grade III AK lesions in the P-PDT group required fewer treatment sessions (P < 0.05). There was no significant difference in the pain score between the two groups (P = 0.752). CONCLUSION: Plum-blossom needle tapping may enhance the efficacy of ALA-PDT by facilitating ALA delivery in the treatment of AK.

Natural photosensitizer-loaded in micellar copolymer to prevent bovine mastitis: A new post-dipping protocol on milking.

Good management practices such as post-dipping applications (post-milking immersion bath) contribute to the dairy cattle health during lactation and minimize the appearance of mastitis (an infection in the mammary gland). The post-dipping procedure is performed conventionally using iodine-based solutions. The search for therapeutic modalities that are not invasive and do not cause resistance to the microorganisms that cause bovine mastitis instigates the interest of the scientific community. In this regard, antimicrobial Photodynamic Therapy (aPDT) is highlighted. The aPDT is based on combining a photosensitizer (PS) compound, light of adequate wavelength, and molecular oxygen (3O2), which triggers a series of photophysical processes and photochemical reactions that generate reactive oxygen species (ROS) responsible for the inactivation of microorganisms. The present investigation explored the photodynamic efficiency of two natural PS: Chlorophyll-rich spinach extract (CHL) and Curcumin (CUR), both incorporated into the Pluronic® F127 micellar copolymer. They were applied in post-dipping procedures in two different experiments. The photoactivity of formulations mediated through aPDT was conducted against Staphylococcus aureus, and obtained a minimum inhibitory concentration (MIC) of 6.8 mg mL-1 for CHL-F127 and 0.25 mg mL-1 for CUR-F127. Only CUR-F127 inhibited Escherichia coli growth with MIC 0.50 mg mL-1. Concerning the count of microorganisms during the days of the application, a significant difference was observed between the treatments and control (Iodine) when the teat surface of cows was evaluated. For CHL-F127 there was a difference for Coliform and Staphylococcus (p < 0.05). For CUR-F127 there was a difference for aerobic mesophilic and Staphylococcus (p < 0.05). Such application decreased bacterial load and maintained the milk quality, being evaluated via total microorganism count, physical-chemical composition, and somatic cell count (SCC).

Enzyme and Reactive Oxygen Species-Responsive Dual-Drug Delivery Nanocomplex for Tumor Chemo-Photodynamic Therapy.

Introduction: Combination therapy is a promising approach to promote the efficacy and reduce the systemic toxicity of cancer therapy. Herein, we examined the potency of a combined chemo-phototherapy approach by constructing a hyaluronidase- and reactive oxygen species-responsive hyaluronic acid nanoparticle carrying a chemotherapy drug and a photosensitizer in a tumor-bearing mouse model. We hypothesized that following decomposition, the drugs inside the nanocomplex will be released in the tumors to provide effective tumor treatment. We aimed to design a smart drug delivery system that can improve traditional chemotherapy drug delivery and enhance the therapeutic efficacy in combination with photodynamic therapy. Methods: Hydrophilic hyaluronic acid (HA) was covalently modified with a hydrophobic 5ß-cholanic acid (CA) via an ROS-cleavable thioketal (tk) linker for a targeted co-deliver of 10-Hydroxy camptothecin (HCPT) and Chlorin e6 (Ce6) into tumors to improve the efficiency of combined chemo-photodynamic therapy. Results: The obtained HA-tk-CA nanoparticle carrying HCPT and Ce6, named HTCC, accumulated in the tumor through the enhanced permeable response (EPR) effect and HA-mediated CD44 targeting after intravenous administration. Upon laser irradiation and hyaluronidase degradation, HTCC was disrupted to release HCPT and Ce6 into the tumors. Compared to the monotherapy approach, HTCC demonstrated enhanced tumor growth inhibition and minimized systemic toxicity in a tumor-bearing mouse model. Conclusion: Our results suggested that controlled dual-drug release not only improved tumor drug delivery efficacy, but also reduced systemic side effects. In addition to HCPT and Ce6 delivery, the HA-tk-CA nanocomplex can be used to deliver other drugs in synergistic cancer therapy. Since most current combined therapy uses free drugs with distinct spatiotemporal distributions, the simultaneous co-delivery of dual drugs with a remote on-demand drug delivery nanosystem provides an alternative strategy for drug delivery design.

