Nanocomplex formation between riboflavin and β-lactoglobulin: Spectroscopic investigation and biological characterization

Photodynamic therapy (PDT) is actively developing, becoming one of the important methods of non-invasive treatment of various oncological and infectious diseases. It is usually carried out using three main components: a photosensitizer, light, and oxygen. The key factors for the effective use of PDT are reactogenic oxygen species, which are produced during the oxidation of photosensitizers under the influence of light irradiation.
 To increase the production of reactogenic oxygen species, a technique was proposed for creating photosensitizers with aggregation-induced emission. At the present stage in oncology, the following PDT methods using photosensitizers with aggregation-induced emission are distinguished: PDT, absorbing near infrared radiation; enzyme- or glutathione-activated PDT; hypoxic PDT, and synergistic therapy.
 Compared to visible light, near infrared radiation (7001700 nm) has been shown to be more effective and safer due to reduced photodamage, less scattering, and deeper light penetration. The development of activated photosensitizers is an effective way to overcome the uncontrolled phototoxicity of photosensitizers during long-term PDT in vivo, providing controlled death of tumor cells. The oxygen concentration in tumor tissue varies depending on tumor progression, angiogenesis, metabolism, and metastasis. Therefore, the development of photosensitizers capable of effectively fluorescing under hypoxic conditions, including catalyzing intracellular substrates with the formation of oxygen and stimulating the production of reactogenic oxygen species through the type I mechanism, has become a potential solution to the problem of PDT of solid tumors.
 The therapeutic efficacy of a single PDT method, as well as most treatment methods in modern oncology, is limited. Therefore, a significant direction is the development of multifunctional treatment systems for synergistic therapy of tumors. Synergistic chemotherapy and PDT is an important area of treatment in oncology. The combination of PDT and immunotherapy is also a promising direction in the treatment of malignant neoplasms.
 There are obvious prospects for PDT in oncology not as a separate method of treatment, but as part of a complex multimodal treatment, including chemotherapy, radiation therapy, surgical treatment, and immunotherapy.

We read with interest the recent article by Wang et al, reporting the clinical application of SF1 (Sonoflora 1)—a sensitizer that can be activated by light and ultrasound. SF1 is an analog of chlorophyll in that its macrocycle backbone is porphyrin-based and the center of the porphyrin ring consists of a metal ion. The chlorophyll derivative has light absorption peaks at 402 and 636 nm. A very unusual combination of this investigational agent and various prototype light sources and ultrasound devices was used in the treatment of three patients who suffered from late stages of breast cancer with systemic metastases to multiple organs. The combination of photosensitizer and light illumination is commonly known as photodynamic therapy (PDT) and the combination of drug or sonosensitizer and acoustic activation as sonodynamic therapy (SDT). In theory, the direct tumoricidal effects of these modalities are mediated by cytotoxic agents generated through photochemical or sonochemical reactions inside tumor tissue. The narrow gap between potential benefit and potential risk is determined by intrinsic cellular sensitivity and the sensitizer ratio between tumor and normal tissue. The synergistic effects of sensitizer and low-power ultrasound have been examined in many in vitro studies and to a lesser extent in in vivo models. Although the sonosensitization-induced cytotoxicity might be attributed to the sonochemical reaction, such as sensitizer-mediated energy transfer and free radical generation, data suggest that the mechanism of sonosensitization is probably not governed by a universal mechanism, but may be influenced by multiple factors including the nature of the biological model, sensitizer distribution, ultrasound parameters and acoustic energy distribution. Nevertheless, to date, the correlation between ultrasound parameters and biological effects has not been fully established in preclinical investigation (in vitro or in vivo). There is no convincing data that shows that ultrasound used in this way is effective in the treatment of primary tumor and multiple metastases. Therefore, this article raises a few basic questions. First of all, without those critical safety and efficacy information, it is unjustifiable to test the unproven prototypes in humans, particularly those in terminal stages for any purposes. The authors state that acoustic activation was delivered after intravenous administration of the chlorophyll derivative in two different modes—local and whole body ultrasound activation. A handheld ultrasound transducer was used for two patients, which was associated with a side effect of pain. Another patient was placed in a water tub to receive whole body ultrasound treatment. It was expected that ultrasound could reach deep-seated tumor(s) and sensitizers that are beyond the reach of external light of 630 nm. Although no details were provided in terms of the number of transducers in the water tub, the geometric distribution of acoustic energy within the body, and its accessibility to the multiple tumor sites (e.g., breast, lung, bones, liver, neck, axillary lymph nodes, and abdominal lymph nodes), the authors indicated that high acoustic power (2 W/cm at 1 MHz for 20 minutes) was used in both settings without providing justifications on the selection of those parameters. It is also questionable that sufficient acoustic energy will reach the deep-seated metastases in lung and bone tissues. Second, single high-dose PDT and metronomic PDT (i.e., to deliver photosensitizer and/or light doses at low rates over an extended period) have distinct and complementary therapeutic goals. In contrast to the conventional PDT regimen of single dose drug administration (intravenous or oral), the authors used a repeated lingual delivery of the chlorophyll derivative (a total dose of 30 or 60 mg) for 2 to 3 consecutive days followed by light plus ultrasound treatment daily for 3 days starting at day 3 or day 4 after the onset

