Unlocking the Mitochondria for Nanomedicine-based Treatments: Overcoming Biological Barriers, Improving Designs, and Selecting Verification Techniques.

Enhanced targeting approaches will support the treatment of diseases associated with dysfunctional mitochondria, which play critical roles in energy generation and cell survival. Obstacles to mitochondria-specific targeting include the presence of distinct biological barriers and the need to pass through (or avoid) various cell internalization mechanisms. A range of studies have reported the design of mitochondrially-targeted nanomedicines that navigate the complex routes required to influence mitochondrial function; nonetheless, a significant journey lies ahead before mitochondrially-targeted nanomedicines become suitable for clinical use. Moving swiftly forward will require safety studies, in vivo assays confirming effectiveness, and methodologies to validate mitochondria-targeted nanomedicines' subcellular location/activity. From a nanomedicine standpoint, we describe the biological routes involved (from administration to arrival within the mitochondria), the features influencing rational design, and the techniques used to identify/validate successful targeting. Overall, rationally-designed mitochondria-targeted-based nanomedicines hold great promise for precise subcellular therapeutic delivery.

An Offset Patterned Cross-ß Structure in Assemblies of C3 -Symmetric Peptide Amphiphiles.

Developing peptide-based materials with controlled morphology is a critical theme of soft matter research. Herein, we report the formation of a novel, patterned cross-ß structure formed by self-assembled C3 -symmetric peptide amphiphiles based on diphenylalanine and benzene-1,3,5-tricarboxamide (BTA). The cross-ß motif is an abundant structural element in amyloid fibrils and aggregates of fibril-forming peptides, including diphenylalanine. The incorporation of topological constraints on one edge of the diphenylalanine fragment limits the number of ß-strands in ß-sheets and leads to the creation of an unconventional offset-patterned cross-ß structure consisting of short 3×2 parallel ß-sheets stabilized by phenylalanine zippers. In the reported assembly, two patterned cross-ß structures bind parallel arrays of BTA stacks in a superstructure within a single-molecule-thick nanoribbon. In addition to a threefold network of hydrogen bonds in the BTA stack, each molecule becomes simultaneously bound by hydrogen bonds from three ß-sheets and four phenylalanine zippers. The diffuse layer of alkyl chains with terminal polar groups prevents the nanoribbons from merging and stabilizes cross-ß-structure in water. Our results provide a simple approach to the incorporation of novel patterned cross-ß motifs into supramolecular superstructures and shed light on the general mechanism of ß-sheet formation in C3 -symmetric peptide amphiphiles.

Critical Design Strategies Supporting Optimized Drug Release from Polymer-Drug Conjugates.

The importance of an adequate linking moiety design that allows controlled drug(s) release at the desired site of action is extensively studied for polymer-drug conjugates (PDCs). Redox-responsive self-immolative linkers bearing disulfide moieties (SS-SIL) represent a powerful strategy for intracellular drug delivery; however, the influence of drug structural features and linker-associated spacers on release kinetics remains relatively unexplored. The influence of drug/spacer chemical structure and the chemical group available for conjugation on drug release and the biological effect of resultant PDCs is evaluated. A "design of experiments" tool is implemented to develop a liquid chromatography-mass spectrometry method to perform the comprehensive characterization required for this systematic study. The obtained fit-for-purpose analytical protocol enables the quantification of low drug concentrations in drug release studies and the elucidation of metabolite presence. and provides the first data that clarifies how drug structural features influence the drug release from SS-SIL and demonstrates the non-universal nature of the SS-SIL. The importance of rigorous linker characterization in understanding structure-function correlations between linkers, drug chemical functionalities, and in vitro release kinetics from a rationally-designed polymer-drug nanoconjugate, a critical strategic crafting methodology that should remain under consideration when using a reductive environment as an endogenous drug release trigger.

NMR-Based Mitochondria Metabolomic Profiling: A New Approach To Reveal Cancer-Associated Alterations.