Near-Infrared Phototheranostic Iron Pyrite Nanocrystals Simultaneously Induce Dual Cell Death Pathways via Enhanced Fenton Reactions in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is considered more aggressive with a poorer prognosis than other breast cancer subtypes. Through systemic bioinformatic analyses, we established the ferroptosis potential index (FPI) based on the expression profile of ferroptosis regulatory genes and found that TNBC has a higher FPI than non-TNBC in human BC cell lines and tumor tissues. To exploit this finding for potential patient stratification, we developed biologically amenable phototheranostic iron pyrite FeS2 nanocrystals (NCs) that efficiently harness near-infrared (NIR) light, as in photovoltaics, for multispectral optoacoustic tomography (MSOT) and photothermal ablation with a high photothermal conversion efficiency (PCE) of 63.1%. Upon NIR irradiation that thermodynamically enhances Fenton reactions, dual death pathways of apoptosis and ferroptosis are simultaneously triggered in TNBC cells, comprehensively limiting primary and metastatic TNBC by regulating p53, FoxO, and HIF-1 signaling pathways and attenuating a series of metabolic processes, including glutathione and amino acids. As a unitary phototheranostic agent with a safe toxicological profile, the nanocrystal represents an effective way to circumvent the lack of therapeutic targets and the propensity of multisite metastatic progression in TNBC in a streamlined workflow of cancer management with an integrated image-guided intervention.

Comprehensive properties of photodynamic antibacterial film based on κ-Carrageenan and curcumin-ß-cyclodextrin complex.

In this study, a biodegradable photodynamic antibacterial film (Car-Cur) was prepared using casting method with κ-Carrageenan (κ-Car) as film-forming substrate and curcumin-ß-cyclodextrin (Cur-ß-CD) complex as photosensitizer. The comprehensive performance of this Car-Cur film was investigated. The obtained results showed that the concentration of Cur-ß-CD was an important factor determining the properties of film including tensile strength (TS) elongation at break (EB), water vapor permeability (WVP), water content (WC) and thermal stability. When the concentration of Cur-ß-CD is 1%, the film demonstrated the maximum TS and EB, increased thermal stability, with desirable WVP and WC. Furthermore, this film also showed good photodynamic antibacterial potential against Staphylococcus aureus and Escherichia coli upon irradiation of blue LED light. Moreover, the film can be degraded in the soil in one week. In conclusion, our results suggested Car-Cur photodynamic film could be developed as biodegradable antimicrobial packaging material for food preservation.

Photomedicine based on heme-derived compounds.

Photoimaging and phototherapy have become major platforms for the diagnosis and treatment of various health complications. These applications require a photosensitizer (PS) that is capable of absorbing light from a source and converting it into other energy forms for detection and therapy. While synthetic inorganic materials such as quantum dots and gold nanorods have been widely explored for their medical diagnosis and photodynamic (PDT) and photothermal (PTT) therapy capabilities, translation of these technologies has lagged, primarily owing to potential cytotoxicity and immunogenicity issues. Of the various photoreactive molecules, the naturally occurring endogenous compound heme, a constituent of red blood cells, and its derivatives, porphyrin, biliverdin and bilirubin, have shown immense potential as noteworthy candidates for clinically translatable photoreactive agents, as evidenced by previous reports. While porphyrin-based photomedicines have attracted significant attention and are well documented, research on photomedicines based on two other heme-derived compounds, biliverdin and bilirubin, has been relatively lacking. In this review, we summarize the unique photoproperties of heme-derived compounds and outline recent efforts to use them in biomedical imaging and phototherapy applications.

Photochemically-Mediated Inflammation and Cross-Presentation of Mycobacterium bovis BCG Proteins Stimulates Strong CD4 and CD8 T-Cell Responses in Mice.

