Optimizing interstitial photodynamic therapy with custom cylindrical diffusers

Interstitial photodynamic therapy (iPDT) has shown promise recently as a minimally invasive cancer treatment, partially due to the development of non‐toxic photosensitizers in the absence of activation light. However, a major challenge in iPDT is the pre‐treatment planning process that specifies the number of diffusers needed, along with their positions and allocated powers, to confine the light distribution to the target volume as much as possible. In this work, a new power allocation algorithm for cylindrical light diffusers including those that can produce customized longitudinal (tailored) emission profiles is introduced. The proposed formulation is convex to guarantee the minimum over‐dose possible on the surrounding organs‐at‐risk. The impact of varying the diffuser lengths and penetration angles on the quality of the plan is evaluated. The results of this study are demonstrated for different photosensitizers activated at different wavelengths and simulated on virtual tumors modeling virtual glioblastoma multiforme cases. Results show that manufacturable cylindrical diffusers with tailored emission profiles can significantly outperform those with conventional flat profiles with an average damage reduction on white matter of 15% to 55% and on gray matter of 23% to 58%.      

Optical coherence tomography to detect acute esophageal radiation‐induced damage in mice: A validation study

Radiation therapy for patients with non‐small‐cell lung cancer is hampered by acute radiation‐induced toxicity in the esophagus. This study aims to validate that optical coherence tomography (OCT), a minimally invasive imaging technique with high resolution (~10 μm), is able to visualize and monitor acute radiation‐induced esophageal damage (ARIED) in mice. We compare our findings with histopathology as the gold standard. Irradiated mice receive a single dose of 40 Gy at proximal and distal spots of the esophagus of 10.0 mm in diameter. We scan mice using OCT at two, three, and seven days post‐irradiation. In OCT analysis, we define ARIED as a presence of distorted esophageal layering, change in backscattering signal properties, or change in the esophageal wall thickness. The average esophageal wall thickness is 0.53 mm larger on OCT when ARIED is present based on histopathology. The overall sensitivity and specificity of OCT to detect ARIED compared to histopathology are 94% and 47%, respectively. However, the overall sensitivity of OCT to assess ARIED is 100% seven days post‐irradiation. We validate the capability of OCT to detect ARIED induced by high doses in mice. Nevertheless, clinical studies are required to assess the potential role of OCT to visualize ARIED in humans.      

1064 nm Nd:YAG laser light affects transmembrane mitochondria respiratory chain complexes

Photobiomodulation (PBM) is a non‐plant‐cell manipulation through a transfer of energy by means of light sources at the non‐ablative or thermal intensity. Authors showed that cytochrome‐c‐oxidase (complex IV) is the specific chromophore's target of PBM at the red (600‐700 nm) and NIR (760‐900 nm) wavelength regions. Recently, it was suggested that the infrared region of the spectrum could influence other chromospheres, despite the interaction by wavelengths higher than 900 nm with mitochondrial chromophores was not clearly demonstrated. We characterized the interaction between mitochondria respiratory chain, malate dehydrogenase, a key enzyme of Krebs cycle, and 3‐hydroxyacyl‐CoA dehydrogenase, an enzyme involved in the β‐oxidation (two mitochondrial matrix enzymes) with the 1064 nm Nd:YAG (100mps and 10 Hz frequency mode) irradiated at the average power density of 0.50, 0.75, 1.00, 1.25 and 1.50 W/cm² to generate the respective fluences of 30, 45, 60, 75 and 90 J/cm². Our results show the effect of laser light on the transmembrane mitochondrial complexes I, III, IV and V (adenosine triphosphate synthase) (window effects), but not on the extrinsic mitochondrial membrane complex II and mitochondria matrix enzymes. The effect is not due to macroscopical thermal change. An interaction of this wavelength with the Fe‐S proteins and Cu‐centers of respiratory complexes and with the water molecules could be supposed.      

