Active Drug Research Articles

Phototactic Biohybrid Microrobot Using Peptide Nanotubes‐Coated Microalgae for pH‐Responsive Active Drug Delivery

Despite the recent wide investigation on active cancer drug delivery, there are still strong medical unmet needs for active tumor‐environment responsive cancer drug delivery in terms of spatiotemporal control. Herein, a biohybrid system of pH‐responsive peptide nanotubes (PNTs)‐coated microalgae for active cancer drug delivery in response to the tumor‐environment is developed. The amphiphilic PNTs are effectively used to encapsulate cancer drugs and coat the living microalgae of C. reinhardtii by electrostatic interactions. The drug‐loaded PNTs‐based biohybrid microalgae maintain agile movement with phototaxis behavior. After in vitro characterization and cytotoxicity assessment, it is shown that the biohybrid microalgae could be phototactically localized to the cancer cells and pH‐responsively disassembled to release cancer drugs in a controlled manner. Finally, with the encapsulation of paclitaxel, the statistically significant suppression of tumor growth in xenograft tumor model animals is successfully demonstrated. Taken together, the feasibility of the multifunctional microrobotic platform for advanced cancer therapy is confirmed.

Functional anticholinergic activity of drugs classified as strong and moderate on the anticholinergic burden scale on bladder and ileum.

Several medications are commonly administered to older Japanese patients. Since some of them have not been included in previously developed scales to estimate the anticholinergic burden, we have developed a new muscarinic receptor binding-based anticholinergic burden scale. This study aimed to investigate the functional inhibitory effects of 60 medications, classified as anticholinergic burden scales 3 and 2 by the anticholinergic burden scale, on muscarinic receptor-mediated contractions in the bladder and ileum. The relaxation response induced by these drugs on isolated rat bladders and ileum smooth muscles constricted by carbachol was assessed using the organ bath method. All drugs inhibited smooth muscle contractile responses induced by the muscarinic receptor activation in a concentration-dependent manner in the rat bladder and ileum. Notably, variations were observed in the relaxation responses of the drugs, and the function EC50 values were positively correlated with the binding IC50 values in the bladder and ileum. The results of this study provide functional pharmacological evidence for the muscarinic receptor binding-based anticholinergic burden scale. Implementation of this scale may help reduce the risk of constipation and urinary retention, which are common side effects associated with anticholinergic drugs.

Strategies to Overcome Antimicrobial Resistance in Nosocomial Infections, A Review and Update.

Nosocomial infections, also known as healthcare-associated infections, are a significant global concern due to their strong association with high mortality and morbidity in both developed and developing countries. These infections are caused by a variety of pathogens, particularly the ESKAPE group of bacteria, which includes the six pathogens Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. These bacteria have demonstrated noteworthy resistance to different antibiotics. Antimicrobial resistance mechanisms can manifest in various forms, including restricting drug uptake, modifying drug targets, inactivating drugs, active drug efflux, and biofilm formation. Accordingly, various strategies have been developed to combat antibiotic-resistant bacteria. These strategies encompass the development of new antibiotics, the utilization of bacteriophages that specifically target these bacteria, antimicrobial combination therapy and the use of peptides or enzymes that target the genomes or essential proteins of resistant bacteria. Among promising approaches to overcome antibiotic resistance, the CRISPR/Cas system stands out and offers many advantages. This system enables precise and efficient editing of genetic material at specific locations in the genome. Functioning as a bacterial "adaptive immune system," the CRISPR/Cas system recognizes, degrades, and remembers foreign DNA sequences through the use of spacer DNA segments that are transcribed into CRISPR RNAs (crRNA). This paper has focused on nosocomial infections, specifically the pathogens involved in hospital infections, the mechanisms underlying bacterial resistance, and the strategies currently employed to address this issue. Special emphasis has been placed on the application of CRISPR/Cas technology for overcoming antimicrobial resistance.