Conventional vaccines are very efficient in the prevention of bacterial infections caused by extracellular pathogens due to effective stimulation of pathogen-specific antibodies. In contrast, considering that intracellular surveillance by antibodies is not possible, they are typically less effective in preventing or treating infections caused by intracellular pathogens such as Mycobacterium tuberculosis. The objective of the current study was to use so-called photochemical internalization (PCI) to deliver a live bacterial vaccine to the cytosol of antigen-presenting cells (APCs) for the purpose of stimulating major histocompatibility complex (MHC) I-restricted CD8 T-cell responses. For this purpose, Mycobacterium bovis BCG (BCG) was combined with the photosensitiser tetraphenyl chlorine disulfonate (TPCS2a) and injected intradermally into mice. TPCS2a was then activated by illumination of the injection site with light of defined energy. Antigen-specific CD4 and CD8 T-cell responses were monitored in blood, spleen, and lymph nodes at different time points thereafter using flow cytometry, ELISA and ELISPOT. Finally, APCs were infected and PCI-treated in vitro for analysis of their activation of T cells in vitro or in vivo after autologous vaccination of mice. Combination of BCG with PCI induced stronger BCG-specific CD4 and CD8 T-cell responses than treatment with BCG only or with BCG and TPCS2a without light. The overall T-cell responses were multifunctional as characterized by the production of IFN-γ, TNF-α, IL-2 and IL-17. Importantly, PCI induced cross-presentation of BCG proteins for stimulation of antigen-specific CD8 T-cells that were particularly producing IFN-γ and TNF-α. PCI further facilitated antigen presentation by causing up-regulation of MHC and co-stimulatory proteins on the surface of APCs as well as their production of TNF-α and IL-1ß in vivo. Furthermore, PCI-based vaccination also caused local inflammation at the site of vaccination, showing strong infiltration of immune cells, which could contribute to the stimulation of antigen-specific immune responses. This study is the first to demonstrate that a live microbial vaccine can be combined with a photochemical compound and light for cross presentation of antigens to CD8 T cells. Moreover, the results revealed that PCI treatment strongly improved the immunogenicity of M. bovis BCG.

Iodinated cyanine dye-based nanosystem for synergistic phototherapy and hypoxia-activated bioreductive therapy.

Photodynamic therapy (PDT) has been applied in cancer treatment by utilizing reactive oxygen species (ROS) to kill cancer cells. However, the effectiveness of PDT is greatly reduced due to local hypoxia. Hypoxic activated chemotherapy combined with PDT is expected to be a novel strategy to enhance anti-cancer therapy. Herein, a novel liposome (LCT) incorporated with photosensitizer (PS) and bioreductive prodrugs was developed for PDT-activated chemotherapy. In the design, CyI, an iodinated cyanine dye, which could simultaneously generate enhanced ROS and heat than other commonly used cyanine dyes, was loaded into the lipid bilayer; while tirapazamine (TPZ), a hypoxia-activated prodrug was encapsulated in the hydrophilic nucleus. Upon appropriate near-infrared (NIR) irradiation, CyI could simultaneously produce ROS and heat for synergistic PDT and photothermal therapy (PTT), as well as provide fluorescence signals for precise real-time imaging. Meanwhile, the continuous consumption of oxygen would result in a hypoxia microenvironment, further activating TPZ free radicals for chemotherapy, which could induce DNA double-strand breakage and chromosome aberration. Moreover, the prepared LCT could stimulate acute immune response through PDT activation, leading to synergistic PDT/PTT/chemo/immunotherapy to kill cancer cells and reduce tumor metastasis. Both in vitro and in vivo results demonstrated improved anticancer efficacy of LCT compared with traditional PDT or chemotherapy. It is expected that these iodinated cyanine dyes-based liposomes will provide a powerful and versatile theranostic strategy for tumor target phototherapy and PDT-induced chemotherapy.

Efficacy of hemoporfin photodynamic therapy for pulsed dye laser-resistant facial port-wine stains in 107 children: A retrospective study.

BACKGROUND: Port-wine stains occur in 0.3-0.5% newborns, mainly on the face and neck. Pulsed dye laser is recognized as the gold standard treatment; nevertheless, it is associated with a low cure rate and a high recurrence rate. AIMS: This study aims to evaluate the efficacy of hemoporfin photodynamic therapy for pulsed dye laser-resistant port-wine stains in children. METHODS: We studied 107 children who received hemoporfin photodynamic therapy for port-wine stains on the face and neck that were resistant to pulsed dye laser. After intravenous injection of 5 mg/kg hemoporfin, the local lesion was irradiated with 532 nm LED green light for 20 min with a power density of 80-100 mW/cm2. A total of 65 patients were given a second treatment after eight weeks. The efficacy and therapeutic responses were recorded at four days and eight weeks after each treatment. RESULTS: The efficacy was positively correlated with the number of treatments received; two treatment sessions yielded significantly better results compared to a single treatment with a response rate of 96.9%, a significant response rate of 50.8% and a cure rate of 21.5%, respectively (P < 0.001). After two treatment sessions, the efficacy was negatively correlated with age (P = 0.04). The efficacy for port-wine stains located on the lateral part was better than that of the central face (P = 0.04). The efficacy for the pink type was better than that for the red and purple types (P = 0.03). No allergic or systematic adverse reactions were reported. LIMITATIONS: No objective measurement data were available. CONCLUSION: Hemoporfin photodynamic therapy is effective and safe for pulsed dye laser-resistant facial port-wine stains in children.

