Tissue-specific Drug Targets Research Articles

Sustainability in anticancer drugs development

Cancer remains one of the most fatal disease threats to mankind. As the development of healthcare and medical science it is important to come up with a sustainable solution to deal with cancer treatment. Despite the fact that many of the approved drugs still exhibit high systemic toxicity, primarily as a result of their lack of tumor selectivity and current pharmacokinetic drawbacks (such as low water solubility), which adversely affect drug circulation time and bioavailability, anticancer research has produced impressive results in recent decades. The sensitivity of anticancer medications to various parameters has been proven by stability tests, which were conducted under gentle settings during their formation or during stressful exposure to high temperature, hydrolytic media, or light source. Because of this, the development of degradation products is evaluated in pharmaceutical formulations as well as in hospital waste released into the environment. Many formulations have been created to date with the goals of enhancing medication stability, lowering hazardous side effects, and attaining tissue-specific drug targeting. In targeted cancer therapy, the creation of prodrugs offers a viable approach to enhancing the stability, effectiveness, and selectivity of active ingredients. According to recent research, anticancer medications can be made more soluble, stable, and pharmacokinetic by incorporating them into vesicular systems like polymeric micelles or cyclodextrins or by using nanocarriers containing chemotherapeutics that bind to monoclonal antibodies. In this work, we provide an overview of the most recent developments in our understanding of the creation of potent, very stable anticancer medications that are either encapsulated in nanosystems or designed as stable prodrugs.

Machine Learning Techniques Applied to the Study of Drug Transporters.

With the advancement of computer technology, machine learning-based artificial intelligence technology has been increasingly integrated and applied in the fields of medicine, biology, and pharmacy, thereby facilitating their development. Transporters have important roles in influencing drug resistance, drug-drug interactions, and tissue-specific drug targeting. The investigation of drug transporter substrates and inhibitors is a crucial aspect of pharmaceutical development. However, long duration and high expenses pose significant challenges in the investigation of drug transporters. In this review, we discuss the present situation and challenges encountered in applying machine learning techniques to investigate drug transporters. The transporters involved include ABC transporters (P-gp, BCRP, MRPs, and BSEP) and SLC transporters (OAT, OATP, OCT, MATE1,2-K, and NET). The aim is to offer a point of reference for and assistance with the progression of drug transporter research, as well as the advancement of more efficient computer technology. Machine learning methods are valuable and attractive for helping with the study of drug transporter substrates and inhibitors, but continuous efforts are still needed to develop more accurate and reliable predictive models and to apply them in the screening process of drug development to improve efficiency and success rates.

Anticancer Drugs: Recent Strategies to Improve Stability Profile, Pharmacokinetic and Pharmacodynamic Properties.

In past decades, anticancer research has led to remarkable results despite many of the approved drugs still being characterized by high systemic toxicity mainly due to the lack of tumor selectivity and present pharmacokinetic drawbacks, including low water solubility, that negatively affect the drug circulation time and bioavailability. The stability studies, performed in mild conditions during their development or under stressing exposure to high temperature, hydrolytic medium or light source, have demonstrated the sensitivity of anticancer drugs to many parameters. For this reason, the formation of degradation products is assessed both in pharmaceutical formulations and in the environment as hospital waste. To date, numerous formulations have been developed for achieving tissue-specific drug targeting and reducing toxic side effects, as well as for improving drug stability. The development of prodrugs represents a promising strategy in targeted cancer therapy for improving the selectivity, efficacy and stability of active compounds. Recent studies show that the incorporation of anticancer drugs into vesicular systems, such as polymeric micelles or cyclodextrins, or the use of nanocarriers containing chemotherapeutics that conjugate to monoclonal antibodies can improve solubility, pharmacokinetics, cellular absorption and stability. In this study, we summarize the latest advances in knowledge regarding the development of effective highly stable anticancer drugs formulated as stable prodrugs or entrapped in nanosystems.