In situ enzymatic peptide-based nanomedicine with combined effects for enhanced tumor radio-immunotherapy

Despite the combination of radiotherapy and immunotherapy in clinical practice have shown promising synergistic anti-tumor effect, the immunosuppressive tumor microenvironment (TME) remains to be one of stumbling block impeding the therapeutic efficacy of radio-immunotherapy. In this study, in situ self-assembled peptide-based drug delivery systems with multiple effects were constructed for enhancing tumor radio-immunotherapy. The two peptide-drug conjugates could co-assembled into peptide-based nanomedicine on the cancer cell membrane under enzyme catalysis and continuously release small molecular active drugs in the cytoplasm, which combined action lead YAP phosphorylation and nuclear transfer failure. By simutaneously suppressing glycolysis and reactivating the dysfunctional Hippo pathway, the peptide-based nanomedicine also remitted the immunosuppressive TME by reducing lactate levels and the expression of immunosuppressive factors, respectively. As a result, the pro-tumorigenic M2 phenotype of tumor-associated macrophages (TAMs) was decreased and the anti-tumorigenic M1 phenotype of TAMs was increased. Such a dual intervention strategy from cellular metabolic level and gene transcription level not only inhibited tumor cell proliferation but also reversed the immunosuppressive TME, thereby augmenting the combined efficacy of radiotherapy and immune checkpoint blockade (ICB) therapy. The work is anticipated to contribute novel insights into anti-cancer drug targeted delivery and tumor multi-modal synergistic therapy.

Diterpene glycosides from Fructus Rubi ameliorates benign prostatic hyperplasia in rats through the androgen and TGF-β/Smad signaling pathway

Fructus Rubi (FR), a food material with medicinal value, is used in traditional Chinese medicine (TCM) for treatment of various kidney-related problems, such as impotence, spermatorrhea, and frequent urination. It is also frequently used to produce diverse functional foods in China. The purpose of this research was to assess the therapeutic effects of FR diterpene glycosides on RWPE-1 epithelial cell (RWPE-1), a human normal prostatic epithelial cell, and benign prostate hyperplasia (BPH) rats, both of which had been exposed to dihydrotestosterone (DHT) and testosterone propionate (TP), respectively, and to investigate the mechanism of action. Target proteins that could stably bind to certain diterpene glycosides were screened through drug affinity responsive target stability combined with mass spectrometry (DARTS/MS). DHT-induced RWPE-1 cells were used to detect drug activity. TP was subcutaneously injected to induce BPH in rats. The extract of diterpene glycosides from FR (FDS) was orally administered for 28 days. The DHT levels in the serum and prostate tissue of the rats were measured through enzyme-linked immunosorbent assay (ELISA), and to analyze cell proliferation and epithelial-mesenchymal transition (EMT), the protein expression of prostate-specific antigen (PSA), androgen receptor (AR), steroid 5α-reductase type 2 (SRD5A2), proliferating cell nuclear antigen (PCNA), S100 calcium-binding protein A2 (S100A2), transforming growth factor-β1 (TGF-β1), E-cadherin, vimentin, and Smad4 was determined through western blotting (WB), immunohistochemistry (IHC), or immunofluorescence (IF). FDS reduced the proliferation of DHT-induced RWPE-1 cells. It also significantly inhibited rat prostate enlargement; decreased DHT levels in the serum and prostate tissue; inhibited the protein expression of AR, PSA, PCNA, S100A2, TGF-β1, E-cadherin, and Smad4; and increased the protein expression of E-cadherin. The present study is the first to report that diterpene glycosides isolated from FR inhibited BPH at the cellular level, regulated the proliferation of prostate cells through the androgen signaling pathway, and prevented EMT in the prostate through the S100A2-mediated TGF-β/Smad signaling pathway. These results indicate that FDS is a promising multitarget therapy for BPH.

The impact of long-course chemoradiotherapy on the myenteric plexus, neuromuscular functions and responses to prokinetic drugs in the human rectum.