Comparison between 5-aminolevulinic acid photodynamic diagnosis and narrow-band imaging for bladder cancer detection.

BACKGROUND: To compare 5-aminolevulinic acid (5-ALA)-mediated photodynamic diagnosis (PDD) with narrow-band imaging (NBI) for cancer detection during transurethral resection of bladder tumour (TURBT). METHODS: Between June 2018 and October 2020, 114 patients and 282 lesions were included in the analysis. Patients were orally administered 5-ALA (20 mg/kg) 2 h before TURBT. The bladder was inspected with white light (WL), PDD, and NBI for each patient, and all areas positive by at least one method were resected or biopsied. The imaging data were then compared to the pathology results. RESULTS: The sensitivities of WL, PDD, and NBI for detecting urothelial carcinoma were 88.1%, 89.6%, and 76.2%, respectively. The specificity, positive predictive value, and negative predictive value for detecting urothelial carcinoma were 47.5%, 80.9%, and 61.3%, respectively, for WL; 22.5%, 74.5%, and 46.2%, respectively, for PDD; and 46.3%, 78.2%, and 43.5%, respectively, for NBI. PDD was significantly more sensitive than NBI for all lesions (p < 0.001) and carcinoma in situ (CIS) lesions (94.6% vs. 54.1%, p < 0.001). CONCLUSIONS: PDD can increase the detection rate of bladder cancer, compared to NBI, by greater than 10%. Therefore, 100% of CIS lesions can be detected by adding PDD to WL.

Phototherapy and optical waveguides for the treatment of infection.

With rapid emergence of multi-drug resistant microbes, it is imperative to seek alternative means for infection control. Optical waveguides are an auspicious delivery method for precise administration of phototherapy. Studies have shown that phototherapy is promising in fighting against a myriad of infectious pathogens (i.e. viruses, bacteria, fungi, and protozoa) including biofilm-forming species and drug-resistant strains while evading treatment resistance. When administered via optical waveguides, phototherapy can treat both superficial and deep-tissue infections while minimizing off-site effects that afflict conventional phototherapy and pharmacotherapy. Despite great therapeutic potential, exact mechanisms, materials, and fabrication designs to optimize this promising treatment option are underexplored. This review outlines principles and applications of phototherapy and optical waveguides for infection control. Research advances, challenges, and outlook regarding this delivery system are rigorously discussed in a hope to inspire future developments of optical waveguide-mediated phototherapy for the management of infection and beyond.

A 12-month follow-up split-scalp study comparing calcipotriol-assisted MAL-PDT with conventional MAL-PDT for the treatment of actinic keratosis: a randomized controlled trial.

To enhance the efficacy of photodynamic therapy (PDT) for actinic keratosis (AKs), physical and chemical pre-treatments, such as calcipotriol (CAL) have been suggested. To compare the long-term 12-month efficacy and safety between methylaminolevulinate (MAL)-PDT and prior application of topical CAL versus conventional MAL-PDT for AKs of the scalp. Twenty patients with multiple AKs on the scalp were randomized to receive conventional PDT on one side of the scalp and CAL-assisted PDT, in which CAL was applied daily for 15 days beforehand, on the other side. Patients were evaluated for AK clearance at three, six and 12 months thereafter. All 20 patients completed the study. At three months, overall AK clearance was 92.07% and 82.04% for CAL-PDT and conventional PDT, respectively (p < 0.001). Similar results were found at six and 12 months: 92.07% and 81.69% (p < 0.001), and 90.69% and 77.46% (p < 0.001) for CAL-PDT and conventional PDT, respectively. Grade I AKs showed a similar response rate for both sides (p = 0.055) at three months and significant differences were obtained at six (p = 0.001) and 12 months (p < 0.001) for CAL-PDT and conventional PDT. Grade II AKs showed greater improvement on the CAL-PDT side (89.55% vs 62.90%) (p < 0.001) at three months. No difference was found at six and 12 months. CAL-PDT proved to be safe and more effective than conventional PDT for the treatment of AKs on the scalp after 12 months. CAL pre-treatment may have enhanced the efficacy of PDT for AK treatment, however, larger trials are needed to corroborate our findings.

