Selective Drug Research Articles

Tumor targeting in situ aggregation of nanoparticle-to-nanoparticle strategy to simultaneously induce ferroptosis and immunogenic cell death using complementary heparin and protamine molecules

Antibody-drug conjugate (ADC)-based tumor-targeting therapies have demonstrated clinical success in selective drug delivery for cancer treatment. However, the effectiveness of these strategies is hindered by the low amount of loaded payload, lack of sustained efficacy, and insufficient therapeutic performance. In this study, we introduce a novel in situ aggregation-based targeting system using two combinable nanoparticles (NP) that leverage the biocompatible and specific interaction between complementary protamine and heparin molecules. To demonstrate it, we developed protamine-based nanoparticles (PPNC NP) containing cytotoxic negatively charged curcumin (NCur), and heparin-based nanoparticles (HDFe NP) encapsulating doxorubicin and Fe3+. The NP-NP treatment successfully formed aggregates at targeted tumor sites. Our findings demonstrate that the initial administration of PPNC NP effectively targets the tumor and the subsequent administration of complementary HDFe NPs results in their significant accumulation in the tumor tissue, directed by the ‘guidance effect’ of PPNC NPs. This sequence of events promotes the formation of in situ aggregates within the tumor tissue, leading to prolonged nanoparticle accumulation, ferroptosis and immunogenic cell death (ICD). In conclusion, our study demonstrates the effectiveness of a biocompatible and in situ aggregating nanoparticle-nanoparticle system as a solution for overcoming the limitations of current nanoparticle-based delivery systems.

Selection criteria for anticoagulants: survey of Japanese cardiologists based on their daily clinical practice: the Selection DOAC study

Background In patients with atrial fibrillation (AF), direct oral anticoagulants (DOACs) have been utilized as an alternative to warfarin, which is known to have several limitations. This study aimed to clarify the selection criteria for anticoagulants, considering both individual patient factors and the differences between various drugs. Methods This study conducted a web-based questionnaire from September 20, 2023 to October 3, 2023, among physicians who were members of a cardiology-specific website. Results In total, 172 respondents were enrolled in this study. Edoxaban was the most frequently selected anticoagulant (39.1%), followed by apixaban (32.7%) and rivaroxaban (16.8%). Logistic regression analysis revealed that increased concern for adherence enhanced the frequency of selecting edoxaban (odds ratio [OR] = 2.42; p = 0.047), with the opposite trend observed for dabigatran (OR = 0.404; p = 0.029). The selection of apixaban is related to whether the patient is able to maintain a regular lifestyle, including adherence to medication schedules (OR = 1.874; p = 0.031). Furthermore, detailing activities from a medical representative, especially regarding a new indication, were found to influence drug selection for rivaroxaban (OR = 2.422; p = 0.047). Conclusion This study revealed that edoxaban is the most frequently selected anticoagulant. Although prescribing cardiologists select drugs based on background factors, adherence to medication and information from medical representatives were also crucial factors in the selection process.

Defective MOFs as nano carrier for drug loading with controlled release

Metal-organic frameworks (MOFs) are considered highly promising nanomedicine carriers due to their well-defined structures, high specific surface area and porosity, adjustable pore size, and ease of chemical functionalization. However, traditional MOFs face limitations in lattice size and strong non-covalent interactions between the host and guest, posing significant challenges for high and responsive drug loading. In this study, defect-engineered MOFs (UiO-66-NH2) with uniform mesopores were successfully prepared by reducing ligands and adding modulators. Compared to perfect UiO-66-NH2, the loading capacity of the defective UiO-66-NH2 increased more than twofold. Utilizing phase change material as a trigger for drug release, precise temperature-responsive drug release was accomplished. This offers a novel strategy for MOFs materials in drug delivery and controlled release. This study will aid future efforts in using MOFs for selective drug delivery to cells, particularly in cancer treatment and related fields.