The long-term effects of chemoradiotherapy on human rectum are poorly understood. The aims were to investigate changes in inflammatory status, myenteric neuron numbers/phenotype, neuromuscular functions and prokinetic drug efficacy. Macroscopically normal proximal-to-mid rectum was obtained from 21 patients undergoing surgery for bowel cancer, 98days (range: 63-350) after concurrent capecitabine and pelvic radiotherapy, and 19 patients without chemoradiotherapy. Inflammatory status was measured by H&E, CD45 staining and qPCR. Myenteric neurons were examined by immunohistochemistry. Neuromuscular functions and drug efficacy were studied using exogenous agents and electrical field stimulation (EFS) to activate intrinsic nerves. Inflammation was not detected. Numbers of myenteric ganglia/neurons were unchanged (11.7±2.4 vs. 10.3±2.2 neurons/mm myenteric plexus with/without chemoradiotherapy) as were the numbers of cholinergic/nitrergic neurons. EFS stimulated cholinergic and nitrergic neurons so the contractile response of the muscle was the sum of both but dominated by cholinergic (causing contraction) or less often, nitrergic activity (relaxation), followed, after termination of EFS, by neuronally mediated contraction. Inhibition of nitric oxide synthase (by L-NAME 300μM) more clearly defined EFS-evoked contractions. The 5-HT4 agonist prucalopride 10μM and the cholinesterase inhibitor donepezil 1µM, respectively increased and greatly increased the composite contractile response to EFS (measured as 'area-under-the curve') and the contractions isolated by L-NAME (respectively, by 22±14% and 334±87%; n=11/8). After chemoradiotherapy, nitrergic-mediated muscle relaxations occurred more often during EFS (in 29.8±6.1% preparations vs. 12.6±5.1% without chemoradiotherapy, n=21/18). With L-NAME, the ability of prucalopride to facilitate EFS-evoked contraction was lost and that of donepezil approximately halved (contractions increased by 132±36%; n=8). Several months after chemoradiotherapy, the rectum was not inflamed and myenteric neuron numbers/phenotype unchanged. However, nitrergic activity was increased relative to cholinergic activity, and prokinetic-like drug activity was lost or greatly reduced. Thus, chemoradiotherapy causes long-term changes in neuromuscular functions and markedly reduces the efficacy of drugs for treating constipation.

Recent Advances in Prodrug Approach over Conventional Drug Therapy

Background: Prodrugs represent a strategically designed category of medicinal compounds aimed at optimizing drug pharmacokinetics. By modifying the pharmacological action of the drug within a prodrug, subsequent enzymatic bioconversion in the human body facilitates the release of the active drug. This strategy has been highly effective, as demonstrated by the substantial number of prodrugs found in commercial pharmaceutical products. Prodrugs have emerged as a recognized strategy for augmenting the physical, chemical, biological, or pharmacokinetic attributes of pharmacologically active molecules in the realm of drug research and development. Objective: This systematic review intended to offer insights into the recent developments in the prodrug approach used in drug research and development, with a focus on highlighting its effectiveness. The objective was to illustrate the diverse applications of prodrugs and their impact on enhancing drug properties and therapeutic outcomes. Area covered: This review is centered on the most recent developments in the prodrug approach used for drug development and research. The prodrug concept has a wide range of practical uses, some of which are illustrated in this review article. These illustrations are categorized based on the intention behind their creation. Results: Prodrugs have been designed to address challenges, such as poor water solubility and low bioavailability. Strategies, like using neutral or charged promoieties, have been reported to be successful in enhancing solubility. For permeability and bioavailability, prodrugs have been employed to mask polar groups, enabling better absorption. Prolonged half-life prodrugs have been developed to extend drug action, while tissue-targeted delivery prodrugs have shown promise in enhancing drug delivery to specific sites. Conclusion: Prodrug design offers promising strategies to optimize drug delivery and efficacy. Despite challenges, ongoing clinical trials and research efforts indicate the potential of prodrugs in improving therapeutic outcomes. Addressing formulation challenges and understanding pharmacokinetic variability are essential for successful prodrug development.

Cross-Linked Thiolated Hydroxypropil-β-Cyclodextrin for Pulmonary Drug Delivery

Inhalable formulations with cyclodextrins (CDs) as solubility and absorption enhancers show promise for pulmonary delivery. Thiolated hydroxypropyl-β-cyclodextrin (HP-β-CD-SH) has mucoadhesive properties, enhancing drug absorption. Moreover, it has self-aggregation capability, which could further improve absorption and drug stability, as well as reduce irritation. This study aims to stabilize CD nanoaggregates using bifunctional cross-linkers and evaluate their benefits for lung drug delivery compared to pristine HP-β-CD-SH. Methods: The effectiveness of cross-linked HP-β-CD-SH nanoparticles (HP-β-CD-SH-NP) was compared to transient nanoaggregates in enhancing the activity of dexamethasone (DMS) and olive leaf extracts (OLE). DMS, a poorly soluble drug commonly used in lung treatments, and OLE, known for its antioxidant properties, were chosen. Drug-loaded HP-β-CD-SH-NP were prepared and nebulized onto a lung epithelial Air–Liquid Interface (ALI) model, assessing drug permeation and activity. Results: HP-β-CD-SH with 25% thiolation was synthesized via microwave reaction, forming 150 nm nanoaggregates and stabilized 400 nm HP-β-CD-SH-NP. All carriers showed good complexing ability with DMS and OLE and were biocompatible in the lung ALI model. HP-β-CD-SH promoted DMS absorption, while stabilized HP-β-CD-SH-NP protected against oxidative stress. Conclusion: HP-β-CD-SH is promising for lung delivery, especially as stabilized nanoaggregates, offering versatile administration for labile molecules like natural extracts.