Studying metabolism may assist in understanding the relationship between normal and dysfunctional mitochondrial activity and various diseases, such as neurodegenerative, cardiovascular, autoimmune, psychiatric, and cancer. Nuclear magnetic resonance-based metabolomics represents a powerful method to characterize the chemical content of complex samples and has been successfully applied to studying a range of conditions. However, an optimized methodology is lacking for analyzing isolated organelles, such as mitochondria. In this study, we report the development of a protocol to metabolically profile mitochondria from healthy, tumoral, and metastatic tissues. Encouragingly, this approach provided quantitative information about up to 45 metabolites in one comprehensive and robust analysis. Our results revealed significant differences between whole-cell and mitochondrial metabolites, which supports a more refined approach to metabolic analysis. We applied our optimized methodology to investigate aggressive and metastatic breast cancer in mouse tissues, discovering that lung mitochondria exhibit an altered metabolic fingerprint. Specific amino acids, organic acids, and lipids showed significant increases in levels when compared with mitochondria from healthy tissues. Our optimized methodology could promote a better understanding of the molecular mechanisms underlying breast cancer aggressiveness and mitochondrial-related diseases and support the optimization of new advanced therapies.

Poly-l-glutamic acid modification modulates the bio-nano interface of a therapeutic anti-IGF-1R antibody in prostate cancer.

Modifying biological agents with polymers such as polyethylene glycol (PEG) has demonstrated clinical benefits; however, post-market surveillance of PEGylated derivatives has revealed PEG-associated toxicity issues, prompting the search for alternatives. We explore how conjugating a poly-l-glutamic acid (PGA) to an anti-insulin growth factor 1 receptor antibody (AVE1642) modulates the bio-nano interface and anti-tumor activity in preclinical prostate cancer models. Native and PGA-modified AVE1642 display similar anti-tumor activity in vitro; however, AVE1642 prompts IGF-1R internalization while PGA conjugation prompts higher affinity IGF-1R binding, thereby inhibiting IGF-1R internalization and altering cell trafficking. AVE1642 attenuates phosphoinositide 3-kinase signaling, while PGA-AVE1642 inhibits phosphoinositide 3-kinase and mitogen-activated protein kinase signaling. PGA conjugation also enhances AVE1642's anti-tumor activity in an orthotopic prostate cancer mouse model, while PGA-AVE1642 induces more significant suppression of cancer cell proliferation/angiogenesis than AVE1642. These findings demonstrate that PGA conjugation modulates an antibody's bio-nano interface, mechanism of action, and therapeutic activity.

Emotional Profiles of Anxiety, Depression, and Stress: Differences in School Anxiety.

INTRODUCTION: This study aims to confirm the existence of profiles according to the combinations of anxiety, depression, and stress, and looks to examine the differences between profiles according to the mean scores obtained in school anxiety. METHODS: A total of 1,234 Spanish students at the secondary education level with an age range of 13-16 years old (M = 14.52; SD = 1.24) participated in the study by completing the abbreviated version of the Depression, Anxiety, and Stress Scale (DASS-21) and the School Anxiety Inventory. RESULTS: The results showed positive, statistically significant, and moderate-sized correlations between all the variables analyzed. The Latent Profile Analysis identified four distinct profiles of depression, anxiety, and stress: Low DAS, Moderate DAS, High DAS, and Very High DAS. The results of the MANOVA showed statistically significant differences between these profiles regarding the school anxiety dimensions, with the profiles Very High DAS and Low DAS being the ones that reported, respectively, the highest and lowest levels in all the school anxiety components. Post hoc analyses revealed significant differences for the large part of profile comparisons, with there being large and moderate differences observed in the majority of cases (d = .30 and 1.66). CONCLUSIONS: The results show the importance of considering social anxiety as a construct that is strongly associated with emotional problems such as depression, anxiety, and stress when developing effective actions to detect them and intervene with adolescents.

Perfectionism and binge eating association: a systematic review and meta-analysis.

