Lysergic Acid Diethylamide Research Articles

Nucleic acid-based nanotherapeutics for treating sepsis and associated organ injuries.

In recent years, gene therapy has been made possible with the success of nucleic acid drugs against sepsis and its related organ dysfunction. Therapeutics based on nucleic acids such as small interfering RNAs (siRNAs), microRNAs (miRNAs), messenger RNAs (mRNAs), and plasmid DNAs (pDNAs) guarantee to treat previously undruggable diseases. The advantage of nucleic acid-based therapy against sepsis lies in the development of nanocarriers, achieving targeted and controlled gene delivery for improved efficacy with minimal adverse effects. Entrapment into nanocarriers also ameliorates the poor cellular uptake of naked nucleic acids. In this study, we discuss the current state of the art in nanoparticles for nucleic acid delivery to treat hyperinflammation and apoptosis associated with sepsis. The optimized design of the nanoparticles through physicochemical property modification and ligand conjugation can target specific organs-such as lung, heart, kidney, and liver-to mitigate multiple sepsis-associated organ injuries. This review highlights the nanomaterials designed for fabricating the anti-sepsis nanosystems, their physicochemical characterization, the mechanisms of nucleic acid-based therapy in working against sepsis, and the potential for promoting the therapeutic efficiency of the nucleic acids. The current investigations associated with nanoparticulate nucleic acid application in sepsis management are summarized in this paper. Noteworthily, the potential application of nanotherapeutic nucleic acids allows for a novel strategy to treat sepsis. Further clinical studies are required to confirm the findings in cell- and animal-based experiments. The capability of large-scale production and reproducibility of nanoparticle products are also critical for commercialization. It is expected that numerous anti-sepsis possibilities will be investigated for nucleic acid-based nanotherapeutics in the future.

Lipid nanoparticles as the drug carrier for targeted therapy of hepatic disorders.

The liver, a complex and vital organ in the human body, is susceptible to various diseases, including metabolic disorders, acute hepatitis, cirrhosis, and hepatocellular carcinoma. In recent decades, these diseases have significantly contributed to global morbidity and mortality. Currently, liver transplantation remains the most effective treatment for hepatic disorders. Nucleic acid therapeutics offer a selective approach to disease treatment through diverse mechanisms, enabling the regulation of relevant genes and providing a novel therapeutic avenue for hepatic disorders. It is expected that nucleic acid drugs will emerge as the third generation of pharmaceuticals, succeeding small molecule drugs and antibody drugs. Lipid nanoparticles (LNPs) represent a crucial technology in the field of drug delivery and constitute a significant advancement in gene therapies. Nucleic acids encapsulated in LNPs are shielded from the degradation of enzymes and effectively delivered to cells, where they are released and regulate specific genes. This paper provides a comprehensive review of the structure, composition, and applications of LNPs in the treatment of hepatic disorders and offers insights into prospects and challenges in the future development of LNPs.

Therapeutic Vaccines and Nucleic Acid Drugs for Cardiovascular Disease.

To combat the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), novel vaccine modalities, such as messenger RNA vaccines, were rapidly developed and have shown high efficacy. This new vaccine technology, underpinned by intensive immunological analysis, is now being applied to the production of other vaccines. For over 10 years, we have been developing therapeutic vaccines for non-infectious diseases. The epitope vaccine approach, which combines a B-cell epitope with exogenous T-cell epitopes presented through major histocompatibility complex molecules, has been proposed to induce antibody production. This vaccine type is designed to efficiently induce a blocking antibody response against the self-antigen without activating cytotoxic T cells. If therapeutic vaccines become established as treatment options for conditions such as hypertension or dyslipidemia, their administration-potentially only a few times per year-could replace the need for daily medication. Nucleic acid drugs, including small interfering RNA and antisense oligonucleotides, have recently received attention as long-term agonists, similar to vaccines. Therefore, therapeutic vaccines or nucleic acid drugs could represent a novel strategy for controlling the progression of cardiovascular diseases. It is hoped that the accumulation of immunological findings and advances in vaccine technology will provide valuable insights into the development of vaccines for treating cardiovascular diseases.