Safety Profile of Mass Administration of Albendazole Among School Children (6-19 Years): A Prospective Active Surveillance Study

Background: Infections with Soil-transmitted Helminths (STHs) impact about 24% of the global population. A disproportionate number of individuals, particularly those from low socioeconomic backgrounds, live in emerging nations. In India, between the ages of one and fourteen, almost 220 million children are susceptible to intestinal worm infestations caused by parasites. The National Deworming Day (NDD) initiative was started by the Indian government in February 2015 as a part of the National Health Mission to address this problem. Though the adverse effects of albendazole in routine therapy are known, the mass administration of the medicine in children as part of a public health program has not been adequately studied. Objective: This study aimed to determine the occurrence, type, and severity of adverse drug reactions resulting from mass administration of albendazole in school children aged 6-19 years in a district of northern India. Methods: Twenty specified clusters were randomly chosen from a total of 94 clusters in the state to participate in this prospective, descriptive, observational study that was carried out in Karnal, Haryana. Both a passive approach and an active adverse drug reaction reporting system were used in the study. The six-step process known as Deb’s Active Surveillance & Assisted Reporting System was employed in our study. Adverse drug reactions were recorded using the suspected Adverse Drug Reaction (ADR) reporting form of the Pharmacovigilance Programme of India (PvPI). Results: Twenty clusters with a combined total of 94 schools and 12,751 students were observed during the study. In this study, there were more female participants (N = 8,060; 63.21%) than male participants (N = 4,691; 36.78%). A total of 29 ADRs were reported. All reported ADRs were mild in nature. It was discovered that there were 1.37 incidences for every 1000 individuals. As illustrated in Fig. (1), the most frequently reported Adverse Drug Reactions (ADRs) were vomiting (N = 10), nausea (N = 4), abdominal pain (N = 2), and headache (N = 1). The majority of ADRs were categorized as probable (N=18; 62.06%), followed by possible (N=11; 37.93%). result: Twenty clusters with a combined total of 94 schools and 12,751 students were observed during the study. In this study, there were more female participants (N = 8,060; 63.21%) than male participants (N = 4,691; 36.78%). A total of 29 ADRs were reported. All reported ADRs were mild in nature. It was discovered that there were 1.37 incidences for every 1000 individuals. As illustrated in figure 1, the most frequently reported adverse drug reactions (ADRs) were vomiting (N = 10), nausea (N = 4), abdominal pain (N = 2), and headache (N = 1). The majority of ADRs were categorized as probable (N=18; 62.06%), followed by possible (N=11; 37.93%). Conclusion: An active surveillance system alongside voluntary passive reporting during the mass administration of medicines can help evaluate the safety profile of the medicinal products. The occurrence of ADRs following mass administration of albendazole in school children was found to be only 1.37 incidences for every 1000 recipients, being mild in nature, with vomiting being the most common.

Peptide-Based Drugs: Development and Therapeutic Applications

Current advances in knowledge about peptides as drugs are of great significance; They have planning potentialities in different sections of medicinal practice. This review will summarize the progress in the synthesis and the biological activities of the peptide-based drug, along with some of the uses. We start with the historical aspect and key points in the development of the corresponding field. In general, the development part describes the approaches of peptides synthesis, design strategies, screening methods, and optimization for stability and bioavailability. We then describe the action of such mechanisms as with respect to receptors, enzymes, and peptides that can penetrate cells. It has also expanded the assessment of the description of peptide drugs in the treatment of cancer, cardiovascular diseases, metabolic diseases, neurological diseases, infectious diseases, and immunotherapy. We cover both the problems in the formation of peptide drugs like stability, delivery, and regulatory issues and the opportunities like nanotechnology, bioprinting, and CRISPR. Last, we discuss the outlook of the peptide-based therapeutics and review features, which are promising for the development of new trends and perspectives of application. The present review is intended to give an up-to-date and easy to grasp information regarding the status and perspectives of peptide-associated medicines in contemporary pharmacology.