Tissue-specific genes as an underutilized resource in drug discovery

Tissue-specific genes are believed to be good drug targets due to improved safety. Here we show that this intuitive notion is not reflected in phase 1 and 2 clinical trials, despite the historic success of tissue-specific targets and their 2.3-fold overrepresentation among targets of marketed non-oncology drugs. We compare properties of tissue-specific genes and drug targets. We show that tissue-specificity of the target may also be related to efficacy of the drug. The relationship may be indirect (enrichment in Mendelian disease and PTVesc genes) or direct (elevated betweenness centrality scores for tissue-specifically produced enzymes and secreted proteins). Reduced evolutionary conservation of tissue-specific genes may represent a bottleneck for drug projects, prompting development of novel models with smaller evolutionary gap to humans. We show that the opportunities to identify tissue-specific drug targets are not exhausted and discuss potential use cases for tissue-specific genes in drug research.

Liposomes; from synthesis to targeting macrophages

Liposomes are a proposed tool to use for cell and tissue specific drug targeting. Because of their phospholipid membranes and carrying capacity within their spheres, liposomes are of particular interest for clinical applications. Stealth liposomes are especially important for these clinical applications because they are able to avoid the body’s immune system. When it comes to synthesizing these liposomes, there are two major categories of synthesis techniques including active and passive loading. This paper focuses on passive loading techniques which involve mechanical dispersion methods, solvent dispersion methods, and detergent removal. Each of these categories of passive loading techniques has several methods for preparation, all of which aim at producing a homogeneous solution of liposomes with a high loading efficiency. Beyond preparation techniques, this paper also explores the use of liposomes in targeting macrophages to reduce inflammation in various diseases. From this, it has been found that liposomes are able to effectively target macrophages as well as deliver drugs to macrophages that cause the cells to reverse from a pro-inflammatory response to an anti-inflammatory response. These findings are critical as they may lead to further targeting of liposomes to specific cell types to treat other diseases in humans.

1008 - Single Cell RNA Sequencing of T Cells in Crohn's Disease Identifies Tissue Specific Drug Targets

1008 - Single Cell RNA Sequencing of T Cells in Crohn's Disease Identifies Tissue Specific Drug Targets

OP028 Single cell RNA sequencing of t-cells in Crohn’s disease identifies tissue specific drug targets

OP028 Single cell RNA sequencing of t-cells in Crohn’s disease identifies tissue specific drug targets

Permeabilization of the Tight Junction: A Perspective for Tissue-Specific Drug Targeting

Permeabilization of the Tight Junction: A Perspective for Tissue-Specific Drug Targeting

TiSGeD: a database for tissue-specific genes

Summary: The tissue-specific genes are a group of genes whose function and expression are preferred in one or several tissues/cell types. Identification of these genes helps better understanding of tissue–gene relationship, etiology and discovery of novel tissue-specific drug targets. In this study, a statistical method is introduced to detect tissue-specific genes from more than 123 125 gene expression profiles over 107 human tissues, 67 mouse tissues and 30 rat tissues. As a result, a novel subject-specialized repository, namely the tissue-specific genes database (TiSGeD), is developed to represent the analyzed results. Auxiliary information of tissue-specific genes was also collected from biomedical literatures.Availability: http://bioinf.xmu.edu.cn/databases/TiSGeD/index.htmlContact: appo@bioinf.xmu.edu.cn; zhiliang.ji@gmail.com

Preparation of polyclonal antibody specific for NOR1 and detection of its expression pattern in human tissues and nasopharyngeal carcinoma