Performance Evaluation of Multi-Drug Rapid Test for Rapid Detection of Multiple Drugs and Drug Metabolites in Human Blood Samples

Objective: The Multi-Drug Rapid Test Cassette, developed by Hangzhou AllTest Biotech Co., Ltd, is a rapid chromatographic immunoassay designed for the qualitative detection of multiple drugs and drug metabolites in human whole blood, serum, or plasma. It aims to simultaneously detect various abused substances, including Amphetamine (AMP), Barbiturates (BAR), Benzodiazepines (BZO), Buprenorphine (BUP), Cocaine (COC), Cannabis (THC), Methadone (MTD), Methamphetamine (MET), 3,4-Methylenedioxymethamphetamine (MDMA), Morphine (MOP/OPI), Propoxyphene (PPX), Tricyclic antidepressants (TCA), Oxycodone (OXY), 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), Cotinine (COT), Tramadol (TML), Fentanyl (FYL), 3,4-Methylenedioxy pyrovalerone (MDPV), Synthetic cannabinoids(K2), Phencyclidine(PCP), Ketamine(KET), Lysergic acid diethylamide(LSD), 3,4-Methylenedioxyamphetamine(MDA), Acetaminophen(ACE), Ketamine(CAT), 6-Monoacetylmorphine (6-MAM), Zolpidem (ZOL), AB-PINACA (ABP/K3). Therefore, the present research was done to evaluate the diagnostic performance of this test. Material and Method: In this study, the accuracy, precision, and sensitivity of the drug testing methods were assessed. Approximately 100 specimens of each drug, obtained from previous drug screening tests, were tested. The results were compared to confirmatory analysis using GC/MS, and the accuracy of the testing was determined based on the comparative classification results. The evaluation of precision included measuring the consistency of measurements within a single run, between different runs, and among different operators, using the AllTest multi-drug detection tool across three different hospitals and three different batches. To evaluate the sensitivity of the detection method, various concentrations of drugs were added to a pool of whole blood, serum, or plasma without any drugs. The positive and negative results obtained from the testing were analyzed to assess the method’s ability to detect drugs at different concentrations. Results: In this study, we evaluated the performance of the Multi-Drug Rapid Test Cassette developed by Hangzhou AllTest Biotech Co., Ltd. The results demonstrated excellent performance of the test in terms of accuracy, sensitivity, and precision. Conclusion: The Multi-Drug Rapid Test Cassette developed by Hangzhou AllTest Biotech Co., Ltd exhibited reliable detection of multiple drugs and drug metabolites, providing trustworthy results for drug abuse screening. These findings have significant implications for drug control and monitoring, as well as supporting the broad application of this test in clinical and legal settings.

Intratracheal administration of programmable DNA nanostructures combats acute lung injury by targeting microRNA-155

Acute lung injury (ALI) is an acute inflammatory process that can result in life-threatening consequences. Programmable DNA nanostructures have emerged as excellent nanoplatforms for microRNA-based therapeutics, offering potential nanomedicines for ALI treatment. Nonetheless, the traditional systematic administration of nanomedicines is constrained by low delivery efficiency, poor pharmacokinetics, and nonspecific side effects. Here, we identify macrophage microRNA-155 as a novel therapeutic target using the magnetic bead sorting technique. We further construct a DNA nanotubular nucleic acid drug antagonizing microRNA-155 (NT-155) for ALI treatment through intratracheal administration. Flow cytometry results demonstrate that NT-155, when inhaled, is taken up much more effectively by macrophages and dendritic cells in the bronchoalveolar lavage fluid of ALI mice. Furthermore, NT-155 effectively silences the overexpressed microRNA-155 in macrophages and exerts excellent inflammation inhibition effects in vitro and ALI mouse models. Mechanistically, NT-155 suppresses microRNA-155 expression and activates its target gene SOCS1, inhibiting the p-P65 signaling pathway and suppressing proinflammatory cytokine secretion. The current study suggests that deliberately designed nucleic acid drugs are promising nanomedicines for ALI treatment and the local administration may open up new practical applications of DNA in the future.

MiR-23b-3p Ameliorates LPS-Induced Pulmonary Fibrosis by Inhibiting EndMT via DPP4 Inhibition.