Peptide-Alkoxyamine Drugs: An Innovative Approach to Fight Schistosomiasis: "Digging Their Graves with Their Forks".

The expansion of drug resistant parasites sheds a serious concern on several neglected parasitic diseases. Our recent results on cancer led us to envision the use of peptide-alkoxyamines as a highly selective and efficient new drug against schistosome adult worms, the etiological agents of schistosomiasis. Indeed, the peptide tag of the hybrid compounds can be hydrolyzed by worm's digestive enzymes to afford a highly labile alkoxyamine which homolyzes spontaneously and instantaneously into radicals-which are then used as a drug against Schistosome adult parasites. This approach is nicely summarized as digging their graves with their forks. Several hybrid peptide-alkoxyamines were prepared and clearly showed an activity: two of the tested compounds kill 50% of the parasites in two hours at a concentration of 100 µg/mL. Importantly, the peptide and alkoxyamine fragments that are unable to generate alkyl radicals display no activity. This strong evidence validates the proposed mechanism: a specific activation of the prodrugs by the parasite proteases leading to parasite death through in situ alkyl radical generation.

Identifying potential drug targets in the kinomes of two monogenean species.

Protein kinases are enzymes involved in essential biological processes such as signal transduction, transcription, metabolism, and the cell cycle. Human kinases are targets for several drugs approved by the US Food and Drug Administration. Therefore, the identification and classification of kinases in other organisms, including pathogenic parasites, is an interesting subject of study. Monogeneans are platyhelminths, mainly ectoparasites, capable of causing health problems in farmed fish. Although some genomes and transcriptomes are available for monogenean species, their full repertoire of kinases is unknown. The aim of this study was to identify and classify the putative kinases in the transcriptomes of two monogeneans, Rhabdosynochus viridisi and Scutogyrus longicornis, and then to predict potential monogenean drug targets (MDTs) and selective inhibitor drugs using computational approaches. Monogenean kinases having orthologs in the lethal phenotype of C. elegans but not in fish or humans were considered MDTs. A total of 160 and 193 kinases were identified in R. viridisi and S. longicornis, respectively. Of these, 22 kinases, belonging mainly to the major groups CAMK, AGC, and TK, were classified as MDTs, five of which were evaluated further. Molecular docking analysis indicated that dihydroergotamine, ergotamine, and lomitapide have the highest affinity for the kinases BRSK and MEKK1. These well-known drugs could be evaluated in future studies for potential repurposing as anti-monogenean agents. The present study contributes valuable data for the development of new antiparasitic candidates for finfish aquaculture.

Microbial Etiology, Immunological Evaluation, and Drug-Resistance Spectrum Profile of Bloodstream Infections Among Cancer Patients

Abstract Background: Bloodstream infection (BSI) in cancer patients is becoming more common due to a number of opportunistic bacteria, some of which show high resistance to antibiotics. Objectives: The study aimed to diagnose the most important bacterial causes of BSI in patients with different cancers of both sexes, estimate the sensitivity of bacterial species to antibiotics, and measure immunological factors in the serum of infected patients. Materials and Methods: The study sample included patients hospitalized at Marjan Teaching Hospital in Babil Province. Microbiological tests and immunological assessments were conducted on the study sample from April 2021 to February 2022. The study included 239 patients (with different types of cancers and showing signs of fever) included 126 (52.71%) females and 113 (47.28%) males. Results: 1007 BSI-causing microorganisms were diagnosed among 239 cancer cases. The most common types of microorganisms isolated were Escherichia coli 169 (16.7%) and Klebsiella pneumonia 165 (16.3%). The results showed significant antimicrobial susceptibility patterns for bacterial and fungal isolates causing BSI. Resistance to ofloxacin, ciprofloxacin, and chloramphenicol was higher than other antibiotics. The results showed a significant elevation of all immunological factors among the BSI group associated with cancer compared to the control group, including IFN-γ, TNF-α, IL-2, IL-4, IL-10, and IL-6. Conclusions: It is necessary to regularly check the prevalence of bacteria and the level of antibiotic resistance in BSI patients. It will help determine whether local rules for the use of antimicrobial agents are appropriate and select appropriate drugs for empirical antibiotic therapy and prophylaxis in high-risk patients.