Corneal riboflavin gradients and UV-absorption characteristics after topical application of riboflavin in concentrations ranging from 0.1 to 0.5.

Avoiding damage of the endothelial cells, especially in thin corneas, remains a challenge in corneal collagen crosslinking (CXL). Knowledge of the riboflavin gradients and the UV absorption characteristics after topical application of riboflavin in concentrations ranging from 0.1% to 0.5% could optimize the treatment. In this study, we present a model to calculate the UV-intensity depending on the corneal thickness. Ten groups of de-epithelialized porcine corneas were divided into 2 subgroups. Five groups received an imbibition of 10 min and the other five groups for 30 min. The applied riboflavin concentrations were 0.1%, 0.2%, 0.3%, 0.4% and 0.5% diluted in a 15% dextran solution for each subgroup. After the imbibition process, two-photon fluorescence microscopy was used to determine fluorescence intensity, which was compared to samples after saturation, yielding the absolute riboflavin concentration gradient of the cornea. The extinction coefficient of riboflavin solutions was measured using a spectrophotometer. Combining the obtained riboflavin concentrations and the extinction coefficients, a depth-dependent UV-intensity profile was calculated for each group. With increasing corneal depth, the riboflavin concentration decreased for all imbibition solutions and application times. The diffusion coefficients of 10 min imbibition time were higher than for 30 min. A higher RF concentration and a longer imbibition time resulted in higher UV-absorption and a lower UV-intensity in the depth of the cornea. Calculated UV-transmission was 6 percentage points lower compared to the measured transmission. By increasing the riboflavin concentration of the imbibition solution, a substantially higher UV-absorption inside the cornea is achieved. This offers a simple treatment option to control the depth of crosslinking e.g. in thin corneas, resulting in a lower risk of endothelial damage.

Nanoparticle-Mediated Delivery Systems in Photodynamic Therapy of Colorectal Cancer.

Colorectal cancer (CRC) involving a malignant tumour remains one of the greatest contributing causes of fatal mortality and has become the third globally ranked malignancy in terms of cancer-associated deaths. Conventional CRC treatment approaches such as surgery, radiation, and chemotherapy are the most utilized approaches to treat this disease. However, they are limited by low selectivity and systemic toxicity, so they cannot completely eradicate this disease. Photodynamic therapy (PDT) is an emerging therapeutic modality that exerts selective cytotoxicity to cancerous cells through the activation of photosensitizers (PSs) under light irradiation to produce cytotoxic reactive oxygen species (ROS), which then cause cancer cell death. Cumulative research findings have highlighted the significant role of traditional PDT in CRC treatment; however, the therapeutic efficacy of the classical PDT strategy is restricted due to skin photosensitivity, poor cancerous tissue specificity, and limited penetration of light. The application of nanoparticles in PDT can mitigate some of these shortcomings and enhance the targeting ability of PS in order to effectively use PDT against CRC as well as to reduce systemic side effects. Although 2D culture models are widely used in cancer research, they have some limitations. Therefore, 3D models in CRC PDT, particularly multicellular tumour spheroids (MCTS), have attracted researchers. This review summarizes several photosensitizers that are currently used in CRC PDT and gives an overview of recent advances in nanoparticle application for enhanced CRC PDT. In addition, the progress of 3D-model applications in CRC PDT is discussed.

Photodynamic Therapy with Tumor Cell Discrimination through RNA-Targeting Ability of Photosensitizer.

Photodynamic therapy (PDT) represents an effective treatment to cure cancer. The targeting ability of the photosensitizer is of utmost importance. Photosensitizers that discriminate cancer cells can avoid the killing of normal cells and improve PDT efficacy. However, the design and synthesis of photosensitizers conjugated with a recognition unit of cancer cell markers is complex and may not effectively target cancer. Considering that the total RNA content in cancer cells is commonly higher than in normal cells, this study has developed the photosensitizer QICY with RNA-targeting abilities for the discrimination of cancer cells. QICY was specifically located in cancer cells rather than normal cells due to their stronger electrostatic interactions with RNA, thereby further improving the PDT effects on the cancer cells. After intravenous injection into mice bearing a xenograft tumor, QICY accumulated into the tumor location through the enhanced permeability and retention effect, automatically targeted cancer cells under the control of RNA, and inhibited tumor growth under 630 nm laser irradiation without obvious side effects. This intelligent photosensitizer with RNA-targeting ability not only simplifies the design and synthesis of cancer-cell-targeting photosensitizers but also paves the way for the further development of highly efficient PDTs.