Acute respiratory distress syndrome is a disease triggered by severe pulmonary and systemic inflammation that may lead to fibrosis and the decline of lung function. Lung capillary endothelial-to-mesenchymal transition (EndMT) is one of the primary sources of fibroblasts in pulmonary fibrosis. The role of miRNAs as molecular markers of pulmonary fibrosis, and miRNAs as nucleic acid drugs has attracted increasing attention. To mock EndMT process, Human pulmonary microvascular endothelial cells (HPMECs) were induced with lipopolysaccharide (LPS). Similarly, LPS treatment was used to generate a mouse model of LPS-induced EndMT and pulmonary fibrosis. LPS-induced EndMT in HPMECs resulted in a significant reduction of miR-23b-3p. miR-23b-3p inhibited the interstitial transition of HPMECs, and miR-23b-3p could mediate this process via inhibiting dipeptidyl peptidase-4 (DPP4). Dual-luciferase assays confirmed the regulatory mechanism of miR-23b-3p. In our mouse model of LPS-induced pulmonary fibrosis, miR-23b-3p and a DPP4 inhibitor (sitagliptin) individually alleviated LPS-induced EndMT progression and pulmonary fibrosis, and their combined use achieved the strongest remission effect. To sum up, miR-23b-3p alleviates EndMT in pulmonary fibrosis by inhibiting the expression of DPP4.

LncRNA LINK-A Remodels Tissue Inflammatory Microenvironments to Promote Obesity.

High-fat diet (HFD)-induced obesity is a crucial risk factor for metabolic syndrome, mainly due to adipose tissue dysfunctions associated with it. However, the underlying mechanism remains unclear. This study has used genetic screening to identify an obesity-associated human lncRNA LINK-A as a critical molecule bridging the metabolic microenvironment and energy expenditure in vivo by establishing the HFD-induced obesity knock-in (KI) mouse model. Mechanistically, HFD LINK-A KI mice induce the infiltration of inflammatory factors, including IL-1β and CXCL16, through the LINK-A/HB-EGF/HIF1α feedback loop axis in a self-amplified manner, thereby promoting the adipose tissue microenvironment remodeling and adaptive thermogenesis disorder, ultimately leading to obesity and insulin resistance. Notably, LINK-A expression is positively correlated with inflammatory factor expression in individuals who are overweight. Of note, targeting LINK-A via nucleic acid drug antisense oligonucleotides (ASO) attenuate HFD-induced obesity and metabolic syndrome, pointing out LINK-A as a valuable and effective therapeutic target for treating HFD-induced obesity. Briefly, the results reveale the roles of lncRNAs (such as LINK-A) in remodeling tissue inflammatory microenvironments to promote HFD-induced obesity.

Safety and tolerability of inhaled N,N-Dimethyltryptamine (BMND01 candidate): A phase I clinical trial

Psychedelics are being increasingly examined for their therapeutic potential in mood disorders. While the acute effects of ayahuasca, psilocybin, and lysergic acid diethylamide (LSD) last over several hours, inhaled N,N-Dimethyltryptamine (DMT) effects last around 10 min, which might provide a cost- and time-effective alternative to the clinical application of oral psychedelics. We aimed at investigating the safety and tolerability of inhaled DMT (BMND01 candidate). We recruited 27 healthy volunteers to receive a first, lower dose and a second, higher dose (5/20 mg, 7.5/30 mg, 10/40 mg, 12.5/50 mg, or 15/60 mg) of inhaled DMT in an open-label, single-ascending, fixed-order, dose-response study design. We investigated subjective experiences (intensity, valence, and phenomenology), physiological effects (blood pressure, heart rate, respiratory rate, blood oxygen saturation, body temperature), biochemical markers (liver, kidney, and metabolic functions), and adverse events during the acute and post-acute effects of DMT. DMT dose-dependently increased intensity, valence and perceptual ratings. There was a mild, transient, and self-limited increase in blood pressure and heart rate. There were no changes in safety blood biomarkers and no serious adverse events. DMT dose-dependently enhanced subjective experiences and positive valence. Inhaled DMT might be an efficient, non-invasive, safe route of administration, which might simplify the clinical use of this substance. This is the first clinical trial to test the effects of inhaled DMT (BMND01 candidate).