Oxidored-nitro domain containing protein 1 (NOR1) gene is a novel nitroreductase gene first isolated from nasopharyngeal carcinoma (NPC). It plays an important role in the formation of chemical carcinogen and the carcinogenesis of NPC for its nitrosation function. Overexpression of the wild-type NOR1 gene in nasopharyngeal carcinoma cells is effective to inhibit cell growth and proliferation. In this study, for the first time, we generated a highly specific NOR1 antibody and analyzed NOR1 distribution in the human tissues and NPC biopsies. The results showed that NOR1 protein is predominantly expressed in human nasopharynx and tracheal tissues. Human heart, liver, spleen, stomach, colon, kidney, skeletal muscle, thymus, and pancreas are all deficient of NOR1 protein. More importantly, we performed immunohistochemistry assay of NOR1 protein expression in the NPC tissues, and the result showed that NOR1 protein is frequently down-expressed in NPC. These data shed light on the selectivity of potential physiological functions of NOR1 and provides an indispensable reference to the carcinogenesis process of NPC and to identify or validate tissue-specific drug targets.

Detecting and profiling tissue-selective genes

The widespread use of DNA microarray technologies has generated large amounts of data from various tissue and/or cell types. These data set the stage to answer the question of tissue specificity of human transcriptome in a comprehensive manner. Our focus is to uncover the tissue-gene relationship by identifying genes that are preferentially expressed in a small number of tissue types. The tissue selectivity would shed light on the potential physiological functions of these genes and provides an indispensable reference to compare against disease pathophysiology and to identify or validate tissue-specific drug targets. Here we describe a systematic computational and statistical approach to profile gene expression data to identify tissue-selective genes with the use of a more extensive data set and a well-established multiple-comparison procedure with error rate control. Expression data of 35,152 probe sets in 97 normal human tissue types were analyzed, and 3,919 genes were identified to be selective to one or a few tissue types. We presented results of these tissue-selective genes and compared them to those identified by other studies.

In vitro cytotoxic activity of phenanthroindolizidine alkaloids from Cynanchum vincetoxicum and Tylophora tanakae against drug-sensitive and multidrug-resistant cancer cells.

Two known phenanthroindolizidine alkaloids, (-)-(R)-13aalpha-antofine (1) and (-)-(R)-13aalpha-6-O-desmethylantofine (2), and two new natural products, (-)-(R)-13aalpha-secoantofine (3) and (-)-(R)-13aalpha-6-O-desmethylsecoantofine (4), were isolated from Cynanchum vincetoxicum. The structures of all compounds were established by means of NMR methods including COSY, NOESY, HSQC, and HMBC experiments, supported by HRMS and optical rotation data. Cytotoxic activity of the isolated alkaloids, and of three other alkaloids previously isolated from Tylophora tanakae, (-)-(R)-13aalpha-tylophorine (5), (-)-(R)-13aalpha-7-O-desmethyltylophorine (6), and (+)-(S)-13abeta-isotylocrebrine (7), was assessed in vitro using a drug-sensitive KB-3-1 and a multidrug-resistant KB-V1 cancer cell line. Structure-activity relationships in this series of alkaloids are discussed. The IC(50) values of some of the alkaloids are in the low nanomolar range, being thus comparable to the activity of clinically used cytotoxic drugs. Previously reported adverse side effects of these alkaloids could possibly be overcome by modern tissue-specific drug targeting techniques.

Analysis of plasma protein adsorption on polymeric nanoparticles with different surface characteristics.

Plasma protein adsorption patterns on colloidal drug carriers acquired after i.v. administration depend on their surface characteristics and are regarded as key factors for their in vivo organ distribution. Polymeric latex particles with strongly differing surface properties were synthesized as models for colloidal drug carriers for tissue-specific drug targeting via the intravenous route. Physicochemical characterization was performed for size, surface charge density, zeta potential, and surface hydrophobicity. The interactions with human plasma proteins were studied by way of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). Considerable differences in protein adsorption on the latex particles were detected with regard to the total amount of surface-bound protein on the various particle types as well as specific proteins adsorbed, for example, fibrinogen, albumin, and a recently identified plasma glycoprotein. Possible correlations between protein adsorption patterns and the physicochemical characteristics and topography of the polymeric surfaces are shown and discussed. Knowledge about protein-nanoparticle interactions can be utilized for the rational design of colloidal drug carriers and also may be useful for optimizing implants and medical devices.