All-in-One Nanohybrids Combining Sonodynamic Photodynamic and Photothermal Therapies.

A wide variety of methods are being developed to ultimately defeat cancer; while some of these strategies have shown highly positive results, there are serious obstacles to overcome to completely eradicate this disease. So, it is crucial to construct multifunctional nanostructures possessing intelligent capabilities that can be utilized to treat cancer. A possible strategy for producing these multifunctional nanostructures is to combine various cancer treatment techniques. Based on this point of view, we successfully synthesized multifunctional HCuS@Cu2S@Au-P(NIPAM-co-AAm)-PpIX nanohybrids. The peculiarities of these thermosensitive polymer-modified and protoporphyrin IX (PpIX)-loaded hollow nanohybrids are that they combine photodynamic therapy (PDT), sonodynamic therapy (SDT), and photothermal therapy (PTT) with an intelligent design. As an all-in-one nanohybrids, HCuS@Cu2S@Au-P(NIPAM-co-AAm)-PpIX nanohybrids were employed in the SDT-PDT-PTT combination therapy, which proved to have a synergistic therapeutic effect for in vitro tumor treatments against breast tumors.

A Hemoglobin Bionics-Based System for Combating Antibiotic Resistance in Chronic Diabetic Wounds via Iron Homeostasis Regulation.

Owing to the increased tissue iron accumulation in patients with diabetes, microorganisms may activate high expression of iron-involved metabolic pathways, leading to the exacerbation of bacterial infections and disruption of systemic glucose metabolism. Therefore, an on-demand transdermal dosing approach that utilizes iron homeostasis regulation to combat antimicrobial resistance is a promising strategy to address the challenges associated with low administration bioavailability and high antibiotic resistance in treating infected diabetic wounds. Here, it is aimed to propose an effective therapy based on hemoglobin bionics to induce disturbances in bacterial iron homeostasis. The preferred "iron cargo" is synthesized by protoporphyrin IX chelated with dopamine and gallium (PDGa), and is delivered via a glucose/pH-responsive microneedle bandage (PDGa@GMB). The PDGa@GMB downregulates the expression levels of the iron uptake regulator (Fur) and the peroxide response regulator (perR) in Staphylococcus aureus, leading to iron nutrient starvation and oxidative stress, ultimately suppressing iron-dependent bacterial activities. Consequently, PDGa@GMB demonstrates insusceptibility to genetic resistance while maintaining sustainable antimicrobial effects (>90%) against resistant strains of both S. aureus and E. coli, and accelerates tissue recovery (<20 d). Overall, PDGa@GMB not only counteracts antibiotic resistance but also holds tremendous potential in mediating microbial-host crosstalk, synergistically attenuating pathogen virulence and pathogenicity.

Nanoparticles drug delivery for 5-aminolevulinic acid (5-ALA) in photodynamic therapy (PDT) for multiple cancer treatment: a critical review on biosynthesis, detection, and therapeutic applications.

Photodynamic therapy (PDT) is a promising cancer treatment that kills cancer cells selectively by stimulating reactive oxygen species generation with photosensitizers exposed to specific light wavelengths. 5-aminolevulinic acid (5-ALA) is a widely used photosensitizer. However, its limited tumour penetration and targeting reduce its therapeutic efficacy. Scholars have investigated nano-delivery techniques to improve 5-ALA administration and efficacy in PDT. This review summarises recent advances in biological host biosynthetic pathways and regulatory mechanisms for 5-ALA production. The review also highlights the potential therapeutic efficacy of various 5-ALA nano-delivery modalities, such as nanoparticles, liposomes, and gels, in treating various cancers. Although promising, 5-ALA nano-delivery methods face challenges that could impair targeting and efficacy. To determine their safety and biocompatibility, extensive preclinical and clinical studies are required. This study highlights the potential of 5-ALA-NDSs to improve PDT for cancer treatment, as well as the need for additional research to overcome barriers and improve medical outcomes.

An Analysis of the Effects of In Vitro Photodynamic Therapy on Prostate Cancer Tissue by Histopathological Examination and Magnetic Resonance Imaging.