BACKGROUND: Perfectionism is considered a vulnerability factor for eating disorders. However, the role of perfectionism in binge eating needs clarification due to notably inconsistencies between studies. The purpose to this study was to conduct a systematic review and meta-analysis to estimate the perfectionism-binge eating association. METHOD: Systematic review was performed according to the PRISMA 2020 statement. Four databases (Web of Science, Scopus, PsycINFO and Psicodoc) were searched to identify studies published until September 2022. The literature search yielded 30 published articles (N = 9392) that provided 33 independent estimations of the correlation between the two variables. RESULTS: Random-effects meta-analysis revealed a small-to-moderate positive average effect size between general perfectionism and binge eating (r+ = .17) with a large heterogeneity. Perfectionistic Concerns showed a significant small-to-moderate relationship with binge eating (r+ = .27), whereas Perfectionistic Strivings presented a negligible relationship with binge eating (r+ = .07). Moderator analyses showed that the age, the type of the sample, the study design, and the tools for assessing both variables were statistically associated with the perfectionism-binge eating effect sizes. CONCLUSIONS: Our findings suggest that Perfectionism Concerns are closely associated with binge eating symptomatology. This relationship might be moderated by certain variables, especially by the clinical or non-clinical nature of the sample and the instrument employed to assess binge eating.

Perfectionism is a trait of personality comprising two facets, Perfectionistic Strivings (entails the desire to reach perfection and to pursue unrealistically high standards) and Perfectionistic Concerns (involves self-criticism, concerns over making mistakes, fears about social negative evaluation and lack of satisfaction with achievements). Perfectionist individuals have an increased risk for developing eating disorders. However, whether perfectionism or any of its facets is associated with binge eating (an episode of overeating together with a feeling of loss of control) is an unanswered question. The purpose of this systematic review and meta-analysis was to clarify this question. Our results evidenced that overall perfectionism is associated with binge eating. It means that perfectionist people are more vulnerable to developing binge eating symptomatology, although Perfectionistic Concerns entails a higher risk in comparison with Perfectionistic Strivings. Our study also provides valuable information on the aspects that might explain the variations in the results of previous studies that have analyzed the perfectionism-binge eating association.

Rational design of poly-L-glutamic acid-palbociclib conjugates for pediatric glioma treatment.

Brain tumors represent the second most common cause of pediatric cancer death, with malignant gliomas accounting for ∼75% of pediatric deaths. Palbociclib, a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has shown promise in phase I clinical trials of pediatric patients with progressive/refractory brain tumors using the oral administration route; however, pharmacokinetic limitations and toxicity issues remain. We synthesized a family of well-defined linear and star-shaped polyglutamate (PGA)-palbociclib conjugates using redox-sensitive self-immolative linkers to overcome limitations associated with free palbociclib. Exhaustive characterization of this conjugate family provided evidence for a transition towards the formation of more organized conformational structures upon increased drug loading. We evaluated the activity of conjugates in patient-derived glioblastoma and diffuse intrinsic pontine glioma cells, which display differing reducing environments due to differential glutathione expression levels. We discovered that microenvironmental parameters and the identified conformational changes determined palbociclib release kinetics and therapeutic output; furthermore, we identified a star-shaped PGA-palbociclib conjugate with low drug loading as an optimal therapeutic approach in diffuse intrinsic pontine glioma cells.

A Rapid, Convergent Approach to the Identification of Exosome Inhibitors in Breast Cancer Models.

