The Photosensitizer Temoporfin (mTHPC) – Chemical, Pre‐clinical and Clinical Developments in the Last Decade†‡

This review follows the research, development and clinical applications of the photosensitizer 5,10,15,20‐tetra(m‐hydroxyphenyl)chlorin (mTHPC, temoporfin) in photodynamic (cancer) therapy (PDT) and other medical applications. Temoporfin is the active substance in the medicinal product Foscan® authorized in the EU for the palliative treatment of head and neck cancer. Chemistry, biochemistry and pharmacology, as well as clinical and other applications of temoporfin are addressed, including the extensive work that has been done on formulation development including liposomal formulations. The literature has been covered from 2009 to early 2022, thereby connecting it to the previous extensive review on this photosensitizer published in this journal [Senge, M. O. and J. C. Brandt (2011) Photochem. Photobiol. 87, 1240–1296] which followed its way from initial development to approval and clinical application

Two-photon cross-sections of the photosensitizers m-THPC and m-THPP in the 1.05–1.45μm range

The two-photon absorption of the photosensitizers 5,10,15,20-tetrakis(m-hydroxyphenyl) porphyrin and the corresponding chlorin has been studied in the near infrared (IR) range using open-aperture z-scan technique. We found cross sections of 10–40 GM in the Q-band region, comparable to values in the Soret-band. Both photosensitizers are promising candidates for IR two-photon photodynamic therapy given the better penetration of IR light into tissue

meso-Tetrahexyl-7,8-dihydroxychlorin and Its Conversion to ß-Modified Derivatives

meso-Tetrahexylporphyrin was converted to its corresponding 7,8-dihydroxychlorin using an osmium tetroxide-mediated dihydroxylation strategy. Its diol moiety was shown to be able to undergo a number of subsequent oxidation reactions to form a chlorin dione and porpholactone, the first meso-alkylporphyrin-based porphyrinoid containing a non-pyrrolic building block. Further, the diol chlorin was shown to be susceptible to dehydration, forming the porphyrin enol that is in equilibrium with its keto-chlorin form. The meso-hexylchlorin dione could be reduced and it underwent mono- and bis-methylation reactions using methyl-Grignard reagents, and trifluoromethylation using the Ruppert-Prakash reagent. The optical and spectroscopic properties of the products are discussed and contrasted to their corresponding meso-aryl derivatives (where known). This contribution establishes meso-tetrahexyl-7,8-dihydroxychlorins as a new and versatile class of chlorins that is susceptible to a broad range of conversions to generate functionalized chlorins and a pyrrole-modified chlorin analogue

Redefining the Social Geography of Community STI Risk: An Ecological Study of the Association, Mediators, and Moderators of Area-Level Prostitution Arrests

Background: Core groups such as sex workers have been implicated in contributing to higher area STI risk but no studies have analyzed mediators and moderators of this relationship using population data. Objectives: Assess the overall association of area-level prostitution and STI risk, and mediators and moderators of the relationship. Methods: Point-level prostitution and drug arrests were geocoded and aggregated by Census blockgroup. Chlamydia (CT), gonorrhea (GC), syphilis and incident HIV positive test results were aggregated by blockgroup after eliminating same-organism positive tests within 14 days of an initial positive test. Census data also defined moderators: blockgroups with >75% black and >20% Latino (top decile) and >60% below 200% of the federal poverty line (top quartile). Negative binomial and zero-inflated negative binomial regressions were used to estimate incident rate ratios (IRR) of each STI. Results: There was a dose-response relationship between prostitution arrest blockgroup quintiles and IRR of each STI. In models including drug arrest data, this association was completely eliminated. Though % black blockgroup composition had significant interaction with prostitution arrest rates and with respect to its relationship with STI IRR, % Latino did not consistently have this association. Blockgroups with proportions of low minority and low poverty had highest drug arrest IRR for each STI. In these areas, prostitution arrest IRR were only significant for CT and GC and were consistently lower than drug arrest IRRs. Conclusions: Though prostitution arrests are associated with STI risk, this relationship is mediated by drug arrests. Associations of both arrest rates are strongest in low minority, low poverty communities, indicating that high baseline STI prevalence is not moderated by levels of drug and prostitution arrests. Implications for Programs, Policy, and Research: These data suggest that important relationships exist for prostitution and, to a greater degree, drug arrests within communities traditionally defined as ‘low-risk’

Use of Cell Phone Diaries to Understand Risk Contexts of Sexual Events Among Female Sex Workers

Background Data collection using mobile technologies, such as cell phones, allows more frequent and real-time data collection and is less prone to recall bias. We describe the feasibility of using twice daily cell phone diaries to capture contextual features of STI/HIV-risk that could impact disease acquisition among female sex workers (FSW). Methods Women engaging in transactional sex in the prior 90 days were recruited utilising incentivized snowball sampling. Participants completed STI testing and baseline/exit surveys. Over 4-weeks, they completed twice-daily electronic diaries assessing event-level sexual behaviour, condom use, and drug use. Weekly in-person interviews used open-ended questions to explore geographical characteristics of sexual encounter locations as well as acceptability of event-level monitoring. Results 25/26 participants (median age 43.5 years) completed the 4-week study. At baseline, 27% tested positive for a STI. Participants completed 84.5% of 1,518 expected surveys and 95% of 106 expected interviews. Patterns of diary compliance were stable over time. Partnered sexual activity was captured in 21.4% of diaries. At the participant-level, most reported giving oral sex (84.7%) or vaginal sex (96.1%); fewer (19.2%) reported engaging in anal sex. Among women reporting partnered sexual behaviour with any partner type (i.e., new/regular customers, romantic partners), using condoms was reported 39.2%, 45.5% and 83.3% of the time for giving oral sex, vaginal sex, and anal sex respectively. At the event-level, the frequency of giving oral sex, vaginal sex or anal sex did not significantly change over time. Conclusions It is feasible to engage and retain FSW in a technologically-advanced study to characterise risk contexts of sexual events. Adherence to study protocol was high indicating event-level monitoring using cell phone based diaries is acceptable. These data can be utilised to improve our understanding of the individual, relational and environmental factors that influence STI/HIV acquisition among FSW