Prostate cancer can significantly shorten the lifetime of a patient, even if he is diagnosed at an early stage. The development of minimally-invasive focal therapies such as photodynamic therapy to reduce the number of neoplastic cells while sparing delicate structures is extremely advantageous for treating prostate cancer. This study investigates the effect of photodynamic therapy performed in prostate tissue samples in vitro, using quantitative magnetic resonance imaging and histopathological analysis. Prostate tissue samples were treated with oxygenated solutions of Rose Bengal (RB) or protoporphyrin IX disodium salt (PpIX), illuminated with visible light, and then analyzed for changes in morphology by microscopy and by measurement of spin-lattice and spin-spin relaxation times at 1.5 Tesla. In the treated prostate tissue samples, histopathological images revealed chromatin condensation and swelling of the stroma, and in some cases, thrombotic necrosis and swelling of the stroma accompanied by pyknotic nuclei occurred. Several samples had protein fragments in the stroma. Magnetic resonance imaging of the treated prostate tissue samples revealed differences in the spin-lattice and spin-spin relaxation times prior to and post photodynamic action.

5-Aminolevulinic acid-based photodynamic diagnosis for detection of urothelial carcinoma cells in bladder washing sediment suspension: A pilot study.

BACKGROUND: Bladder cancer is a common malignant disease in developed countries. Early detection of malignancy is important using urine cytology. The 5-aminolevulinic acid (ALA)-based photodynamic diagnosis (ALA-PDD) has not been routinely applied in urine cytology analysis yet, although it has been well accepted for tumor lesion marking in cystoscopy. METHODS: A total of eight volunteers were enrolled in this study. The cells of sediment suspension from bladder washing fluid and random urine were stained by ALA-induced protoporphyrin IX (ALA-PpIX) and the fluorescent intensity of ALA-PpIX was analyzed by ImageJ. RESULTS: The cutoff value of fluorescent intensity was 90.260 per pixel. The proposed protocol provided an objective fluorescent intensity for evaluation. Sensitivity was 0.931 and specificity was 1.000. CONCLUSIONS: The staining procedure applied was ALA-PpIX for suspicious cells in the cellular suspension from bladder wash fluid and random urine. ImageJ was applied to the objective measurement for the fluorescent intensity of the stained cells. The cutoff value for the positive result was 90.260 per pixel. Therefore, the protocol proposed in this study provides a potential means to enhance accuracy for urine cytology analysis.

Mechanisms of Resistance to Photodynamic Therapy (PDT) in Vulvar Cancer.

Photodynamic therapy (PDT) is a valuable treatment method for vulvar intraepithelial neoplasia (VIN). It allows for the treatment of a multifocal disease with minimal tissue destruction. 5-Aminolevulinic acid (5-ALA) is the most commonly used prodrug, which is converted in the heme pathway to protoporphyrin IX (PpIX), an actual photosensitizer (PS). Unfortunately, not all patients treated with PDT undergo complete remission. The main cause of their failure is resistance to anticancer therapy. In many cancers, resistance to various anticancer treatments is correlated with increased activity of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1). Enhanced activity of drug pumps may also affect the effectiveness of therapy. To investigate whether multidrug resistance mechanisms underlie PDT resistance in VIN, porphyrins were isolated from sensitive and resistant vulvar cancer cells and their culture media. APE1 activity was measured, and survival assay after PDT combined with APE1 inhibitor was performed. Our results revealed that resistant cells accumulated and effluxed less porphyrins than sensitive cells, and in response to PDT, resistant cells increased APE1 activity. Moreover, PDT combined with inhibition of APE1 significantly decreased the survival of PDT-resistant cells. This means that resistance to PDT in vulvar cancer may be the result of alterations in the heme synthesis pathway. Moreover, increased APE1 activity may be essential for the repair of PDT-mediated DNA damage, and inhibition of APE1 activity may increase the efficacy of PDT.

A Versatile Nanoplatform for Broad-Spectrum Immunotherapy by Reversing the Tumor Microenvironment.