Targeting cancer cell exosome release and biogenesis represents a potentially efficient means to treat tumors and prevent cancer recurrence/metastasis; however, the complexity and time-consuming nature of currently employed methods to purify and characterize exosomes represent obstacles to progression. Herein, we describe a rapid, convergent, and cost-efficient strategy to analyze candidate U.S. Food and Drug Administration (FDA)-approved drugs that inhibit exosome release and/or biogenesis using breast cancer cell line models in the hope of repurposing them for the clinical treatment of metastatic tumors. We combined the ExoScreen assay based on AlphaScreenTM technology with the antibody-mediated detection of an atypical lipid (lysobisphosphatidic acid - LBPA) present in the intra-luminal vesicle/exosomal fraction to achieve both extracellular and intracellular information on exosome modulation after treatment. As proof of concept for this strategy, we identified docetaxel, biscurcumin, primaquine, and doxorubicin as potential exosome release inhibitors in the Her-2 positive MDA-MB-453 and luminal A MCF7 cell lines. Dinaciclib also functioned as an exosome release inhibitor in MCF7 cells. Further, we explored the expression of proteins involved in exosome biogenesis (TSG101, CD9 tetraspanin, Alix, SMase2) and release (Rab11, Rab27) to decipher and validate the possible molecular mechanisms of action of the identified exosome inhibitors. We anticipate that our approach could help to create robust high-throughput screening methodologies to accelerate drug repurposing when using FDA-approved compound libraries and to develop rationally-designed single/combination therapies (including nanomedicines) that can target metastasis progression by modulating exosome biogenesis or release in various tumor types.

Profiles of Perfectionistic Automatic Thoughts and Aggression.

In recent years, the study of perfectionistic automatic thoughts (PAT) has increased given its maladaptive nature since it is link to numerous psychological disorders. From our knowledge, no previous research has addressed the relationship between PAT and the four components of aggressive behavior (anger, hostility, verbal aggression, and physical aggression). This study had a double goal. The first aim was to identify distinct profiles of PAT in a sample of 3060 Ecuadorian undergraduates (Mage = 22.7, SD = 2.46). The second aim of this study was to determine whether or not statistically significant differences exist between these profiles, based on the four components of aggressive behavior. The Perfectionism Cognitions Inventory (PCI) and the Aggression Questionnaire (AQ) were used. Five profiles with different intensities in the dimensions of perfectionistic automatic thoughts were identified by Latent Class Analysis ((1) No-Perfectionistic Automatic Thoughts, (2) Low Perfectionistic Automatic Thoughts, (3) High Perfectionistic Demands, (4) Moderate Perfectionistic Automatic Thoughts, and (5) High Perfectionistic Automatic Thoughts). The moderate and high perfectionistic automatic thoughts profiles obtained the highest mean scores for all components of aggressive behavior (i.e., the four factors that make up AQ: Physical Aggression, Verbal Aggression, Anger, and Hostility), while the No-perfectionistic automatic thoughts and Low perfectionistic automatic thoughts profiles had the lowest mean scores. These results provide new knowledge about the prevalence of PAT in the context of Ecuador. Also, they suggest further research on the topic given the positive relationship of PAT and aggressive behavior.

Perfectionistic Self-Presentation Scale in Ecuador: psychometric properties and latent mean differences across genders / Escala de Autopresentación Perfeccionista en Ecuador: propiedades psicométricas y diferencias de medias latentes en función del género

Abstract Introduction: This paper aims to examine the psychometric properties, i.e., validity, reliability, factorial invariance, and latent mean differences based on gender, of the Perfectionistic Self-Presentation Scale, PSPS, in the Ecuadorian context. Method: A sample consisting of 597 Ecuadorian undergraduates participated in the study. Results: Confirmatory Factor Analysis supported a 14-item and three-dimensional model of the scale: Perfectionistic Self-Promotion, Nondisplay of Imperfection, and Nondisclosure of Imperfection. This model presented configural; measurement, i.e., metric, strong, and strict; as well as structural invariance across genders. Discriminant validity was observed by analysing correlations between PSPS factors and perfectionism traits. Males exhibited higher latent means of Perfectionistic Self-Promotion and also Nondisplay of Imperfection than females. Conclusions: The Spanish-translated and brief version of the PSPS represents a reliable and valid tool for assessing perfectionistic self-presentation in Ecuador.