Immunomodulatory therapy of precancers of the cervix – opinion of medical professionals and students

Objective. To assess the relevance of immunomodulatory therapy of precancerous diseases of the cervix among medical professionals and students. Precancerous diseases of the cervix combine pathological processes characterized by the structural changes in the epithelium of the cervix. If not treated, they lead to the development of cervical cancer. At present there are no selective drugs for the human papillomavirus. To administer immunotropic medicines it is necessary to know the mechanism of effect on the immune system. Materials and methods. The study was conducted using an anonymous online questionnaire on the Google Forms platform (https://vk.com/away.php?utf=1to=https%3A%2F%2Fforms.gle%2FRtT7PktnCrLqBB1x8). The questionnaire is presented as part of a one-stage (cross-sectional) study. Data analysis was carried out using Microsoft Excel 2010 graphs and tables. Empirical, sociological and statistical research methods were used. The indicators of the structure of the respondents were calculated, the reliability of the differences was determined by the Student's t-criterion, confidence differences were considered at significance of p 0.05. Results. The average age of the respondents was 30.4 ± 10.8 years. 46 people (75.4 %) are aware of the possibility of using immunomodulation as therapy for precancerous diseases of the cervix, and 15 people (24.6 %) are not aware of it. 41 respondents (67.2 %) would administer the therapy themselves and their close people; 12 people (19.7 %) find it difficult to answer; 8 respondents (13.1 %) do not agree to administer the therapy. Conclusions. Medical students have an idea about immunomodulatory therapy in gynecology in 55.9 % of cases. Doctors of different specialties in 100 % of cases are aware of the treatment, see the benefits of prescribing drugs. Students` awareness of the possibilities of immunomodulatory therapy is sufficient, they get additional knowledge from clinical recommendations on the specialty in the practical course.

Using nanotechnology to progress the utilization of marine natural products in combating multidrug resistance in cancer: A prospective strategy.

Achieving targeted, customized, and combination therapies with clarity of the involved molecular pathways is crucial in the treatment as well as overcoming multidrug resistance (MDR) in cancer. Nanotechnology has emerged as an innovative and promising approach to address the problem of drug resistance. Developing nano-formulation-based therapies using therapeutic agents poses a synergistic effect to overcome MDR in cancer. In this review, we aimed to highlight the important pathways involved in the progression of MDR in cancer mediated through nanotechnology-based approaches that have been employed to circumvent them in recent years. Here, we also discussedthe potential use of marine metabolites to treat MDR in cancer, utilizing active drug-targeting nanomedicine-based techniques to enhance selective drug accumulation in cancer cells. The discussion also provides future insights for developing complex targeted, multistage responsive nanomedical drug delivery systemsfor effective cancer treatments. We propose more combinational studies and their validation for the possible marine-based nanoformulations for future development.

Extracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation.

Potassium channels of the Two-Pore Domain (K2P) subfamily, KCNK1-KCNK18, play crucial roles in controlling the electrical activity of many different cell types and represent attractive therapeutic targets. However, the identification of highly selective small molecule drugs against these channels has been challenging due to the high degree of structural and functional conservation that exists not only between K2P channels, but across the whole K+ channel superfamily. To address the issue of selectivity, here we generate camelid antibody fragments (nanobodies) against the TREK-2 (KCNK10) K2P K+ channel and identify selective binders including several that directly modulate channel activity. X-ray crystallography and CryoEM data of these nanobodies in complex with TREK-2 also reveal insights into their mechanisms of activation and inhibition via binding to the extracellular loops and Cap domain, as well as their suitability for immunodetection. These structures facilitate design of a biparatropic inhibitory nanobody with markedly improved sensitivity. Together, these results provide important insights into TREK channel gating and provide an alternative, more selective approach to modulation of K2P channel activity via their extracellular domains.