Immunotherapy is currently an important adjuvant therapy for malignant tumors besides surgical treatment. However, the heterogeneity and low immunogenicity of the tumor are two main challenges of the immunotherapy. Here, we have constructed a nanoplatform (CP@mRBC-PpIX) to realize reversion of the tumor acidosis and hypoxia through alkali and oxygen generation triggered by tumor acidosis. By targeting tumor universal features other than endogenous biomarkers, it was found that CP@mRBC-PpIX could polarize tumor-associated macrophages to anti-tumor M1 phenotype macrophages to enhance tumor immune response. Furthermore, under regional light irradiation, the reactive oxygen species produced by photosensitizers located in CP@mRBC-PpIX could increase the immunogenicity of tumors, so that tumor changes from an immunosuppressive "cold tumor" to an immunogenic "hot tumor," thereby increasing the infiltration and response of T cells, further amplifying the effect of immunotherapy. This strategy circumvented the problem of tumor heterogeneity to realize a kind of broad-spectrum immunotherapy, which could effectively prevent tumor metastasis and recurrence.

Fluorescence and thermal imaging of non-melanoma skin cancers before and during photodynamic therapy.

BACKGROUND: Photodynamic therapy (PDT) has been shown to be less effective on the extremities. Protoporphyrin-IX (PpIX) fluorescence and skin surface temperature are variables that have been implicated in the differences in efficacy with body site, but objective studies have not been undertaken. OBJECTIVES: To further investigate observations from our previous study that temperature and fluorescence during pro-drug incubation are correlated, through a prospective objective investigation of the relationships between fluorescence and skin surface temperature before and during PDT and relationships with body site and efficacy. METHODS: Eighteen patients with Bowen's disease or basal cell carcinoma, who had been referred for PDT, were recruited to this study. PpIX fluorescence and thermal measurements were recorded at intervals during the pro-drug incubation and irradiation phases of PDT. Pain immediately after irradiation, and outcome at 3- and 12-months were recorded. RESULTS: Temperature and PpIX fluorescence were higher on the trunk than lower leg immediately before treatment (median temperature 32.7 °C vs. 27.8 °C, p < 0.05 and median fluorescence 16.5 vs. 6.7, p < 0.05). Higher pain levels were reported during PDT on the extremities (median 5.7 vs. 2.2, p < 0.05). Clearance rates at 12-months were 80 %. CONCLUSIONS: The study supports a correlation between temperature and PpIX fluorescence during PDT, providing robust objective data to support our previous hypothesis and observations. The higher pain levels, lower PpIX fluorescence on the lower leg, and the high efficacy rates at all body sites irrespective of temperature and fluorescence indicates that relationships between PDT treatment conditions and parameters is likely to be multifactorial.

The sustaining of fluorescence in photodynamic diagnosis after the administration of 5-aminolevulinic acid in carcinogen-induced bladder cancer orthotopic rat model and urothelial cancer cell lines.

BACKGROUND: The administration of 5-aminolevulic acid hydrochloride (5-ALA·HCl) 3 h (range: 2-4 h) before photodynamic diagnosis (PDD) is recommended for detecting bladder tumors. However, there is insufficient evidence on the time duration for the fluorescence of PDD after oral administration of 5-ALA. We investigated the sustainability of the photodynamic effect and protoporphyrinⅨ (PpⅨ) after 5-ALA administration in a carcinogen-induced bladder tumor rat model and bladder cancer cell lines. METHODS: The carcinogen-induced bladder tumor orthotopic rat model was established by the administration of N-butyl-N-(4-hydroxybutyl) nitrosamine. RESULTS: Red fluorescence was visible 2-8 h after the oral administration of 5-ALA in the carcinogen-induced bladder tumor rat model. Plasma and intratissue PpⅨ (nM) progressed to a higher level at 2 h and remained almost constant 2-8 h after oral administration of 5-ALA. The peak fluorescence intensity of PpⅨ was observed 3-4 h after the administration of 5-ALA in bladder cancer cell lines. The accumulated PpⅨ remained for 4 h after the removal of 5-ALA in UMUC3 cells. It was not clearly visible 3 h after the removal of 5-ALA in MGHU3 and T24 cells. The expression level of ferrochelatase was significantly lower in UMUC3 cells than in other cells. Our findings suggest that 5-ALA-assisted PDD (ALA-PDD) can aid in detecting non-muscle-invasive bladder cancer 2-8 h after 5-ALA administration. CONCLUSION: Urologists might not be required to make excess effort to start ALA-PDD-assisted transurethral resection of bladder tumor after the administration of 5-ALA.