Resumen Introducción: Este artículo tiene como objetivo examinar las propiedades psicométricas, i.e., validez, fiabilidad, invarianza factorial y diferencias de medias latentes en función del género, de la Escala de Autopresentación Perfeccionista, PSPS, en el contexto de Ecuador. Método: La muestra se compuso de 597 universitarios ecuatorianos. Resultados: El análisis factorial confirmatorio apoyó una estructura de la escala compuesta por 14 ítems y tres dimensiones: autopromoción perfeccionista, no-divulgación de la imperfección, y no-verbalización de la imperfección. Este modelo mostró invarianza configural; de medida, métrica, escalar y estricta; y estructural a través del género. El análisis de correlaciones entre los factores de la PSPS y los rasgos perfeccionistas evidenció la validez discriminante de la escala. Los hombres obtuvieron medias latentes significativamente más altas en comparación con las mujeres en los factores autopromoción perfeccionista y no-divulgación de la imperfección. Conclusiones: La versión de la PSPS abreviada y traducida al español representa una medida fiable y válida para evaluar la autopresentación perfeccionista en Ecuador.

Perfectionism and Emotional Intelligence: A Person-Centered Approach.

This study examined the relationship between perfectionistic concerns (PC) and perfectionistic strivings (PS) with the subcomponents of emotional intelligence (EI) through a latent class person-centered approach. A sample of 1582 Ecuadorian adolescents (619 females) aged from 12 to 18 was employed. The trait meta-mood scale-24 (TMMS-24) and the child and adolescent perfectionism scale (CAPS) were used, respectively, for assessing three subcomponents of EI (i.e., emotional attention, emotional clarity, and mood repair) and two perfectionist dimensions (PC and PS). A three-class solution (High perfectionism, moderate perfectionism, and nonperfectionism) was identified by using latent class analysis. High perfectionism significantly scored higher on emotional attention in comparison with the moderate and nonperfectionism classes, with small and moderate effect sizes. Overall, results suggest that people with high perfectionism might be at greater risk of developing maladaptive emotional self-regulation strategies, such as rumination, because of their tendency to excessively attend their negative mood states.

Transplantation of Human-Fetal-Spinal-Cord-Derived NPCs Primed with a Polyglutamate-Conjugated Rho/Rock Inhibitor in Acute Spinal Cord Injury.

Neural precursor cell (NPC) transplantation represents a promising therapy for treating spinal cord injuries (SCIs); however, despite successful results obtained in preclinical models, the clinical translation of this approach remains challenging due, in part, to the lack of consensus on an optimal cell source for human neuronal cells. Depending on the cell source, additional limitations to NPC-based therapies include high tumorigenic potential, alongside poor graft survival and engraftment into host spinal tissue. We previously demonstrated that NPCs derived from rat fetal spinal cords primed with a polyglutamate (PGA)-conjugated form of the Rho/Rock inhibitor fasudil (PGA-SS-FAS) displayed enhanced neuronal differentiation and graft survival when compared to non-primed NPCs. We now conducted a similar study of human-fetal-spinal-cord-derived NPCs (hfNPCs) from legal gestational interruptions at the late gestational stage, at 19-21.6 weeks. In vitro, expanded hfNPCs retained neural features, multipotency, and self-renewal, which supported the development of a cell banking strategy. Before transplantation, we established a simple procedure to prime hfNPCs by overnight incubation with PGA-SS-FAS (at 50 µM FAS equiv.), which improved neuronal differentiation and overcame neurite-like retraction after lysophosphatidic-acid-induced Rho/Rock activation. The transplantation of primed hfNPCs into immune-deficient mice (NU(NCr)-Foxn1nu) immediately after the eighth thoracic segment compression prompted enhanced migration of grafted cells from the dorsal to the ventral spinal cord, increased preservation of GABAergic inhibitory Lbx1-expressing and glutamatergic excitatory Tlx3-expressing somatosensory interneurons, and elevated the numbers of preserved, c-Fos-expressing, activated neurons surrounding the injury epicenter, all in a low percentage. Overall, the priming procedure using PGA-SS-FAS could represent an alternative methodology to improve the capabilities of the hfNPC lines for a translational approach for acute SCI treatment.