The immunological landscape and silico analysis of key paraptosis regulator LPAR1 in gastric cancer patients

This study aims to identify key regulators of paraptosis in gastric cancer (GC) and explore their potential in guiding therapeutic strategies, especially in stomach adenocarcinoma (STAD). Genes associated with paraptosis were identified from the references and subjected to Cox regression analysis in the TCGA-STAD cohort. Using machine learning models, LPAR1 consistently ranked highest in feature importance. Multiple sequencing data showed that LPAR1 was significantly overexpressed in cancer-associated fibroblasts (CAFs). LPAR1 expression was significantly higher in normal tissues, and ROC analysis demonstrated its discriminative ability. Copy number alterations and microsatellite instability were significantly associated with LPAR1 expression. High LPAR1 expression correlated with advanced tumor grades and specific cancer immune subtypes, and multivariate analysis confirmed LPAR1 as an independent predictor of poor prognosis. LPAR1 expression was associated with different immune response metrics, including immune effector activation and upregulated chemokine secretion. High LPAR1 expression also correlated with increased sensitivity to compounds, such as BET bromodomain inhibitors I-BET151 and RITA, suggesting LPAR1 as a biomarker for predicting drug activity. FOXP2 showed a strong positive correlation with LPAR1 transcriptional regulation, while increased methylation of LPAR1 promoter regions was negatively correlated with gene expression. Knockdown of LPAR1 affected cell growth in most tumor cell lines, and in vitro experiments demonstrated that LPAR1 influenced extracellular matrix (ECM) contraction and cell viability in the paraptosis of CAFs. These findings suggest that LPAR1 is a critical regulator of paraptosis in GC and a potential biomarker for drug sensitivity and immunotherapy response. This underscores the role of CAFs in mediating tumorigenic effects and suggests that targeting LPAR1 could be a promising strategy for precision medicine in GC.

Optimizing structural design in SN38 delivery: More assembly stability and activation efficiency

Dimeric prodrug self-assembly nanoparticles (DPS NPs) present promising avenues for chemotherapeutic delivery, yet optimizing the linker design for effective SN38 delivery remains challenging. We developed various SN38 dimeric prodrugs with differing linker lengths to explore how linker length impacts DPS NP performance. Our study reveals that linker length critically affects the nanoparticles assembly stability and activation efficiency. Specifically, too short linkers compromise assembly stability and lead to premature drug activation in the bloodstream, raising safety concerns. Conversely, too long linkers hinder both assembly stability and activation efficiency within tumor cells, diminishing anti-tumor effectiveness. The optimal linker (C12) achieved the best balance, ensuring robust assembly stability and high activation efficiency, thereby enhancing anti-tumor efficacy while maintaining a favorable safety profile. This work underscores the significance of linker length in designing effective DPS NPs for cancer treatment.

Synthesis of biodegradable Janus dendrimer conjugates with chlorambucil and naproxen

To improve the anticancer activity of commercial drugs, a series of well-defined Janus dendrimer conjugates with chlorambucil (CLB) and naproxen, which feature diethanolamine groups and ethylene glycol in the structure, were synthesized and characterized in detail. The anticancer activity of all synthesized dendrons and dendrimers were tested and screened against six human cancer cells. In vitro all conjugates at 25 μM exhibit selectivity towards human mammary adenocarcinoma (MFC-7) cells as compared to U-251, PC-3, and HCT-15 cells, while being only slightly active in SKLU-1 and K-562 cells. The IC50 values showed that the best growth suppressor of MFC-7 (4 ± 0.3 μM) was the second-generation dendrimer with four chlorambucil and four naproxen moieties. The result indicates that Janus dendrimers are promising molecular scaffolds for the design of more potent anticancer drugs. Further biological evaluations, such as the anticancer activity of the Janus dendrimers in vivo, are ongoing.