Co-delivery of chitosan nanoparticles of 5-aminolevulinic acid and shGBAS for improving photodynamic therapy efficacy in oral squamous cell carcinomas.

BACKGROUND: The improvement of gene therapy provides hope for the treatment of cancer. However, malignant tumor is a multifactorial disease, which remains difficult to be cured with a single therapy. Our previous study reported that mitochondrial genes glioblastoma-amplified sequence (GBAS) plays a role in the development and treatment of oral squamous cell carcinoma (OSCC). The current study focused on building a mitochondrial-targeting drug co-delivery system for combined photodynamic therapy (PDT) and gene therapy. METHODS: 5-aminolevulinic acid (ALA) photosensitizer loaded chitosan (CS) nanoparticles were prepared using ionic crosslinking method, and further synthesized with the GBAS gene plasmid DNA (shGBAS) by electrostatic attraction. We detected the effects of PDT using the co-delivery system (CS-ALA-shGBAS) on cell proliferation and mitochondrial injury by MTT and reactive oxygen species (ROS) assays, respectively. Additionally, a oral cancer Xenograft model of nude mice was built to test its inhibitive effect on the cancerous growth in vivo. RESULTS: A novel nanocomposite, CS-ALA-shGBAS, was found to be spherical structures and had good dispersion, stability and hypotoxicity. Gel retardation assay showed that CS-ALA nanoparticle could synthesize shGBAS at and above Nanoparticle/Plasmid ratios of 1/2. Excitingly, the co-delivery system was suitable for transfected cells and displayed a superior mitochondrially targeted killing effect on OSCC in vitro and in vivo. CONCLUSION: Our study provides evidence that the chitosan-based co-delivery system of ALA-induced protoporphyrin IX (PpIX) photosensitizer and GBAS gene may be a novel mode of combined therapy for OSCC.

Photodynamic and Sonodynamic Therapy with Protoporphyrin IX: In Vitro and In Vivo Studies.

Sono-photodynamic therapy is a promising anticancer technique based on the combination of sonodynamic and photodynamic therapy to improve the cancer treatment effectiveness. This study was aimed at analyzing the effects of the sono-photodynamic (SPD) activity on protoporphyrin IX (PpIX) solution and PpIX-loaded rat liver. In vitro, PpIX 5 µM solutions were irradiated with light (635 nm, 30-50 mW/cm2), ultrasound (1 MHz, 1-2 W/cm2) and both. The PpIX absorption spectra recorded over exposure time revealed that the PpIX decay rate induced by SPD activity (combined irradiation) was approximately the sum of those induced by photodynamic and sonodynamic activity. In vivo, rats were intraperitoneally injected with 5-aminolevulinic acid at the dose of 500 mg/kg weight. After 3 h of injection, the PpIX-loaded livers were irradiated with light (635 nm, 180 ± 9 J/cm2), ultrasound (1.0 MHz, 770 ± 40 J/cm2) and both using a single probe capable of illuminating and sonicating the liver simultaneously. After 30 h, the liver damage induced by each protocol was analyzed histologically. It was found that a greater necrosis depth was induced by the SPD activity. These results suggest that the SPD activity could improve the PpIX decay rate and have greater scope than photodynamic or sonodynamic activity. Further studies should be performed to gain a better understanding of this protocol.

Uptake of silver, gold, and hybrids silver-iron, gold-iron and silver-gold aminolevulinic acid nanoparticles by MCF-7 breast cancer cells.