New-generation photosensitizer-anchored gold nanorods for a single near-infrared light-triggered targeted photodynamic-photothermal therapy.

Traditional combined photodynamic and photothermal therapy (PDT/PTT) was limited in clinical treatment of cancer due to the exceptionally low drug delivery efficiency to tumor sites and the activation by laser excitation with different wavelengths. We have accidentally discovered that our synthesized chlorin e6-C-15-ethyl ester (HB, a new type of photosensitizer) be activated by a laser with an excitation wavelength of 660 nm. Herein, we utilized Au nanorods (AuNRs) as 660 nm-activated PTT carriers to be successively surface-functionalized with HB and tumor-targeting peptide cyclic RGD (cRGD) to develop HB-AuNRs@cRGD for single NIR laser-induced targeted PDT/PTT. The HB-AuNRs@cRGD could be preferentially accumulated within tumor sites and rapidly internalized by cancer cells. Thereby, the HB-AuNRs@cRGD could exhibit amplified therapeutic effects by producing both significant reactive oxygen species (ROS) and hyperthermia simultaneously under the guidance of fluorescence imaging. The tumor inhibition rate on ECA109 esophageal cancer model was approximately 77.04%, and the negligible systematic toxicity was observed. This study proposed that HB-AuNRs@cRGD might be a promising strategy for single NIR laser-induced and imaging-guided targeted bimodal phototherapy.

Rationally designed upconversion nanoparticles for NIR light-controlled lysosomal escape and nucleus-based photodynamic therapy.

Cell nucleus-based photodynamic therapy is a highly effective method for cancer therapy, but it is still challenging to design nucleus-targeting photosensitizers. Here, we propose the "one treatment, multiple irradiations" strategy to achieve nucleus-based photodynamic therapy using the photosensitizer rose bengal (RB)-loaded and mesoporous silica-coated upconversion nanoparticles with the surface modification of amine group (UCNP/RB@mSiO2-NH2 NPs). After implementation into cancer cells, the rationally designed UCNP/RB@mSiO2-NH2 NPs could be specifically accumulated in the acidic lysosomes due to their amino group-decorated surface. Upon a short-term (3 min) irradiation of 980 nm near-infrared light, the reactive oxygen species produced by RB through the Förster resonance energy transfer between the upconversion nanoparticles and RB molecules could effectively destroy lysosomes, followed by the release of the UCNP/RB@mSiO2-NH2 NPs from the lysosomes. Subsequently, these released UCNP/RB@mSiO2-NH2 NPs could be transferred into the cell nucleus, where a second 980 nm light irradiation was conducted to achieve the nucleus-based photodynamic therapy. The rationally designed UCNP/RB@mSiO2-NH2 NPs showed excellent anticancer performance in both two-dimensional and three-dimensional cell models using the "one treatment, multiple irradiations" strategy.

In Vivo Study of the Efficacy and Safety of 5-Aminolevulinic Radiodynamic Therapy for Glioblastoma Fractionated Radiotherapy.

To treat malignant glioma, standard fractionated radiotherapy (RT; 60 Gy/30 fractions over 6 weeks) was performed post-surgery in combination with temozolomide to improve overall survival. Malignant glioblastoma recurrence rate is extremely high, and most recurrent tumors originate from the excision cavity in the high-dose irradiation region. In our previous study, protoporphyrin IX physicochemically enhanced reactive oxygen species generation by ionizing radiation and combined treatment with 5-aminolevulinic acid (5-ALA) and ionizing radiation, while radiodynamic therapy (RDT) improved tumor growth suppression in vivo in a melanoma mouse model. We examined the effect of 5-ALA RDT on the standard fractionated RT protocol using U251MG- or U87MG-bearing mice. 5-ALA was orally administered at 60 or 120 mg/kg, 4 h prior to irradiation. In both models, combined treatment with 5-ALA slowed tumor progression and promoted regression compared to treatment with ionizing radiation alone. The standard fractionated RT protocol of 60 Gy in 30 fractions with oral administration of 120 and 240 mg/kg 5-ALA, the human equivalent dose of photodynamic diagnosis, revealed no significant increase in toxicity to normal skin or brain tissue compared to ionizing radiation alone. Thus, RDT is expected to enhance RT treatment of glioblastoma without severe toxicity under clinically feasible conditions.