Review of the research and development status of siRNA drugs for gene therapy

Gene therapy is a new kind of therapy technology, which can modify or manipulate gene expression, gene silencing, and other functions, or change the biological characteristics of cells, so as to achieve the goal of curing disease at the gene level. It is not restricted by the drug-forming property of the target protein and has obvious advantages compared with traditional protein drug therapy. To develop small interfering ribonucleic acid (siRNA) drugs for gene therapy, the mechanism of ribonucleic acid interference (RNAi), which was discovered more than 30 years ago, can be taken as a basis. Later, scientists' unremitting exploration made siRNA drugs develop rapidly. So far, there are five kinds of siRNA drugs listed, with good application prospects. This paper aims to summarize the existing siRNA drugs and explore their shortcomings, as well as some existing improvement measures, thereby pointing out the direction of drug development and providing some help for the better application of siRNA drugs. According to the analysis, it is found that there are still some dilemmas in the research and development of siRNA drugs in terms of stability, targeting accuracy, long-term effectiveness, efficiency, and safety. Meanwhile, the performance of the drug delivery system also determines whether the drug can play an effective role. Some improvements have been proposed in this paper, such as modifying drug molecules or improving delivery systems to help drugs function better, which could be the direction of future drug progress.

Effectiveness of buffered acetylsalicylic acid compared to other drugs in diseases patients in clinical practice: results of the CARDINAL observational retrospective study

Aim. To evaluate the effectiveness of acetylsalicylic acid (ASA) drugs for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in clinical practice and compare the effectiveness of the Cardiomagnyl with other ASA drugs.Material and methods. This observational, non-interventional, retrospective study included data from electronic medical records of 18199 patients with ASCVD who were divided into 2 following groups: patients who received ASA 75-100 mg (n=9784) and patients who did not receive ASA (n=8325). The prescription rate of ASA, the choice of the first drug, the duration of ASA therapy, the frequency of switching ASA during treatment, and the choice of the second ASA drug when changing therapy were assessed. Due to the heterogeneity of patients in the above groups, to assess the clinical outcomes, propensity score matching was performed and comparable groups were selected to evaluate the effectiveness of ASA drugs 75-100 mg in patients with ASCVD (n= 427) in comparison with patients not receiving ASA (n=427) and to assess the effectiveness of Cardiomagnyl 75 mg (n=1308) in comparison with enterosoluble ASA 100 mg (CRA) (n=1308) taking into account 24 parameters.Results. The average proportion of patients with ASCVD taking ASA drugs was 58%. During treatment, 54% of patients underwent a change in drug therapy from one ASA drug to another. The prescription rate of Cardiomagnyl as a first-choice drug was 33%, and as a second drug when changing therapy — 21%. The duration of Cardiomagnyl therapy was the longest compared to other ASA drugs and amounted to 16,3 months. The incidence of ischemic stroke, myocardial infarction and major adverse cardiovascular events in the group of patients who received ACS 75-100 mg was significantly lower than in patients who did not take ASA drugs and amounted to 4,7% vs 8,7%, 0,9% vs 3,3%, 5,6% vs 11,9%, respectively. Significantly lower incidence of unstable angina (0,8% vs 2,0%), myocardial infarction (1,5% vs 3,9%) and major adverse cardiovascular events (5,4% vs 7,8%) in group of patients who received Cardiomagnyl 75 mg as opposed to enterosoluble ASA.Conclusion. Significant advantages of buffered ASA (Cardiomagnyl) were revealed in comparison with enterosoluble ASA in clinical practice.

Zwitterionic materials for nucleic acid delivery and therapeutic applications

Nucleic acid therapeutics have demonstrated substantial potential in combating various diseases. However, challenges persist, particularly in the delivery of multifunctional nucleic acids. To address this issue, numerous gene delivery vectors have been developed to fully unlock the potential of gene therapy. The advancement of innovative materials with exceptional delivery properties is critical to propel the clinical translation of nucleic acid drugs. Cationic vector materials have received extensive attention, while zwitterionic materials remain relatively underappreciated in delivery. In this review, we outline a diverse range of zwitterionic material nucleic acid carriers, predominantly encompassing zwitterionic lipids, polymers and peptides. Their respective chemical structures, synthesis approaches, properties, advantages, and therapeutic applications are summarized and discussed. Furthermore, we highlight the challenges and future opportunities associated with the development of zwitterionic vector materials. This review will aid to understand the zwitterionic materials in aiding gene delivery, contributing to the continual progress of nucleic acid therapeutics.

Early-onset alcohol, tobacco, and illicit drug use with age at onset of hypertension: a survival analysis.