BACKGROUND: Nanoparticles show promise for theranostic applications in cancer. The metal-based nanoparticles can be used both as photosensitizers and delivery vehicles. In bimetallic particles based on gold or silver and iron, a combination of the plasmonic features of the gold or silver components with the magnetic properties of the iron makes these hybrid nanomaterials suitable for both imaging and therapeutic applications. Herein, we discuss toxicity and cell internalization of metallic (silver and gold) and bimetallic (silver-iron, gold-iron, and silver-gold) aminolevulinic acid (ALA) nanoparticles. ALA can control the production of an intracellular photosensitizer, protoporphyrin IX (PpIX), commonly used in photodynamic therapy. METHODS: Nanoparticles were synthesized by photoreduction method and characterized by UV/Vis spectra, Zeta potential, FTIR, XRD, and transmission electron microscopy. The amount of singlet oxygen generation by a yellow LED, and ultrasound was studied for gold, gold-iron, and silver-gold nanoparticles. Cytotoxicity assays of MCF-7 in the presence of nanoparticles were performed, and PpIX fluorescence was quantified by high content screening (HCS). RESULTS: Red fluorescence observed after 24 h of nanoparticles incubation on MCF-7 cells, indicated that the ALA in surface of nanoparticles was efficiently converted to PpIX. The best results for singlet oxygen generation with LED or ultrasound irradiation were obtained with ALA:AgAuNPs. CONCLUSIONS: The studied nanoparticles present the potential to deliver aminolevulinic acid to breast cancer cells efficiently, generate singlet oxygen, and convert ALA into PpIX inside the cells allowing photodiagnosis and therapies such as photodynamic and sonodynamic therapies.

Photodynamic antimicrobial chemotherapy in mice with Pseudomonas aeruginosa-infected wounds.

This study examined the antibacterial effect of protoporphyrin IX-ethylenediamine derivative (PPIX-ED)-mediated photodynamic antimicrobial chemotherapy (PPIX-ED-PACT) against Pseudomonas aeruginosa in vitro and in vivo. PPIX-ED potently inhibited the growth of Pseudomonas aeruginosa by inducing reactive oxygen species production via photoactivation. Atomic force microscopy revealed that PPIX-ED-PACT induced the leakage of bacterial content by degrading the bacterial membrane and wall. As revealed using acridine orange/ethidium bromide staining, PPIX-ED-PACT altered the permeability of the bacterial membrane. In addition, the antibacterial effect of PPIX-ED-PACT was demonstrated in an in vivo model of P. aeruginosa-infected wounds. PPIX-ED (100 µM) decreased the number of P. aeruginosa colony-forming units by 4.2 log10. Moreover, histological analysis illustrated that the wound healing rate was 98% on day 14 after treatment, which was 10% higher than that in the control group. According to the present findings, PPIX-ED-PACT can effectively inhibit the growth of P. aeruginosa in vitro and in vivo.

ABCG2 influence on the efficiency of photodynamic therapy in glioblastoma cells.

BACKGROUND: Photodynamic therapy with 5-aminolevulinic acid (5-ALA PDT) is a promising novel therapeutic approach in the therapy of malignant brain tumors. 5-ALA occurs as a natural precursor of protoporphyrin IX (PpIX), a tumor-selective photosensitizer. The ATP-binding cassette transporter ABCG2 plays a physiologically significant role in porphyrin efflux from living cells. ABCG2 is also associated with stemness properties. Here we investigate the role of ABCG2 on the susceptibility of glioblastoma cells to 5-ALA PDT. METHODS: Accumulation of PpIX in doxycycline-inducible U251MG glioblastoma cells with or without induction of ABCG2 expression or ABCG2 inhibition by KO143 was analyzed using flow cytometry. In U251MG cells, ABCG2 was inducible by doxycycline after stable transfection with a tet-on expression plasmid. U251MG cells with high expression of ABCG2 were enriched and used for further experiments (sU251MG-V). PDT was performed on monolayer cell cultures by irradiation with laser light at 635 nm. RESULTS: Elevated levels of ABCG2 in doxycycline induced sU251MG-V cells led to a diminished accumulation of PpIX and higher light doses were needed to reduce cell viability. By inhibiting the ABCG2 transporter with the efficient and non-toxic ABCG2 inhibitor KO143, PpIX accumulation and PDT efficiency could be strongly enhanced. CONCLUSION: Glioblastoma cells with high ABCG2 expression accumulate less photosensitizer and require higher light doses to be eliminated. Inhibition of ABCG2 during photosensitizer accumulation and irradiation promises to restore full susceptibility of this crucial tumor cell population to photodynamic treatment.

The Effects of PK11195 and Protoporphyrin IX Can Modulate Chronic Alcohol Intoxication in Rat Liver Mitochondria under the Opening of the Mitochondrial Permeability Transition Pore.