Photodynamic therapy (PDT) mediated by hematoporphyrin derivative (HPD) is a new treatment for cancers of small volume undergoing Phase II or III clinical trials in various medical fields. However, there is a lack of prognostic criteria of efficacy as in other cancer treatment. Cell DNA content or cell kinetics throughout the cell cycle were analyzed by flow cytometry and propidium iodide staining before and after HPD-PDT in 33 patients with Tis or T1 cancers of the gastrointestinal tract. The authors compared results in near-diploid cancers with those obtained in normal corresponding tissue. Complete local tumor destruction and negative histologic findings (complete response [CR]) were observed in 17 of 33 patients during a period averaging 15.7 months. Flow cytometry DNA analysis was feasible in 32 patients. Aneuploidy, found in 15 of the 32 indicated a poor prognosis because 5 of 15 patients with aneuploid tumors were classified as having CR, compared with 12 of 17 patients with near-diploid tumors (P < 0.05). Changes in ploidy after PDT in 11 patients consisted of a reduction in the number of aneuploid peaks in 8 patients and the appearance of one aneuploid peak in 3 patients. Percentages of cells in SG2M phase in near-diploid tumors differed from those observed in control subjects for adenocarcinomas, and there was no significant decrease after HPD-PDT. There was no correlation between the decrease of SG2M cells and the response to HPD-PDT. Results obtained with PDT in this series of patients confirm previously published findings. Changes occurring in the ploidy of PDT-treated patients demonstrate that PDT acts directly on cancer cells in humans and not only on tumor vasculature. However, response to PDT varies from one cell population to another. The appearance of aneuploid populations after PDT suggests that destruction of sensitive cell populations allows the growth of aneuploid clones that initially are not detectable by flow cytometry.

There is progress in applying photodynamic therapy in cancer clinic during the last decade. The promising direction to develop this way of treatment is the use of photosensitizers with given characteristics. It is based on a local activation of a photosensitizer in a cancer tissue by using luminous radiation of an appropriate wave length to launch photochemical reaction following the atypical cells’ destruction. In spite of a successful experience of using photodynamic therapy in different areas of medicine, not all its opportunities are studied. There are general information in this literature survey about the use of photodynamic therapy and its perspectives in oncology.

合成一系列以SNO-Schiff Base (L1-H - L8-H) 與聯吡啶共配位基的二價銅錯合物 [LnCu(dppn)](ClO4) (1 - 8) (n = 1 (R = 3,5-tert-Butylbenzene); 2 (R = t-butyl); 3 (R = 3-OMe); 4 (R = 4-OMe); 5 (R = 5-OMe); 6 (R = H); 7 (R = 4-NEt2); 8 (R = 5-NO2))。錯合物 [LnCu(dppn)](ClO4) 結構經元素分析、ESI-MS及X-ray晶體繞射鑑定結構，並由FT-IR、CV、UV/Vis吸收光譜與EPR探討其物理性質。 在DNA光裂解實驗中，利用紫外光(365 nm)與藍光(430 nm)為燈源，探討錯合物之DNA光裂解活性與反應機制，並進一步探討錯合物在HeLa、SCC15等癌細胞的光毒性。其中錯合物 5 在藍光下具有較好的光動力潛力，且在不同溶液下穩定存在，期望在生物醫藥方面有更廣泛的應用。