To examine the associations of age when first substance use and early-onset substance use before age 18 with age at onset (AAO) of hypertension. This study included 19,270 individuals with AAO of hypertension from the 2015-2019 National Survey on Drug Use and Health. Age when first use of 10 substance use variables included alcohol, daily cigarettes, cigars, smokeless tobacco, marijuana, cocaine, hallucinogens, lysergic acid diethylamide (LSD), inhalants, and methamphetamine use. The outcome was AAO of hypertension and variable cluster analysis was used to classify the exposures and outcome. Substance use status was classified into three categories: early-onset substance use (first used substance before age 18), late-onset substance use (first used substance after age 18), and never used. The mean AAO of hypertension was 42.7years. Age when first use of 10 substance use variables had significant correlations with AAO of hypertension (all p values < 0.001). Individuals with early-onset alcohol, cigars, smokeless tobacco, marijuana, hallucinogens, inhalants, cocaine, LSD, and methamphetamine use revealed significantly earlier onset of hypertension than those never used. Compared with never used substances, the Cox regression model showed that early-onset alcohol, smokeless tobacco, marijuana, inhalants, and methamphetamine use had an increased risk of AAO of hypertension [hazard ratio (HR) (95%CI) = 1.22 (1.13, 1.31), 1.36 (1.24, 1.49), 1.85 (1.75, 1.95), 1.41 (1.30, 1.52), and 1.27 (1.07,1.50), respectively]. These findings suggest that intervention strategies or programs focusing on preventing early-onset substance use before age 18 may delay the onset of adult hypertension.

Psychedelics and cognitive function: A systematic review

Introduction: With the progressive advancement of clinical and experimental trials aimed at investigating the pharmacotherapeutic potential of psychedelic substances, there is also the development of other conceptions of use, not only for the treatment of psychiatric disorders, but also for the improvement of emotional/cognitive functions. Objective: The present study is a systematic review of investigations aimed at evaluating the effects of psychedelics on cognitive functions in healthy volunteers. Methods: A search was performed in PubMed database, using the search terms “psychedelics and cognitive enhancement” and “psychedelics and cognitive performance”. Results and conclusions: Of the experimental studies analyzed, only forty-six (46) met the inclusion criteria. The results obtained showed that 3,4-methylenedioxy-methamphetamine (MDMA) was the most studied drug, with eighteen (18) articles. Fourteen (14) articles were published with psilocybin. Lysergic acid diethylamide (LSD) ranked third, with six (6) articles; other two (2) studies focused on investigating the beverage ayahuasca, and another (1) its psychoactive-containing molecule: dimethyltryptamine (DMT). Eight (8) studies investigated the effects of other psychedelic drugs, like S-ketamine, mescaline, 3,4-methylenedioxy-amphetamine (MDE), and ibogaine. Although there were no serious adverse effects resulting from the use of the investigated psychedelic drugs, rigorous assessment of the potential risks of long-term use and of the advantages of the continuous use of these drugs through neuropsychological assessments are still warranted.

Tranexamic acid (class I drug) reduced and capped gold nanoparticles as a potential hemostatic agent with enhanced performance

External hemostatic agents play a crucial role in stabilizing an impaired process during pathological conditions. The idea is to stabilize the in vivo system as soon as possible. This study uses a class I hemostatic drug tranexamic acid as a reducing and capping agent for synthesizing the gold nanoparticles (Tr-AuNPs). Being the synthetic analogue of lysine and a biologically inspired alkylamine molecule, the chemistry can be fine-tuned for stable material that can simultaneously target the intrinsic and extrinsic hemostatic pathway, making it promising for hemostatic applications. The Tr-AuNPs of hydrodynamic diameter ∼46 nm were synthesized and evaluated physio-chemically using various analytical techniques wherein they showed hemocompatibility and increased thrombus weight compared to the native drug. The decrease in prothrombin time (PT) and international normalized ratio supported by the dynamic thromboelastography (TEG) study indicates the prepared nano-conjugate’s potential in reducing time for attaining hemostasis as compared to the native tranexamic acid drug. At a 9 μg ml−1 concentration, Tr-AuNPs had a procoagulant effect, shown by decreased reaction time (R) and coagulation time (K) with improved α angle and MA. There was a significant increase in the rate of coagulation in vivo by Tr-AuNPs, i.e. (52 s) compared to the native tranexamic acid (360 s). Radiolabelling studies ascertained the in vivo biocompatibility (non-invasive distribution, residence, clearance, and stability) of the Tr-AuNPs. The short-term toxicity studies were conducted to establish a proof of concept for the biomedical application of the material. The results highlighted the use of biologically alkyl amine molecules as capping and reducing agents for the synthesis of nanoparticles, which have shown a synergistic effect on the coagulation cascade while holding the potential for also acting as potential theranostic agents.