Decades of active research have shown that mitochondrial dysfunction, the associated oxidative stress, impaired anti-stress defense mechanisms, and the activation of the proapoptotic signaling pathways underlie pathological changes in organs and tissues. Pathologies caused by alcohol primarily affect the liver. Alcohol abuse is the cause of many liver diseases, such as steatosis, alcoholic steatohepatitis, fibrosis, cirrhosis, and, potentially, hepatocellular cancer. In this study, the effect of chronic alcohol exposure on rat liver mitochondria was investigated. We observed an ethanol-induced increase in sensitivity to calcium, changes in the level of protein kinase Akt and GSK-3ß phosphorylation, an induction of the mitochondrial permeability transition pore (mPTP), and strong alterations in the expression of mPTP regulators. Moreover, we also showed an enhanced effect of PK11195 and PPIX, on the parameters of the mPTP opening in rat liver mitochondria (RLM) isolated from ethanol-treated rats compared to the RLM from control rats. We suggest that the results of this study could help elucidate the mechanisms of chronic ethanol action on the mitochondria and contribute to the development of new therapeutic strategies for treating the effects of ethanol-related diseases.

Optimization of 5-aminolevulinic acid-based photodynamic therapy protocol for breast cancer cells.

BACKGROUND: Photodynamic therapy (PDT) is a therapeutic strategy for the treatment of cancer. 5-aminolevulinic acid (5-ALA) as a precursor of the protoporphyrin IX (PpIX) has a great potential for PDT application. Although 5-ALA-based PDT has been studied in many pre-clinical and clinical studies for breast cancer, there are different PDT application protocols in the literature. Therefore, the aim of this study was to determine the optimal in vitro protocol for 5-ALA-based PDT in breast cancer treatment. METHODS: The therapeutic effects of 5-ALA (1 and 2.5 mM) on two different subtypes of breast cancer cell line (MCF-7 and MDA-MB-231) were evaluated by PpIX-fluorescence accumulation and WST-1 analysis. Then, the cells were irradiated with diode laser at different doses (1.5, 3, 6, 9 and 12 J/cm2). After irradiation, the anticancer effects of 5-ALA were analyzed through cell viability and cell death analysis. RESULTS: Our results showed that 5-ALA exhibited a higher PpIX fluorescence in both breast cancer cells for 4 h incubation. After irradiation, 1 mM 5-ALA significantly reduced the proliferation of breast cancer cells in a laser dose-dependent manner and induced apoptotic cell death upon 24 h incubation (p < 0.05). However, MDA-MB-231 cells were more sensitive to 5-ALA-based PDT than MCF-7 cells in a dose of 9 J/cm2 and 12 J/cm2. CONCLUSION: Our preliminary findings proposed an optimal in vitro protocol of 5-ALA-based PDT by using a laser diode for breast cancer. However, there is a need to investigate the underlying molecular mechanisms of 5-ALA/PDT sensitivity among the subtypes of breast cancer.

Mitomycin C-induced cell cycle arrest enhances 5-aminolevulinic acid-based photodynamic therapy for bladder cancer.

BACKGROUND: Photodynamic therapy (PDT) and diagnosis (PDD) using 5-aminolevulinic acid (ALA) to control the production of the intracellular photosensitizer protoporphyrin IX (PpIX) are commonly used clinically. Previously, we demonstrated that dormant and drug-induced dormancy-like cancer cells accumulated high PpIX levels, making them sensitive to ALA-PDT. Because EAU Guidelines awarded a level of evidence of 1a to mitomycin C, the drug is widely used to treat bladder cancer. In this study, we investigated that the effect of mitomycin C-induced cell cycle arrest on porphyrin metabolism, including that induced by ALA-PDT. METHODS: T24 human urinary bladder carcinoma cells were selected for this research. T24 cells were irradiated using a light-emitting diode emitting red light for the ALA-PDT assay. Cell cycle analysis was conducted by flow cytometry using bromodeoxyuridine. Cell viability was confirmed using the MTT or colony formation assay. Furthermore, mRNA gene expression analysis was performed using our previously reported methods. RESULTS: The cell cycle of T24 cells was arrested at G2/M phase by mitomycin C. PpIX accumulation was dramatically increased by mitomycin C treatment. Cell viability after ALA-PDT was remarkably decreased by mitomycin C pretreatment. The gene expression of porphyrin transporters was consistent with the metabolic and morphological results. Finally, we confirmed that ALA-PDT combined with mitomycin C treatment exerted a long-term inhibitory effect on cell proliferation. CONCLUSION: This study demonstrated a new approach to enhance the effects of ALA-PDT using drugs that induce a dormancy-like status and upregulate porphyrin metabolism.