Recent changes in duty hour allowances and economic constraints are forcing a paradigm shift in graduate medical education in the United States. Internet-based learning is a rapidly growing component of postgraduate medical education, including the field of critical care medicine. Here, we define the key concepts of Internet-based learning, summarize the current literature, and describe how Internet-based learning may be uniquely suited for the critical care provider. A MEDLINE/PubMed search from January 2000 to July 2011 using the search terms: "e-learning," "Web-based learning," "computer-aided instruction," "adult learning," "knowledge retention," "intensive care," and "critical care." The growth of the Internet is marked by the development of new technologies, including more user-derived tools. Nonmedical fields have embraced Internet-based learning as a valuable teaching tool. A recent meta-analysis described Internet-based learning in the medical field as being more effective than no intervention and likely as efficacious as traditional teaching methods. Web sites containing interactive features are aptly suited for the adult learner, complementing the paradigm shift to more learner-centered education. Interactive cases, simulators, and games may allow for improvement in clinical care. The total time spent utilizing Internet-based resources, as well as the frequency of returning to those sites, may influence educational gains. Internet-based learning may provide an opportunity for assistance in the transformation of medical education. Many features of Web-based learning, including interactivity, make it advantageous for the adult medical learner, especially in the field of critical care medicine, and further work is necessary to develop a robust learning platform incorporating a variety of learning modalities for critical care providers.

The conjugation of tetrapyrroles and related photosensitisers with proteins or targeting peptides is now a well-established approach for enhancing the solubility and tissue selectivity of such molecules in the photodynamic therapy (PDT) of cancer. We are interested in developing chemical strategies for the generation of novel porphyrin-related molecules for targeted PDT, and also porphyrin-based systems whose structures are tailored for use in the light-triggered delivery of therapeutic agents by photochemical internalisation (PCI) [1]. PCI is a light-based approach that exploits the technique of PDT to enhance the delivery of nano-sized biotherapeutics that would normally be prevented from reaching their intended intracellular targets due to sequestration in certain sub-units or organelles within the cell. Effective PCI requires the use of photosensitisers that have the appropriate physical properties to localize in the membranes of the organelles (endosomes or lysosomes) where a therapeutic agent may be trapped. Upon irradiation, reactive oxygen species that are generated may then induce a highly selective damaging effect and cause partial rupture of the organelles, allowing entrapped molecules to escape to their targets within the cell. In this communication, we will describe some of our studies on the synthesis and biological evaluation of porphyrin and chlorin derivatives that are targeted with cationic cell-penetrating peptides (CPPs) via biorthogonal ligation chemistries [1, 2], and the application of these conjugates for PCI of saporin, a nano-sized protein toxin. We will also describe the extension of this principle to the CPP-targeting of liposomal nanocarriers [3] to produce molecular assemblies that allow the codelivery of a porphyrin photosensitizer and a macromolecular therapeutic in order to produce an optimal PCI effect.[1] R. Dondi, E. Yaghini, K. M. Tewari, L. Wang, F. Giuntini, M. Loizidou, A. J. MacRobert and I. M. Eggleston, Org. Biomol. Chem. 2016, 14, 11488-11501.[2] E. Yaghini, R. Dondi, K. M. Tewari, M. Loizidou, I. M. Eggleston and A. J. MacRobert, Sci. Rep. 2017, 7, 6059.[3] E. Yaghini, R. Dondi, K. J. Edler, M. Loizidou, A. J. MacRobert and I. M. Eggleston, Nanoscale 2108, 10, 20366-20376.