Renal Nano-drug delivery for acute kidney Injury: Current status and future perspectives.

Acute kidney injury (AKI) causes considerable morbidity and mortality, particularly in the case of post-cardiac infarction or kidney transplantation; however, the site-specific accumulation of small molecule reno-protective agents for AKI has often proved ineffective due to dynamic fluid and solute excretion and non-selectivity, which impedes therapeutic efficacy. This article reviews the current status and future trajectories of renal nanomedicine research for AKI management from pharmacological and clinical perspectives, with a particular focus on appraising nanosized drug carrier (NDC) use for the delivery of reno-protective agents of different pharmacological classes and the effectiveness of NDCs in improving renal tissue targeting selectivity and efficacy of said agents. This review reveals the critical shift in the role of the small molecule reno-protective agents in AKI pharmacotherapy - from prophylaxis to treatment - when using NDCs for delivery to the kidney. We also highlight the need to identify the accumulation sites of NDCs carrying reno-protective agents in renal tissues during in vivo assessments and detail the less-explored pharmacological classes of reno-protective agents whose efficacies may be improved via NDC-based delivery. We conclude the paper by outlining the challenges and future perspectives of NDC-based reno-protective agent delivery for better clinical management of AKI.

School anxiety profiles in Spanish adolescents and their differences in psychopathological symptoms.

School anxiety and psychopathological symptoms tend to co-occur across development and persist in adulthood. The present study aimed to determine school anxiety profiles based on Lang's model of the triple response system (cognitive anxiety, psychophysiological anxiety, and behavioral anxiety) and to identify possible differences between these profiles in psychopathological symptoms (depression, hostility, interpersonal sensitivity, somatization, anxiety, psychoticism, obsessive-compulsive, phobic anxiety, and paranoid ideation). The School Anxiety Inventory (SAI) and the Symptom Assessment-45 Questionnaire (SA-45) were administered to 1525 Spanish students (49% girls) between 15 and 18 years old (M = 16.36, SD = 1.04). Latent Profile Analysis identified four school anxiety profiles: Low School Anxiety, Average School Anxiety, High School Anxiety, and Excessive School Anxiety. A multivariate analysis of variance revealed statistically significant differences among the school anxiety profiles in all the psychopathological symptoms examined. Specifically, adolescents with Excessive School Anxiety showed significantly higher levels of the nine psychopathological symptoms than their peers with Average School Anxiety and Low School Anxiety. In addition, the Excessive School Anxiety profile scored significantly higher in phobic anxiety than the High School Anxiety group. These findings allow to conclude that it is necessary enhance well-being and reduce psychopathology of those adolescents who manifest high and very high reactivity in cognitive, psychophysiological, and behavioral anxiety.

Depletion of Mannose Receptor-Positive Tumor-associated Macrophages via a Peptide-targeted Star-shaped Polyglutamate Inhibits Breast Cancer Progression in Mice.

Although many studies have explored the depletion of tumor-associated macrophages (TAM) as a therapeutic strategy for solid tumors, currently available compounds suffer from poor efficacy and dose-limiting side effects. Here, we developed a novel TAM-depleting agent ("OximUNO") that specifically targets CD206+ TAMs and demonstrated efficacy in a triple-negative breast cancer (TNBC) mouse model. OximUNO comprises a star-shaped polyglutamate (St-PGA) decorated with the CD206-targeting peptide mUNO that carries the chemotherapeutic drug doxorubicin (DOX). In the TNBC model, a fluorescently labeled mUNO-decorated St-PGA homed to CD206+ TAMs within primary lesions and metastases. OximUNO exhibited no acute liver or kidney toxicity in vivo. Treatment with OximUNO reduced the progression of primary tumor lesions and pulmonary metastases, significantly diminished the number of CD206+ TAMs and increased the CD8/FOXP3 expression ratio (indicating immunomodulation). Our findings suggest the potential benefit of OximUNO as a TAM-depleting agent for TNBC treatment. Importantly, our studies also represent a novel design of a peptide-targeted St-PGA as a targeted therapeutic nanoconjugate. Significance: A peptide-targeted nanoformulation of DOX exclusively eliminates mannose receptor+ TAMs in breast cancer models, generating response without off-target effects (a drawback of many TAM-depleting agents under clinical study).