CircMAPK1 promoted CD8 + T cell infiltration in LUAD by improving the IGF2BP1 dependent CCL5 upregulation

Lung adenocarcinoma (LUAD) is the most common pathological subtype of lung cancer and has a poor prognosis. Immune Checkpoint Blockage (ICB) have been shown to improve the survival of LUAD in the last decade. CD8 + T cell infiltration is significantly related to LUAD prognosis and plays a critical role in ICB response efficiency. Chemokines expressed and secreted by tumor and microenvironment cells regulate the recruitment of CD8 + T cells. A cytoplasm-dominant circRNA, termed circMAPK1, was found to be down-regulated in LUAD and dramatically suppressed the growth of LUAD upon circMAPK1 overexpression in immunocompetent mice. Meanwhile, it was found that circMAPK1 significantly promoted the CD8 + T cell intratumoral infiltration in vitro and in vivo. CircMAPK1 was identified as binding IGF2BP1 in the cytoplasm and inducing IGF2BP1 to occupy the 3′UTR of CCL5 mRNA, resulting in retained stability of CCL5 mRNA. In general, circMAPK1 is a microenvironment-associated circRNA that recruits CD8 + T cells in LUAD. CircMAPK1 is an effective microenvironment regulator and a potential nucleic acid drug that can be combined with ICB to improve immunotherapy response efficiency.

Bioinformatics-led discovery of liver-specific genes and macrophage infiltration in acute liver injury.

Acute liver injury (ALI) is an important global health concern, primarily caused by widespread hepatocyte cell death, coupled with a complex immune response and a lack of effective remedies. This study explores the underlying mechanisms, immune infiltration patterns, and potential targets for intervention and treatment ALI. The datasets of acetaminophen (APAP), carbon tetrachloride (CCl4), and lipopolysaccharide (LPS)-induced ALI were obtained from the GEO database. Differentially expressed genes (DEGs) were individually identified using the limma packages. Functional enrichment analysis was performed using KEGG, GO, and GSEA methods. The overlapping genes were extracted from the three datasets, and hub genes were identified using MCODE and CytoHubba algorithms. Additionally, PPI networks were constructed based on the String database. Immune cell infiltration analysis was conducted using ImmuCellAI, and the correlation between hub genes and immune cells was determined using the Spearman method. The relationship between hub genes, immune cells, and biochemical indicators of liver function (ALT, AST) was validated using APAP and triptolide (TP) -induced ALI mouse models. Functional enrichment analysis indicated that all three ALI models were enriched in pathways linked to fatty acid metabolism, drug metabolism, inflammatory response, and immune regulation. Immune analysis revealed a significant rise in macrophage infiltration. A total of 79 overlapping genes were obtained, and 10 hub genes were identified that were consistent with the results of the biological information analysis after screening and validation. Among them, Clec4n, Ms4a6d, and Lilrb4 exhibited strong associations with macrophage infiltration and ALI.

Polymerizable 2-Propionic-3-methylmaleic Anhydrides as a Macromolecular Carrier Platform for pH-Responsive Immunodrug Delivery.

The design of functional polymers coupled with stimuli-triggered drug release mechanisms is a promising achievement to overcome various biological barriers. pH trigger methods yield significant potential for controlled targeting and release of therapeutics due to their simplicity and relevance, especially upon cell internalization. Here, we introduce reactive polymers that conjugate primary or secondary amines and release potential drugs under acidic conditions. For that purpose, we introduced methacrylamide-based monomers with pendant 2-propionic-3-methylmaleic anhydride groups. Such groups allow the conjugation of primary and secondary amines but are resistant to radical polymerization conditions. We, therefore, polymerized 2-propionic-3-methylmaleic anhydride amide-based methacrylates via reversible addition-fragmentation chain transfer (RAFT) polymerization. Their amine-reactive anhydrides could sequentially be derivatized by primary or secondary amines into hydrophilic polymers. Acidic pH-triggered drug release from the polymeric systems was fine-tuned by comparing different amines. Thereby, the conjugation of primary amines led to the formation of irreversible imide bonds in dimethyl sulfoxide, while secondary amines could quantitatively be released upon acidification. In vitro, this installed pH-responsiveness can contribute to an effective release of conjugated immune stimulatory drugs under endosomal pH conditions. Interestingly, the amine-modified polymers generally showed no toxicity and a high cellular uptake. Furthermore, secondary amine-modified immune stimulatory drugs conjugated to the polymers yielded better receptor activity and immune cell maturation than their primary amine derivatives due to their pH-sensitive drug release mechanism. Consequently, 2-propionic-3-methylmaleic anhydride-based polymers can be considered as a versatile platform for pH-triggered delivery of various (immuno)drugs, thus enabling new strategies in macromolecule-assisted immunotherapy.