Exploring AKAPs in visual signaling.

The complex nature of the retina demands well-organized signaling to uphold signal accuracy and avoid interference, a critical aspect in handling a variety of visual stimuli. A-kinase anchoring proteins (AKAPs), known for binding protein kinase A (PKA), contribute to the specificity and efficiency of retinal signaling. They play multifaceted roles in various retinal cell types, influencing photoreceptor sensitivity, neurotransmitter release in bipolar cells, and the integration of visual information in ganglion cells. AKAPs like AKAP79/150 and AKAP95 exhibit distinct subcellular localizations, impacting synaptic transmission and receptor sensitivity in photoreceptors and bipolar cells. Furthermore, AKAPs are involved in neuroprotective mechanisms and axonal degeneration, particularly in retinal ganglion cells. In particular, AKAP6 coordinates stress-specific signaling and promotes neuroprotection following optic nerve injury. As our review underscores the therapeutic potential of targeting AKAP signaling complexes for retinal neuroprotection and enhancement, it acknowledges challenges in developing selective drugs that target complex protein-protein interactions. Overall, this exploration of AKAPs provides valuable insights into the intricacies of retinal signaling, offering a foundation for understanding and potentially addressing retinal disorders.

Studying Signaling Pathway Activation in TRAIL-Resistant Macrophage-Like Acute Myeloid Leukemia Cells.

Acute myeloid leukemia (AML) is a malignant neoplasm characterized by extremely low curability and survival. The inflammatory microenvironment and maturation (differentiation) of AML cells induced by it contribute to the evasion of these cells from effectors of antitumor immunity. One of the key molecular effectors of immune surveillance, the cytokine TRAIL, is considered a promising platform for developing selective anticancer drugs. Previously, under in vitro conditions of the inflammatory microenvironment (a three-dimensional high-density culture of THP-1 AML cells), we demonstrated the emergence of differentiated macrophage-like THP-1ad clones resistant to TRAIL-induced death. In the present study, constitutive activation of proinflammatory signaling pathways, associated transcription factors, and increased expression of the anti-apoptotic BIRC3 gene were observed in TRAIL-resistant macrophage-like THP-1ad AML cells. For the first time, a bioinformatic analysis of the transcriptome revealed the main regulator, the IL1B gene, which triggers proinflammatory activation and induces resistance to TRAIL in THP-1ad macrophage-like cells.

Analyzing a series of ligands against malaria through the application of molecular docking, molecular quantum similarity, and reactivity indices

Background The primary goal of this research is to underscore the significance of molecular docking in the context of malaria drug discovery. Molecular docking plays a crucial role in comprehending the interactions between prospective drugs and the target proteins found in Plasmodium parasites. The study delves into the docking interactions of various compounds, emphasizing the necessity of stabilizing the active site to formulate potent and selective drugs. Methods The research focuses on highlighting compound-specific interactions with residues, stressing the importance of stabilizing the active site to design drugs tailored to specific target proteins. Inhibiting the function of these target proteins disrupts the life cycle of the malaria parasite. Quantum Similarity Analysis, utilizing Overlap and Coulomb operators, is employed to identify electronic similarities. The resulting quantum similarity values guide subsequent chemical reactivity analysis. Global reactivity indices such as chemical potential, hardness, softness, and electrophilicity contribute to drug design by showcasing compound-specific indices that underscore the significance of stability and electrophilicity. Fukui functions are utilized to visualize regions for stabilization, providing insights crucial for potential malaria treatment. Results The enhancement of drug-target binding affinity is observed through stabilizing interactions in the active site. Understanding electrophilicity at the active site emerges as a critical factor in drug design and selectivity. The rational manipulation of electrophilic interactions holds promise for developing potent and selective drugs against malaria. Consequently, the integration of molecular docking, quantum similarity analysis, and chemical reactivity indices offers a comprehensive approach to malaria drug discovery. Conclusions The study identifies potential lead compounds, emphasizing the crucial role of stabilizing the active site. Additionally, it sheds light on electronic considerations vital for the design of effective and resistance-resistant drugs. The insights provided by Fukui functions into regions susceptible to -H bond formation make these compounds promising candidates for malaria treatment.