Oxygen Self-Sufficient Core-Shell Metal-Organic Framework-Based Smart Nanoplatform for Enhanced Synergistic Chemotherapy and Photodynamic Therapy.

The abnormal angiogenesis and insufficient oxygen supply in solid tumors lead to intratumoral hypoxia, which severely limits the efficacy of traditional photodynamic therapy (PDT). Here, a multifunctional nanoplatform (ZDZP@PP) based on a zeolitic imidazolate framework-67 (ZIF-67) core as a hydrogen peroxide catalyst, a zeolitic imidazolate framework-8 (ZIF-8) shell with a pH-responsive property, and a polydopamine-poly(ethylene glycol) (PDA-PEG) layer for improving the biocompatibility is fabricated for not only relieving tumor hypoxia but also enhancing the efficacy of combination chemo-photodynamic therapy. The chemotherapy drug doxorubicin (DOX) and photosensitizer protoporphyrin IX (PpIX) are encapsulated in different layers independently; thus, a unique two-stage stepwise release becomes possible. Moreover, the nanoplatform can effectively decompose hydrogen peroxide to produce oxygen and thus relieve tumor hypoxia, which further facilitates the production of cytotoxic reactive oxygen species (ROS) by PpIX under laser irradiation. Both in vitro and in vivo experimental results confirm that the combination chemo-photodynamic therapy with the ZDZP@PP nanoplatform can provide more effective cancer treatment than chemotherapy or PDT alone. Consequently, the oxygen self-sufficient multifunctional nanoplatform holds promising potential to overcome hypoxia and treat solid tumors in the future.

Development of a system to treat and online monitor photodynamic therapy of skin cancer using PpIX near-infrared fluorescence.

The limited adoption of photodynamic therapy (PDT) around the medical field may be tied to the unpredicted treatment response that an unmonitored therapy could deliver. Given the high variability in the lesions optical and physiological parameters, it is of fundamental importance to monitor PDT, since different lesions require different therapeutic parameters. We developed a system to treat and online monitor PDT of skin cancer, using protoporphyrin-IX (PpIX) near-infrared fluorescence imaging. The system can be operated up to 150 mW/cm2 at 633 nm, with real-time fluorescence monitoring around 700 nm, using the treatment light itself for fluorescence excitation. This technology allows system portability, simplicity, and low cost. This study describes the system development and its comparison with a 400-450 nm commercial system to detect the PpIX fluorescence during a PDT in murine skin cancer model. The developed device was able to acquire considerably more fluorescence signal from deeper regions when compared to the violet excitation device.

Use of dermograph for improvement of PpIX precursor's delivery in photodynamic therapy: Experimental and clinical pilot studies.

BACKGROUND: Photodynamic Therapy (PDT) is a treatment for non-melanoma skin cancer. One of the main challenges of topical PDT is to increase the precursor penetration when applied on the lesion. Protoporphyrin IX (PpIX) is an endogenous photosensitizer (PS) widely used, obtained by the administration of precursors such as aminolevulinic acid and methyl aminolevulinate. Aiming for the technique improvement by providing greater PS penetration in skin lesions, we tested a new approach for drug delivery with a minimally invasive technique. A dermograph is a device currently used in aesthetic procedures to promote skin rejuvenation or to micropigmentation. The use of dermograph for drug delivery has not been particularly explored for PDT so far, and the present study explores that approach as its main goal. METHODS: This study evaluated the PpIX distribution and PDT damage in normal rat skin model; the response of dermograph application in a pilot clinical study was also investigated. RESULTS: The animal tests showed that more homogeneous PpIX distribution and greater penetration in the tissue was observed with dermograph when compared to the topical application. Six nodular basal cell carcinoma lesions were treated with PDT using intradermal delivery by dermograph, and no recurrence was observed after 28 months of follow-up. CONCLUSIONS: The precursor's penetration improvement and the consequent increase in PpIX distribution in-depth both favor PDT response, providing upgrades concerning problems that hinder the clinical practice acceptance.