Remediating Desmoplasia with EGFR-Targeted Photoactivable Multi-Inhibitor Liposomes Doubles Overall Survival in Pancreatic Cancer.

Desmoplasia is characteristic of pancreatic ductal adenocarcinoma (PDAC), which exhibits 5-year survival rates of 3%. Desmoplasia presents physical and biochemical barriers that contribute to treatment resistance, yet depleting the stroma alone is unsuccessful and even detrimental to patient outcomes. This study is the first demonstration of targeted photoactivable multi-inhibitor liposomes (TPMILs) that induce both photodynamic and chemotherapeutic tumor insult, while simultaneously remediating desmoplasia in orthotopic PDAC. TPMILs targeted with cetuximab (anti-EGFR mAb) contain lipidated benzoporphyrin derivative (BPD-PC) photosensitizer and irinotecan. The desmoplastic tumors comprise human PDAC cells and patient-derived cancer-associated fibroblasts. Upon photoactivation, the TPMILs induce 90% tumor growth inhibition at only 8.1% of the patient equivalent dose of nanoliposomal irinotecan (nal-IRI). Without EGFR targeting, PMIL photoactivation is ineffective. TPMIL photoactivation is also sixfold more effective at inhibiting tumor growth than a cocktail of Visudyne-photodynamic therapy (PDT) and nal-IRI, and also doubles survival and extends progression-free survival by greater than fivefold. Second harmonic generation imaging reveals that TPMIL photoactivation reduces collagen density by >90% and increases collagen nonalignment by >103 -fold. Collagen nonalignment correlates with a reduction in tumor burden and survival. This single-construct phototoxic, chemotherapeutic, and desmoplasia-remediating regimen offers unprecedented opportunities to substantially extend survival in patients with otherwise dismal prognoses.

Global cognitive performance at 4-year follow-up in individuals with atrial fibrillation-findings from The Irish Longitudinal Study on Ageing.

INTRODUCTION: Atrial fibrillation (AF) has been proposed as a risk factor for cognitive impairment, even in the absence of a history of stroke. This study investigates whether AF is associated with increased risk of cognitive decline in a community-dwelling population of adults over the age of 50. METHODS: Data from the 1st and 3rd waves of The Irish Longitudinal Study on Ageing (TILDA) were used (4-year follow-up period). TILDA is a large prospective cohort study of community-dwelling adults over the age of 50 in Ireland. AF was assessed via electrocardiogram. Global cognitive function was assessed at baseline and follow-up using Montreal Cognitive Assessment (MOCA). Analysis of global cognition was repeated stratifying by age. Mixed-effects Poisson regression was used to assess for change in rate of errors on MOCA and MOCA subdomains. RESULTS: A total of 3,417 participants were included in the study. Results found that participants with AF had a greater increase in rate of errors on MOCA over 4-year follow-up (incident rate ratio (IRR) 1.18; 95% confidence interval (CI) 1.02, 1.37; P-value 0.023). However, this was no longer significant on controlling for age, sex and level of education (IRR 1.08; 95% CI 0.93, 1.25; P-value 0.332). There was no difference when stratifying by age group, or when separating MOCA into subdomains. CONCLUSION: Individuals with AF were more likely to show an increase in rate of errors between waves 1 and 3 (4-year follow-up period) in the TILDA population; however, results were not significant when controlling for age, sex and level of education.

Is Tumor Cell Specificity Distinct from Tumor Selectivity In Vivo?: A Quantitative NIR Molecular Imaging Analysis of Nanoliposome Targeting.

The significance and ability for receptor targeted nanoliposomes (tNLs) to bind to their molecular targets in solid tumors in vivo has been questioned, particularly as the efficiency of their tumor accumulation and selectivity is not always predictive of their efficacy or molecular specificity. This study presents, for the first time, in situ NIR molecular imaging-based quantitation of the in vivo specificity of tNLs for their target receptors, as opposed to tumor selectivity, which includes influences of enhanced tumor permeability and retention. Results show that neither tumor delivery nor selectivity (tumor-to-normal ratio) of cetuximab and IRDye conjugated tNLs correlate with EGFR expression in U251, U87 and 9L tumors, and in fact underrepresent their imaging-derived molecular specificity by up to 94.2%. Conversely, their in vivo specificity, which we quantify as the concentration of tNL-reported tumor EGFR provided by NIR molecular imaging, correlates positively with EGFR expression levels in vitro and ex vivo (Pearson's r= 0.92 and 0.96, respectively). This study provides a unique opportunity to address the problematic disconnect between tNL synthesis and in vivo specificity. The findings encourage their continued adoption as platforms for precision medicine, and facilitates intelligent synthesis and patient customization in order to improve safety profiles and therapeutic outcomes.

Short-Chained Anthracene Strapped Porphyrins and their Endoperoxides.

The syntheses of short-chained anthracene-strapped porphyrins and their Zn(II)complexes are reported. The key synthetic step is a [2+2] condensation between a dipyrromethane and an anthracene bisaldehyde, 2,2'-((anthracene-9,10-diylbis(methylene))bis(oxy))dibenzaldehyde. Following exposure to white light, self-sensitized singlet oxygen and the anthracene moieties underwent [4+2] cycloaddition reactions to yield the corresponding endoperoxides. 1H NMR studies demonstrate that the endoperoxide readily formed in [D]chloroform and decayed at 85 °C. X-ray crystallography and absorption spectroscopy were used to confirm macrocyclic distortion in the parent strapped porphyrins and endoperoxides. Additionally, X-ray crystallography indicated that endoperoxide formation occurred exclusively on the outside face of the anthracene moiety.

In vitro cytotoxicity of a library of BODIPY-anthracene and -pyrene dyads for application in photodynamic therapy.