Intoxication in the city: Investigating spatial patterns and determinants of drugs and alcohol-related illegal activities in India's geostrategic corridor

Illicit drug and alcohol-related activities pose significant challenges to metropolitan centres globally, impacting public safety and socio-economic stability. This research analyzes the spatial and temporal patterns of drugs and alcohol-related illegal activities (DARIA) in Siliguri, known as the "Gateway of North-East India." The primary objectives are to explore DARIA patterns, identify clusters and concentrated areas, and investigate contributing factors. Using GIS-based spatial analysis and geographical models, we studied incidents recorded over three years from 2021 to 2023. Advanced spatial statistical approaches were applied to identify specific clusters of DARIA occurrences. The pure temporal analysis highlighted periods of increased illegal activity. Various geographical models, including ordinary least squares (OLS), geographically weighted regression (GWR), and multiscale geographically weighted regression (MGWR), were used to examine the spatial association. The MGWR model, with an explanatory power of R2 = 0.816, provided a detailed understanding of spatial relationships and variations in DARIA. Our findings indicate specific zones with frequent DARIA occurrences, mainly near major transportation hubs, commercial points, and areas with significant mobility. Key exploratory factors such as illiteracy rate, population density, proximity to playgrounds and slums were highly associated with DARIA incidents. These findings contribute to developing safer, more resilient, and more sustainable cities worldwide.

High Therapeutic Index α-Helical AMPs and Their Therapeutic Potential on Bacterial Lung and Skin Wound Infections.

Antimicrobial peptides (AMPs) possess strong antibacterial activity and low drug resistance, making them ideal candidates for bactericidal drugs for addressing the issue of traditional antibiotic resistance. In this study, a template (G(XXKK)nI, G = Gly; X = Leu, Ile, Phe, or Trp; n = 2, 3, or 4; K = Lys; I = Ile.) was employed for the devised of a variety of novel α-helical AMPs with a high therapeutic index. The AMP with the highest therapeutic index, WK2, was ultimately chosen following a thorough screening process. It demonstrates broad-spectrum and potent activity against both standard and multidrug-resistant bacteria, while also showing low hemolysis and rapid and efficient time-kill kinetics. Additionally, WK2 exhibits excellent efficacy in treating mouse models of Klebsiella pneumonia-induced lung infections and methicillin-resistant Staphylococcus aureus (MRSA)-induced skin wound infections while demonstrating good safety profiles in vivo. In conclusion, the template-based design methodology for novel AMPs with high therapeutic indices offers new insights into addressing antibiotic resistance problems. WK2 represents a promising antimicrobial agent.

Sunitinib for the treatment of patients with advanced pheochromocytomas or paragangliomas: The phase 2 non-randomized SUTNET clinical trial

BackgroundMetastatic Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors characterized by high morbidity and limited systemic treatment options, mainly based on radiometabolic treatments or chemotherapy. Based on the preclinical rationale that PGGLs carcinogenesis relies on angiogenesis, treatment with tyrosine kinase inhibitors (TKI) may represent another viable therapeutic option. MethodsWe conducted a prospective phase II study in patients with metastatic or unresectable PGGLs. Patients received sunitinib (50 mg daily for 4 weeks, followed by a 2-week rest period) until progressive disease (PD), unacceptable toxicity or consent withdrawal. The primary endpoint was 12-month progression-free survival (PFS) rate; secondary endpoints were safety overall response rate (ORR) according to RECIST 1.1 criteria and overall survival (OS). EudraCT Number: 2011–002632-99. ResultsFifty patients were included. At a median follow-up of 71.7 months (IQR 35.4–100.1), the 1 year-PFS rate was 53.4 % (95 %CI 41.1–69.3) and median PFS was 14.1 months (95 % CI 8.9–25.7). ORR was 15.6 %, the median OS was 49.4 months (95 %CI 21.2-NA), and grade 3 or higher treatment-related adverse events were reported in 34 % patients. No significant correlation was found between specific genetic alterations or genomic clusters and sunitinib efficacy. ConclusionSunitinib is an active drug in patients with advanced PGGLs, capable of inducing prolonged disease control with a manageable toxicity profile.

The Role of Intracellular and Extracellular Vesicles in the Development of Therapy Resistance in Cancer.