Anti-inflammatory activities of novel heat shock protein 90 isoform selective inhibitors in BV-2 microglial cells.

Heat shock protein 90 (Hsp90) is a family of chaperone proteins that consists of four isoforms: Hsp90α, Hsp90β, glucose-regulated protein 94 (Grp94), and tumor necrosis factor type 1 receptor-associated protein (TRAP1). They are involved in modulating the folding, maturation, and activation of their client proteins to regulate numerous intracellular signaling pathways. Previous studies demonstrated that pan-Hsp90 inhibitors reduce inflammatory signaling pathways resulting in a reduction of inflammation and pain but show toxicities in cancer-related clinical trials. Further, the role of Hsp90 isoforms in inflammation remains poorly understood. This study aimed to determine anti-inflammatory activities of Hsp90 isoforms selective inhibitors on the lipopolysaccharide (LPS)-induced inflammation in BV-2 cells, a murine microglial cell line. The production of inflammatory mediators such as nitric oxide (NO), interleukin 1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) was measured. We also investigated the impact of Hsp90 isoform inhibitors on the activation of nuclear factor kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), and mitogen-activated protein kinases (MAPKs). We found that selective inhibitors of Hsp90β reduced the LPS-induced production of NO, IL-1β, and TNF-α via diminishing the activation of NF-κB and Extracellular signal-regulated kinases (ERK) MAPK. The Hsp90α, Grp94, TRAP1 inhibitors had limited effect on the production of inflammatory mediators. These findings suggest that Hsp90β is the key player in LPS-induced neuroinflammation. Thereby providing a more selective drug target for development of medications involved in pain management that can potentially contribute to the reduction of adverse side effects associated with Hsp90 pan inhibitors.

Imrecoxib: Advances in Pharmacology and Therapeutics.

Imrecoxib, a cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug (NSAID), was discovered via the balanced inhibition strategy of COX-1/COX-2. It is indicated for the relief of painful symptoms of osteoarthritis. There have been some pharmacological and therapeutic advances since the approval of imrecoxib in 2011. However, an update review in this aspect is not yet available. Relevant literature until January 2024 was identified by search of PubMed, Web of science, Embase and CNKI. From the perspective of efficacy, imrecoxib provides relief of osteoarthritis symptoms, and potential off-label use for treatment of idiopathic pulmonary fibrosis, perioperative pain, hand-foot syndrome, axial spondyloarthritis, COVID-19, cartilage injury, and malignancies such as lung and colon cancer. From a safety point of view, imrecoxib showed adverse effects common to NSAIDs; however, it has lower incidence of new-onset hypertension than other types of selective COX-2 inhibitors, less gastrointestinal toxicities than non-selective NSAIDs, weaker risk of drug interaction than celecoxib, and more suitable for elderly patients due to balanced inhibition of COX-1/COX-2. From a pharmacoeconomic perspective, imrecoxib is more cost-effective than celecoxib and diclofenac for osteoarthritis patients. With the deepening of the disease pathophysiology study of osteoarthritis, new therapeutic schemes and pharmacological mechanisms are constantly discovered. In the field of osteoarthritis treatment, mechanisms other than the analgesic and anti-inflammatory effects of COX-2 inhibitors are also being explored. Taken together, imrecoxib is a moderate selective COX-2 inhibitor with some advantages, and there would be more clinical applications and research opportunities in the future.

Histone deacetylase as emerging pharmacological therapeutic target for neuropathic pain: From epigenetic to selective drugs.