Effect of the Photodynamic Therapy Applications with Potent Microalgae Constituents on Several Types of Tumor

Background

In recent years, microalgae (MA) have attracted much interest considering their possible therapeutic application. They contain active natural compounds or derivatives (extracts, pure or chemically modified compounds) that have increasing applications in the pharmaceutical industry.

Development of a novel inducer for EBV lytic therapy

Epstein-Barr virus (EBV) is a human herpesvirus that infects over 90% of the world's population that persists as a latent infection in various lymphoid and epithelial malignancies. The total number of EBV associated malignancies is estimated to exceed 200,000 new cancers per year. Current chemotherapeutic treatments of EBV-positive cancers include broad-spectrum cytotoxic drugs that ignore the EBV positive status of tumors and have limited safety and selectivity. In an effort to develop new and more efficacious molecules for inducing EBV reactivation, we have developed high-throughput screening assays to identify a class of small molecules (referred to as the C60 series) that efficiently activate the EBV lytic cycle in multiple latency types, including lymphoblastoid and nasopharyngeal carcinoma cell lines. In this paper we report our preliminary structure activity relationship studies and demonstrate reactivation of EBV in the SNU719 gastric carcinoma mouse model and the AGS-Akata gastric carcinoma mouse model.     

Optimization of peptidic HIV‐1 fusion inhibitor T20 by phage display

The HIV fusion inhibitor T20 has been approved to treat those living with HIV/AIDS, but treatment gives rise to resistant viruses. Using combinatorial phage‐displayed libraries, we applied a saturation scan approach to dissect the entire T20 sequence for binding to a prefusogenic five‐helix bundle (5HB) mimetic of HIV‐1 gp41. Our data set compares all possible amino acid substitutions at all positions, and affords a complete view of the complex molecular interactions governing the binding of T20 to 5HB. The scan of T20 revealed that 12 of its 36 positions were conserved for 5HB binding, which cluster into three epitopes: hydrophobic epitopes at the ends and a central dyad of hydrophilic residues. The scan also revealed that the T20 sequence was highly adaptable to mutations at most positions, demonstrating a striking structural plasticity that allows multiple amino acid substitutions at contact points to adapt to conformational changes, and also at noncontact points to fine‐tune the interface. Based on the scan result and structural knowledge of the gp41 fusion intermediate, a library was designed with tailored diversity at particular positions of T20 and was used to derive a variant (T20v1) that was found to be a highly effective inhibitor of infection by multiple HIV‐1 variants, including a common T20‐escape mutant. These findings show that the plasticity of the T20 functional sequence space can be exploited to develop variants that overcome resistance of HIV‐1 variants to T20 itself, and demonstrate the utility of saturation scanning for rapid epitope mapping and protein engineering.     

Effect of curcumin-nanoemulsion associated with photodynamic therapy in breast adenocarcinoma cell line

Curcumin, a natural compound has several antineoplastic activities and is a promising natural photosensitizer used in photodynamic therapy. However, its low solubility in physiological medium limit the clinical use of curcumin. This study aimed to analyze the action of curcumin-nanoemulsion, a new and well-designed Drug Delivery System (DDS+) molecule, used as a photosensitizing agent in photodynamic therapy in an in vitro breast cancer model, MCF-7 cells. The empty nanoemulsion fulfils all necessary requirements to be an excellent DDS. Furthermore, the use of curcumin-nanoemulsion in photodynamic therapy resulted in a high phototoxic effect after activation at 440?nm, decreasing to <10% viable tumor cells after two irradiations and increasing the reactive oxygen species (ROS) production. The use of curcumin-nanoemulsion associated with photodynamic therapy resulted in an increase in the levels of caspase 3/7 activity for the studied MCF-7 cell model, indicating that this therapy triggers a cascade of events that lead to cell death, such as cellular apoptosis. In conclusion, curcumin-nanoemulsion proved to be efficient as a photosensitizing agent, had phototoxic effects, significantly decreased the proliferation of MCF-7 cells and stimulating the ROS production in combination with photodynamic therapy, so, this formulation has a great potential for use in treatment of breast cancer.