Dipyrrinato‐Iridium(III) Complexes for Application in Photodynamic Therapy and Antimicrobial Photodynamic Inactivation

The generation of bio-targetable photosensitizers is of utmost importance to the emerging field of photodynamic therapy and antimicrobial (photo-)therapy. A synthetic strategy is presented in which chelating dipyrrin moieties are used to enhance the known photoactivity of iridium(III) metal complexes. Formed complexes can thus be functionalized in a facile manner with a range of targeting groups at their chemically active reaction sites. Dipyrrins with N- and O-substituents afforded (dipy)iridium(III) complexes via complexation with the respective Cp*-iridium(III) and ppy-iridium(III) precursors (dipy=dipyrrinato, Cp*=pentamethyl-eta(5)-cyclopentadienyl, ppy=2-phenylpyridyl). Similarly, electron-deficient [Ir-III(dipy)(ppy)(2)] complexes could be used for post-functionalization, forming alkenyl, alkynyl and glyco-appended iridium(III) complexes. The phototoxic activity of these complexes has been assessed in cellular and bacterial assays with and without light; the [Ir-III(Cl)(Cp*)(dipy)] complexes and the glyco-substituted iridium(III) complexes showing particular promise as photomedicine candidates. Representative crystal structures of the complexes are also presented

Sexually transmitted infections in association with area-level prostitution and drug-related arrests

Objectives: Examine the mediators and moderators of area-level prostitution arrests and sexually transmitted infections (STI) using population level data. Methods Using justice and public health STI/HIV data in Marion County (Indianapolis), Indiana, over an 18-year period, we assessed the overall association of area-level prostitution and drug-related arrests and STI /HIV, and mediators and moderators of the relationship. Point-level arrests were geocoded and aggregated by census block group. Results: Results indicate a positive relationship between numbers of prostitution arrests and area-level STI rates. There was a dose-response relationship between prostitution arrests and STI rates when accounting for drug-related arrests. The highest quintile block groups had significantly higher rates of reported chlamydia (IRR: 3.29, 95% CI: 2.82, 3.84), gonorrhea (IRR: 4.73, 95% CI: 3.90, 5.57), syphilis (IRR: 4.28, 95% CI: 3:47, 5.29), and HIV (IRR: 2.76, 95% CI: 2.24, 3.39) compared with the lowest quintile. When including drug arrests, the second (IRR: 1.19, 95% CI: 1.03, 1.38) and the third (IRR: 1.20, 95% CI: 1.02, 1.41) highest quintile block groups had lower IRR for reported rates of chlamydia, indicating that drug arrests mediated the prostitution arrest effect. Conclusions: These findings inform public health agencies and community-based organizations that conduct outreach in these areas to expand their efforts to include harm reduction and HIV/STI testing for both sex workers and individuals experiencing substance use disorder. Another implication of these data is the importance of greater collaboration in public health and policing efforts to address overlapping epidemics that engage both health and legal intervention

Investigating Alkylated Prodigiosenes and Their Cu(II)-Dependent Biological Activity: Interactions with DNA, Antimicrobial and Photoinduced Anticancer Activity

Prodigiosenes are a family of red pigments with versatile biological activity. Their tripyrrolic core structure has been modified many times in order to manipulate the spectrum of activity. We have been looking systematically at prodigiosenes substituted at the C ring with alkyl chains of different lengths, in order to assess the relevance of this substituent in a context that has not been investigated before for these derivatives: Cu(II) complexation, DNA binding, self-activated DNA cleavage, photoinduced cytotoxicity and antimicrobial activity. Our results indicate that the hydrophobic substituent has a clear influence on the different aspects of their biological activity. The cytotoxicity study of the Cu(II) complexes of these prodigiosenes shows that they exhibit a strong cytotoxic effect towards the tested tumor cell lines. The Cu(II) complex of a prodigiosene lacking any alkyl chain excelled in its photoinduced anticancer activity, thus demonstrating the potential of prodigiosenes and their metal complexes for an application in photodynamic therapy (PDT). Two derivatives along with their Cu(II) complexes showed also antimicrobial activity against Staphylococcus aureus strains

Lipid-DNAs as Solubilizers of mTHPC

Hydrophobic drug candidates require innovative formulation agents. We designed and synthesized lipidDNA polymers containing varying numbers of hydrophobic alkyl chains. The hydrophobicity of these amphiphiles is easily tunable by introducing a defined number of alkyl chain-modified nucleotides during standard solid-phase synthesis of DNA using an automated DNA synthesizer. We observed that the resulting self-assembled micelles solubilize the poorly water-soluble drug, meta-tetra-hydroxyphenyl-chlorin (mTHPC) used in photodynamic therapy (PDT) with high loading concentrations and loading capacities. A cell viability study showed that mTHPCloaded micelles exhibit good biocompatibility without irradiation, and high PDT efficacy upon irradiation. LipidDNAs provide a novel class of drug-delivery vehicle, and hybridization of DNA offers a potentially facile route for further functionalization of the drug-delivery system with, for instance, targeting or imaging moieties