Micro/Nanomotors for Oral Delivery of Drugs: From Design to Application

Oral administration, as a traditional approach of taking therapeutic drugs, is easily accepted by patients due to its convenience and compliance. However, the harsh digestive environment and mucosa‐epithelial cell barriers limit the absorption of drugs through the oral route, particularly for biomacromolecules such as protein, peptide, or nucleic acid drugs. To address this issue, active carriers such as micro/nanomotors and mechanical devices have been engineered as novel delivery systems that are capable of converting various energy into mechanical force. The active delivery of these carriers holds promise for overcoming absorptive barriers and improving drug delivery efficiency, making them an attractive option for precision medicine applications that include drug delivery, gene and cell therapy, biopsy, tissue penetration, intracellular delivery, and biosensing. This article presents an overview of the progress and challenges associated with orally delivering macromolecular drugs, as well as strategies to enhance drug absorption. Additionally, it discusses recent developments and potential applications of active carriers in drug delivery and related fields, which may provide inspiration for future research.

Abstract C106: Identification of nucleic acid drug candidates against mesenchymal transition and its application to breast cancer and glioblastoma cells

Abstract Cancer stem-like cells (CSLC) have a feature of epithelial-mesenchymal transition (EMT) responsible for tumor heterogeneity and therapeutic resistance. To identify molecular targets of CSLC, we underwent shRNA screening for epithelialization of MDA-MB-231 mesenchymal breast cancer cell line with novel EMT/MET dual reporter system and identified 2 shRNAs (shP1 and shH1) which reverse EMT in mesenchymal breast cancer as well as glioblastoma cells. While mesenchymal breast cancer cells undergo adipogenic differentiation upon PPAR gamma activation, shP1-induced epithelialization suppresses adipogenic differentiation. Of the two shRNAs, the shH1 strongly inhibited their growth, indicating shH1-specific sequence has a therapeutic potential for nucleic acid therapeutics. Metabolome/transcriptome analyses of immortalized human mammary epithelial cells (HMLE) undergoing EMT in the presence of absence of H-Ras oncogene revealed global metabolic change upon EMT, including reduced glycolysis, increased shunting to pentose phosphate pathways, shift in TCA, and increased glutathione biosynthesis. Ras-mesenchymal CSLC cells overcame the effects of EMT on glycolysis and acquired hybrid metabolic state. In summary, we have revelaed metabolic plasticity of mesenchymal cancer cells and identified nucleic acid drug candidates against mesenchymal transition. Citation Format: Kiyotsugu Yoshikawa, Rei Takahashi. Identification of nucleic acid drug candidates against mesenchymal transition and its application to breast cancer and glioblastoma cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C106.

Lipid Nanoparticles Optimized for Targeting and Release of Nucleic Acid.

Lipid nanoparticles (LNPs) are currently the most promising clinical nucleic acids drug delivery vehicles. LNPs prevent the degradation of cargo nucleic acids during blood circulation. Upon entry into the cell, specific components of the lipid nanoparticles can promote the endosomal escape of nucleic acids. These are the basic properties of lipid nanoparticles as nucleic acid carriers. As LNPs exhibit hepatic aggregation characteristics, enhancing targeting out of the liver is a crucial way to improve LNPs administrated in vivo. Meanwhile, endosomal escape of nucleic acids loaded in LNPs is often considered inadequate, and therefore, much effort is devoted to enhancing the intracellular release efficiency of nucleic acids. Here, different strategies to efficiently deliver nucleic acid delivery from LNPs are concluded and their mechanisms are investigated. In addition, based on the information on LNPs that are in clinical trials or have completed clinical trials, the issues that are necessary to be approached in the clinical translation of LNPs are discussed, which it is hoped will shed light on the development of LNP nucleic acid drugs.