The facile synthesis and in vitro activity of a library of heavy atom-free BODIPY-anthracene, -pyrene dyads (BAD-13-BPyrD-19) and a control (BODIPY 20) are reported. We demonstrate that singlet oxygen produced from dyad triplet states formed from charge-separated states is sufficient to induce cytotoxicity in human breast cancer cells (MDA-MB-468) at micromolar concentrations. The compounds in this series are promising candidates for photodynamic therapy, especially BAD-17 which displays significant photocytotoxicity (15% cell viability) at a concentration of 5 × 10-7 M, with minimal toxicity (89% cell viability) in the absence of light.

Is Baseline Orthostatic Hypotension Associated With a Decline in Global Cognitive Performance at 4-Year Follow-Up? Data From TILDA (The Irish Longitudinal Study on Ageing).

Background It is postulated that orthostatic hypotension ( OH ), a reduction in blood pressure (≥20/10 mm Hg) within 3 minutes of standing, may increase cognitive decline because of cerebral hypoperfusion. This study assesses the impact of OH on global cognition at 4-year follow-up, and the impact of age and hypertension on this association. Methods and Results Data from waves 1 and 3 of TILDA (The Irish Longitudinal Study on Ageing) were used. Baseline blood pressure response to active stand was assessed using beat-to-beat blood pressure monitoring. Two measures of OH were used-at 40 seconds ( OH 40) and 110 seconds ( OH 110). Global cognition was measured using the Montreal Cognitive Assessment. Mixed-effects Poisson regression assessed whether baseline OH was associated with a decline in global cognition at 4-year follow-up. The analysis was repeated, stratifying by age (age 50-64 years and age ≥65 years), and including an interaction between OH and hypertension. Baseline OH 110 was associated with an increased error rate in Montreal Cognitive Assessment at follow-up (incident rate ratio 1.17, P=0.028). On stratification by age, the association persists in ages 50 to 64 years (incident rate ratio 1.25, P=0.048), but not ages ≥65 years. Including an interaction with hypertension found those with co-existent OH 110 and hypertension (incident rate ratio 1.27, P=0.011), or OH 40 and hypertension (incident rate ratio 1.18, P=0.017), showed an increased error rate; however, those with isolated OH 110, OH 40, or isolated hypertension did not. Conclusions OH is associated with a decline in global cognition at 4-year follow-up, and this association is dependent on age and co-existent hypertension.

Control of triplet state generation in heavy atom-free BODIPY-anthracene dyads by media polarity and structural factors.

A family of heavy atom-free BODIPY-anthracene dyads (BADs) exhibiting triplet excited state formation from charge-transfer states is reported. Four types of BODIPY scaffolds, different in the alkyl substitution pattern, and four anthracene derivatives have been used to access BADs. Fluorescence and intersystem crossing (ISC) in these dyads depend on donor-acceptor couplings and can be accurately controlled by substitution or media polarity. Under conditions that do not allow charge transfer (CT), the dyads exhibit fluorescence with high quantum yields. Formation of charge-transfer states triggers ISC and the formation of long-lived triplet excited states in the dyads. The excited state properties were studied by steady-state techniques and ultrafast pump-probe spectroscopy to determine the parameters of the observed processes. Structural information for various BADs was derived from single crystal X-ray structure determinations alongside DFT molecular geometry optimization, revealing the effects of mutual orientation of subunits on the photophysical properties. The calculations showed that alkyl substituents on the BODIPY destabilize CT states in the dyads, thus controlling the charge transfer between the subunits. The effect of the dyad structure on the ISC efficiency was considered at the M06-2X level of theory, and a correlation between mutual orientation of the subunits and the energy gap between singlet and triplet CT states was studied using a multireference CASSCF method.

The good, the bad, and the ugly - controlling singlet oxygen through design of photosensitizers and delivery systems for photodynamic therapy.

Singlet oxygen, although integral to photodynamic therapy, is notoriously uncontrollable, suffers from poor selectivity and has fast decomposition rates in biological media. Across the scientific community, there is a conscious effort to refine singlet oxygen interactions and initiate selective and controlled release to produce a consistent and reproducible therapeutic effect in target tissue. This perspective aims to provide an insight into the contemporary design principles behind photosensitizers and drug delivery systems that depend on a singlet oxygen response or controlled release. The discussion will be accompanied by in vitro and in vivo examples, in an attempt to highlight advancements in the field and future prospects for the more widespread application of photodynamic therapy.

Delayed release singlet oxygen sensitizers based on pyridone-appended porphyrins.

A new type of porphyrin photosensitizer capable of generating singlet oxygen upon irradiation, storing it through binding to pyridone subunits, followed by slow release at 20-40 °C, is reported. The timescale of singlet oxygen release can be varied depending on the pyridone group substitution pattern, forming endoperoxides of different stabilities. Modified tetra- and octa-substituted pyridone-porphyrins showed solubility in water, allowing for straightforward delivery into cells. The effect of delayed singlet oxygen formation due to endoperoxide decomposition was demonstrated on cancer cells in vitro.

Neurocardiovascular Instability and Cognition.

Neurocardiovascular instability (NCVI) refers to abnormal neural control of the cardiovascular system affecting blood pressure and heart rate behavior. Autonomic dysfunction and impaired cerebral autoregulation in aging contribute to this phenomenon characterized by hypotension and bradyarrhythmia. Ultimately, this increases the risk of falls and syncope in older people. NCVI is common in patients with neurodegenerative disorders including dementia. This review discusses the various syndromes that characterize NCVI icluding hypotension, carotid sinus hypersensitivity, postprandial hypotension and vasovagal syncope and how they may contribute to the aetiology of cognitive decline. Conversely, they may also be a consequence of a common neurodegenerative process. Regardless, recognition of their association is paramount in optimizing management of these patients.