In Vivo Antitumor and Antimetastatic Efficacy of a Polyacetal-Based Paclitaxel Conjugate for Prostate Cancer Therapy.

Prostate cancer (PCa), one of the leading causes of cancer-related deaths, currently lacks effective treatment for advanced-stage disease. Paclitaxel (PTX) is a highly active chemotherapeutic drug and the first-line treatment for PCa; however, conventional PTX formulation causes severe hypersensitivity reactions and limits PTX use at high concentrations. In the pursuit of high molecular weight, biodegradable, and pH-responsive polymeric carriers, one conjugates PTX to a polyacetal-based nanocarrier to yield a tert-Ser-PTX polyacetal conjugate. tert-Ser-PTX conjugate provides sustained release of PTX over 2 weeks in a pH-responsive manner while also obtaining a degree of epimerization of PTX to 7-epi-PTX. Serum proteins stabilize tert-Ser-PTX, with enhanced stability in human serum versus PBS (pH 7.4). In vitro efficacy assessments in PCa cells demonstrate IC50 values above those for the free form of PTX due to the differential cell trafficking modes; however, in vivo tolerability assays demonstrate that tert-Ser-PTX significantly reduces the systemic toxicities associated with free PTX treatment. tert-Ser-PTX also effectively inhibits primary tumor growth and hematologic, lymphatic, and coelomic dissemination, as confirmed by in vivo and ex vivo bioluminescence imaging and histopathological evaluations in mice carrying orthotopic LNCaP tumors. Overall, the results suggest the application of tert-Ser-PTX as a robust antitumor/antimetastatic treatment for PCa.

Current hurdles to the translation of nanomedicines from bench to the clinic.

The field of nanomedicine has significantly influenced research areas such as drug delivery, diagnostics, theranostics, and regenerative medicine; however, the further development of this field will face significant challenges at the regulatory level if related guidance remains unclear and unconsolidated. This review describes those features and pathways crucial to the clinical translation of nanomedicine and highlights considerations for early-stage product development. These include identifying those critical quality attributes of the drug product essential for activity and safety, appropriate analytical methods (physical, chemical, biological) for characterization, important process parameters, and adequate pre-clinical models. Additional concerns include the evaluation of batch-to-batch consistency and considerations regarding scaling up that will ensure a successful reproducible manufacturing process. Furthermore, we advise close collaboration with regulatory agencies from the early stages of development to assure an aligned position to accelerate the development of future nanomedicines.

Identification of an ASC oligomerization inhibitor for the treatment of inflammatory diseases.

The ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)) protein is an scaffold component of different inflammasomes, intracellular multiprotein platforms of the innate immune system that are activated in response to pathogens or intracellular damage. The formation of ASC specks, initiated by different inflammasome receptors, promotes the recruitment and activation of procaspase-1, thereby triggering pyroptotic inflammatory cell death and pro-inflammatory cytokine release. Here we describe MM01 as the first-in-class small-molecule inhibitor of ASC that interferes with ASC speck formation. MM01 inhibition of ASC oligomerization prevents activation of procaspase-1 in vitro and inhibits the activation of different ASC-dependent inflammasomes in cell lines and primary cultures. Furthermore, MM01 inhibits inflammation in vivo in a mouse model of inflammasome-induced peritonitis. Overall, we highlight MM01 as a novel broad-spectrum inflammasome inhibitor for the potential treatment of multifactorial diseases involving the dysregulation of multiple inflammasomes.