Cancer is the second leading cause of global mortality and claims approximately 10 million lives annually. Despite advances in treatments such as surgery, chemotherapy, and immunotherapy, resistance to these methods has emerged. Multidrug resistance (MDR), where cancer cells resist diverse treatments, undermines therapy effectiveness, escalating mortality rates. MDR mechanisms include, among others, drug inactivation, reduced drug uptake, enhanced DNA repair, and activation of survival pathways such as autophagy. Moreover, MDR mechanisms can confer resistance to other therapies like radiotherapy. Understanding these mechanisms is crucial for improving treatment efficacy and identifying new therapeutic targets. Extracellular vesicles (EVs) have gathered attention for their role in cancer progression, including MDR development through protein transfer and genetic reprogramming. Autophagy, a process balancing cellular resources, also influences MDR. The intersection of EVs and autophagy further complicates the understanding of MDR. Both extracellular (exosomes, microvesicles) and intracellular (autophagic) vesicles contribute to therapy resistance by regulating the tumor microenvironment, facilitating cell communication, and modulating drug processing. While much is known about these pathways, there is still a need to explore their potential for predicting treatment responses and understanding tumor heterogeneity.

Drug and biomarker tissue levels in a randomized presurgical trial on exemestane alternative schedules.

The drug's activity at the target tissue could help to define the minimal effective dose to promote cancer preventive therapy. Here we present exemestane and sex hormone concentrations within breast tissue from a pre-surgical study of alternative exemestane schedules. Postmenopausal women candidate for breast surgery for estrogen receptor-positive breast cancer were randomized to exemestane 25 mg once daily (QD), 25 mg three times/week (TIW), or 25 mg per/week (QW) for 4-6 weeks before surgery. Drug and sex hormones were analyzed from homogenized frozen tissue using a QTRAP 6500+ LC-MS/MS System. Tissue drug concentrations were detectable only in the QD arm with higher concentrations in non-malignant tissue. Estradiol was nearly suppressed in all groups in the non-malignant tissue (QD vs TIW p = .364 and QD vs QW p = .693). In contrast, a dose-response trend was observed in cancer tissue. Based on estradiol suppression in non-malignant tissue, lower exemestane schedules should be explored for breast cancer preventive therapy.

Light-Controlled Bioorthogonal Chemistry Altered Natural Killer Cell Activity for Boosted Adoptive Immunotherapy.

Natural killer (NK) cell-based immunotherapy has received much attention in recent years. However, the practical application is still suffering from the decreased function, inadequate infiltration, and immunosuppressive microenvironment in solid tumor. Herein, we construct the light-responsive porphyrin Fe array-armed NK cells (denoted as NK@p-Fe) for cell behavior modulation via bioorthogonal catalysis. By installing cholesterol-modified porphyrin Fe molecules on NK cell surface, it forms a catalytic array with light-harvesting capabilities. This functionality transforms NK cells into cellular factories, capable of catalyzing the production of active agents in a light-controlled manner. The NK@p-Fe can generate active antineoplastic drug doxorubicin through bioorthogonal reactions to enhance the cytotoxic function of NK cells. Beyond drug synthesis, the NK@p-Fe can also bioorthogonally catalyze to produce FDA approved immune agonist, imiquimod (IMQ). The activated immune agonist plays a dual role by inducing DC maturation for NK cells activation and reshaping tumor immunosuppressive microenvironment for NK cells infiltration. This work represents a paradigm for modulation of adoptive cell behaviors to boost cancer immunotherapy by bioorthogonal catalysis.

Eco-friendly Approaches to Chromene Derivatives: A Comprehensive Review of Green Synthesis Strategies.

Synthetic routes of chromene are an area of thrust research due to its wide application as pigments, agrochemicals, cosmetics, and an important nucleus scaffold for various pharmaco-logically active drugs. The chromene nucleus is an important moiety for the discovery of new drug candidates owing to its broad range of pharmacological actions like antitumor, anti-inflammatory, antiviral, and many others. However, traditional synthesis techniques frequently use unsafe reagents and produce hazardous waste, presenting environmental issues. The eco-friendly production of chromene derivatives utilizes sustainable raw materials, non-toxic cata-lysts, and gentle reaction conditions to reduce ecological consequences. Innovative methods like microwave irradiation, ultrasound synthesis, the use of environmentally friendly solvents, a cata-lyst-based approach with minimal environmental impact, and mechanochemistry-mediated syn-thesis are implemented. These approaches provide benefits in scalability, cost-effectiveness, and ease of purification. This review compiles and presents various recently reported green synthetic strategies of chromene and its derivatives and gives the reader a clear idea of the detailed and crit-ical aspects of various synthetic protocols described.