Neuropathic pain remains a formidable challenge for modern medicine. The first-line pharmacological therapies exhibit limited efficacy and unfavorable side effect profiles, highlighting an unmet need for effective therapeutic medications. The past decades have witnessed an explosion in efforts to translate epigenetic concepts into pain therapy and shed light on epigenetics as a promising avenue for pain research. Recently, the aberrant activity of histone deacetylase (HDAC) has emerged as a key mechanism contributing to the development and maintenance of neuropathic pain. In this review, we highlight the distinctive role of specific HDAC subtypes in a cell-specific manner in pain nociception, and outline the recent experimental evidence supporting the therapeutic potential of HDACi in neuropathic pain. We have summarized studies of HDAC in neuropathic pain in Pubmed. HDACs, widely distributed in the neuronal and non-neuronal cells of the dorsal root ganglion and spinal cord, regulate gene expression by deacetylation of histone or non-histone proteins and involving in increased neuronal excitability and neuroinflammation, thus promoting peripheral and central sensitization. Importantly, pharmacological manipulation of aberrant acetylation using HDAC-targeted inhibitors (HDACi) has shown promising pain-relieving properties in various preclinical models of neuropathic pain. Yet, many of which exhibit low-specificity that may induce off-target toxicities, underscoring the necessity for the development of isoform-selective HDACi in pain management. Abnormally elevated HDACs promote neuronal excitability and neuroinflammation by epigenetically modulating pivotal gene expression in neuronal and immune cells, contributing to peripheral and central sensitization in the progression of neuropathic pain, and HDACi showed significant efficacy and great potential for alleviating neuropathic pain.

Specific delivery of metronidazole using microparticles and thermosensitive in situ hydrogel for intrapocket administration as an alternative in periodontitis treatment

Periodontitis is a common chronic inflammatory disease primarily caused by the prevalence of bacterial overgrowth resulting in the development of an inflammatory condition that destroys the tooth’s supporting tissues and eventual tooth loss. Comparatively, to other treatment methods, it is difficult for topical antibacterial drugs to effectively permeate the biofilm’s physical barrier, making conventional therapy for periodontitis more challenging. This novel study combines thermosensitive in situ hydrogel with microparticles (MPs) to enhance the targeted delivery of metronidazole (MET) to the periodontal pocket. Polycaprolactone (PCL) polymer was utilized to produce bacteria-sensitive MPs. Additionally, the study assessed the attributes of MPs and demonstrated an enhancement in the in vitro antibacterial efficacy of MPs towards Staphylococcus aureus (SA) and Escherichia coli (EC). Subsequently, we incorporated MET-MPs into thermosensitive in situ hydrogel formulations using chitosan. The optimized formulations exhibited stability, appropriate gelation temperature, mucoadhesive strength, and viscosity. In vitro permeation tests showed selective and prolonged drug release against SA and EC. Ex vivo experiments demonstrated no significant differences between in situ hydrogel containing pure MET and MET–MPs in biofilm quantity, bacterial counts, and metabolic activity in biofilms. According to in vitro tests and the effectiveness of the antibacterial activity, this study has exhibited a novel methodology for more efficacious therapies for periodontitis. This study aims to utilize MET in MPs to improve its effectiveness, enhance its antibacterial activity, and improve patient treatment outcomes. In further research, the efficacy of the treatment should be investigated in vivo using an appropriate animal model.

Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

Nociceptive sensory neurons convey pain-related signals to the CNS using action potentials. Loss-of-function mutations in the voltage-gated sodium channel NaV1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but clinical trials seeking to treat pain by inhibiting NaV1.7 pharmacologically have struggled. This may reflect the variable contribution of NaV1.7 to nociceptor excitability. Contrary to claims that NaV1.7 is necessary for nociceptors to initiate action potentials, we show that nociceptors can achieve similar excitability using different combinations of NaV1.3, NaV1.7, and NaV1.8. Selectively blocking one of those NaV subtypes reduces nociceptor excitability only if the other subtypes are weakly expressed. For example, excitability relies on NaV1.8 in acutely dissociated nociceptors but responsibility shifts to NaV1.7 and NaV1.3 by the fourth day in culture. A similar shift in NaV dependence occurs in vivo after inflammation, impacting ability of the NaV1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests. Flexible use of different NaV subtypes exemplifies degeneracy – achieving similar function using different components – and compromises reliable modulation of nociceptor excitability by subtype-selective inhibitors. Identifying the dominant NaV subtype to predict drug efficacy is not trivial. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level.

Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs.

Nociceptive sensory neurons convey pain-related signals to the CNS using action potentials. Loss-of-function mutations in the voltage-gated sodium channel NaV1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but clinical trials seeking to treat pain by inhibiting NaV1.7 pharmacologically have struggled. This may reflect the variable contribution of NaV1.7 to nociceptor excitability. Contrary to claims that NaV1.7 is necessary for nociceptors to initiate action potentials, we show that nociceptors can achieve similar excitability using different combinations of NaV1.3, NaV1.7, and NaV1.8. Selectively blocking one of those NaV subtypes reduces nociceptor excitability only if the other subtypes are weakly expressed. For example, excitability relies on NaV1.8 in acutely dissociated nociceptors but responsibility shifts to NaV1.7 and NaV1.3 by the fourth day in culture. A similar shift in NaV dependence occurs in vivo after inflammation, impacting ability of the NaV1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests. Flexible use of different NaV subtypes exemplifies degeneracy - achieving similar function using different components - and compromises reliable modulation of nociceptor excitability by subtype-selective inhibitors. Identifying the dominant NaV subtype to predict drug efficacy is not trivial. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level.

Anti-Netrin-1 decorated nanoparticles combined with chemotherapy for the treatment of triple-negative breast cancer

Nanoparticle's success as drug delivery systems for cancer treatment has been achieved through passive targeting mechanisms. However, tumor heterogeneity and rapid drug clearance limit the treatment efficacy. Improved outcomes and selective drug release can be achieved by grafting ligands at the surface of nanocarriers that bind molecules overexpressed in the tumor microenvironment (TME). In this work, we developed a docetaxel-loaded nanoemulsions (NEs) binding an anti-netrin-1 monoclonal antibody (NP137) to selectively target the netrin-1 protein overexpressed in many different tumors. The goal is to refine a combined approach utilizing NP137 and docetaxel as an improved tumor-targeting chemotherapeutic agent for addressing triple-negative breast cancer (TNBC). Several factors have been considered for the optimization of the active targeted drug delivery system via the click-chemistry conjugation, as the impact of PEGylated surfactant that stabilize the NEs shell on conjugation efficiency, cytocompatibility with EMT6 cell line and colloidal stability over time of NEs. Results showed that a 660 Da PEG chain length contributed to NEs colloidal stability and had no impact on cell viability or on the antibody binding ability for its ligand after surface conjugation. Moreover, docetaxel was encapsulated into the oily core of NEs, with an encapsulation efficiency of 70 %. To validate our treatment strategy in vivo, the 4T1 murine breast cancer model was used. As a result, the comparison of active-targeted and non-targeted NEs revealed that only active-targeted NE could decrease the tumor growth rate.

Functional effects of drugs and toxins interacting with NaV1.4.

NaV1.4 is a voltage-gated sodium channel subtype that is predominantly expressed in skeletal muscle cells. It is essential for producing action potentials and stimulating muscle contraction, and mutations in NaV1.4 can cause various muscle disorders. The discovery of the cryo-EM structure of NaV1.4 in complex with β1 has opened new possibilities for designing drugs and toxins that target NaV1.4. In this review, we summarize the current understanding of channelopathies, the binding sites and functions of chemicals including medicine and toxins that interact with NaV1.4. These substances could be considered novel candidate compounds or tools to develop more potent and selective drugs targeting NaV1.4. Therefore, studying NaV1.4 pharmacology is both theoretically and practically meaningful.