Photodynamic therapy for onychomycosis: A systematic review

Photodynamic therapy (PDT) is a considerably new kind of photochemotherapeutic treatment in medical field. It combines the use of three components, which are a photosensitizer, light and oxygen. Photosensitizer is a compound activated by light. The application can be oral, topical or intravenous. It usually member of porphyrin group with ampiphilic characteristics. Photosensitizer can be of generation I, II or III, each generation step develops more specificity, selectivity and deeper tissue application. This review will discuss photosensitizer development consecutively, with its benefit and lackness. The light used is usually on red region, while the oxygen is involved in reactive oxygen species generation. Its mechanism action can go through either in type I or type II reaction. This kind of therapy is usually being used in oncology, especially in superficial and in-lining cancers, dermatology and ophthalmology field. This therapy can be safely given to patients with complication and has distinct advantages compare with other treatment such as chemotherapy and surgery. It also considerably has lesser side effects and risks. Broader application is being developed through various experiments and photosensitizer modification. Keywords: light spectrum, photoactivation, photodynamic therapy, photosensitizer

Summary - Proteins from skim milk, paracaseinate and whey have been successfully analyzed by reverse-phase high-pertormance liquid chromatography (RP-HPLC) cou pied with electrospray ionization mass spectrometry (ESI-MS). The major milk proteins were identified by comparison of molecular masses determined by ESI-MS to molecular masses calculated from amino acid composition deduced from primary structures and cDNA sequences for some proteins. This method has permilted the simultaneous identification of caseins and whey protein variants. Observed molecular masses of major milk proteins were found to be 19038.0 ± 2.2 Da forK-CN A-l P (number of experiments n =6); 19007.0 ± 1.1 Da for K-CN B-1P (n = 4); 25230.0 ± 2.1 Da for as2-CN A (n = 9); 23617.2 ± 1.3 Da for as1-CN B-8P (n = 14); 24 092.0 ± 1.7 Da for ~-CN B-5P (n = 6); 24 025.3 ± 1.0 Da for ~-CN A 1-5P (n =14); 23 984.8 ± 0.7 Da for ~-CN A2_5P (n =14); 18278.3 ± 2.2 Da for the monomeric form of ~-LG B (n = 5); 18 364.8 ± 1.6 Da for the monomeric form of ~-LG A (n = 5); 14 179.21 ± 3.14 Da for a-LA (n =5). Hence an accuracy of 0.01 % was obtained by ESI-MS analysis. It was also shown that the on-line coupling of HPLC with ESI-MS offers a very promising alternative for studying the proteolysis and determining the specificity of used enzymes in some technological treatments as shown for milk-clotting enzymes.

One-step green synthesis of platinum mesoporous nanoparticles by riboflavin for light activated antitumoral therapy

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

Chapter 13 - Lipids and natural polymer–based carrier systems for photodynamic therapy

Recently a few demonstration on the use of Photodynamic Reaction as possibility to eliminate larvae that transmit diseases for men has been successfully demonstrated. This promising tool cannot be vastly used due to many problems, including the lake of investigation concerning the mechanisms of larvae killing as well as security concerning the use of photosensitizers in open environment. In this study, we investigate some of the mechanisms in which porphyrin (Photogem) is incorporated on the Aedes aegypti larvae previously to illumination and killing. Larvae at second instar were exposed to the photosensitizer and after 30 minutes imaged by a confocal fluorescence microscope. It was observed the presence of photosensitizer in the gut and at the digestive tract of the larva. Fluorescence-Lifetime Imaging showed greater photosensitizer concentration in the intestinal wall of the samples, which produces a strong decrease of the Photogem fluorescence lifetime. For Photodynamic Therapy exposition to different light doses and concentrations of porphyrin were employed. Three different light sources (LED, Fluorescent lamp, Sun light) also were tested. Sun light and fluorescent lamp shows close to 100% of mortality after 24 hrs. of illumination. These results indicate the potential use of photodynamic effect against the LARVAE of Aedes aegypti .

The use of photosensitizers in the treatment of skin diseases is not new to the field of dermatology. This concept was first popularized by Goeckerman in 1925 with the use of topically applied crude coal tar and ultraviolet (UV) light to treat psoriasis.¹In more recent years, the use of 8-methoxypsoralen as a photosensitizer in combination with high-intensity UV-A has become a standard form of "photochemotherapy" for psoriasis. Photodynamic therapy (PDT), a term synonymous with photochemotherapy, refers to the combination of a photosensitizer and nonionizing radiation to provide a beneficial therapeutic effect. Use of PDT provides a unique approach for the selective therapy of diseases localized to the skin. By confining the photoactivation of the drug to the disease site in the skin, generalized systemic toxicity can, in theory, be avoided. The addition of new chemicals that sensitize diseased cells and tissues to electromagnetic radiation in the near UV