Drug delivery and drug targeting: Drug targeting using thermally responsive polymers and local hyperthermia.
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Journal Article↗
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[Multi-targeting drugs and multi-drug targeting in metastatic renal cell carcinoma. Concept of co-inhibition of the epidermal growth].
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Antineoplastic Agents↗
Drug targeting to the liver with lactosylated albumins: does the glycoprotein target the drug or is the drug targeting the glycoprotein?
The isolated perfused rat liver preparation was employed to study hepatic disposition of the model drug-carrier conjugate fluorescein-lactosylated albumin (F-LnHSA) with special reference to the influence of the organic anion fluorescein on liver cell specificity of the endocytosed neoglycoprotein. Hepatic clearance of fluoresceinated neoglycoproteins was significantly faster than clearance of radioiodinated neoglycoproteins. Perfusate clearance of F-L7HSA and F-L25HSA could not completely be inhibited by a dose of 10 mg asialoorosomucoid that saturates the hepatocyte receptor-mediated endocytic process. From these data, we inferred an additional hepatic uptake mechanism, competing with the Ashwell-receptor-mediated internalization of galactose-terminated glycoproteins. Clearance experiments with fluoresceinated 125I-human serum albumin in the presence of the polyanionic probe dextran sulfate revealed a nearly complete (approximately 90%) inhibition of hepatic uptake, while also a pronounced effect was obtained with colloidal carbon. These data point to nonparenchymal cell uptake of fluoresceinated protein via interaction with scavenger receptors. In wash-out studies, it was shown that about 25% of ligand sequestrated by sinusoidal liver cells escaped degradation and recycled to the perfusion medium. Our results show that care should be taken in the use of neoglycoproteins as drug carriers to hepatocytes, since a load of only 2 to 3 moles fluorescein per mole neoglycoprotein considerably affects intrahepatic distribution. The relative contribution of nonparenchymal cell uptake by coupling of acidic drugs to the neoglycoproteins is very probably inversely related to the number of exposing galactose groups per molecule neoglycoprotein. This phenomenon of "inversed targeting" could therapeutically both be useful or detrimental, dependent on the spectrum of cell types that should be reached by the drug.
Animals↗
Drug targeting by drug entrapment into ultrafine compartments as carriers.
The incorporation of drugs into vesicles is one of several technological methods for the optimization of targeted drug delivery and controlled drug targeting. The main problems will always remain: To design inert auxiliary accompanying materials in order to overcome side reactions; To use body-friendly and biodegradable macromolecular carrier materials for the therapeutic system; To miniaturize the dosage form dramatically in the submicroscopic size range in order to eliminate foreign body irritations; To develop ultrafine solid and amorphous vesicular compartments (nanocapsules, nanopellets, nanoparticles) to get stable systems with good tissue transfer and organ targeting properties The actual stand of the incorporation of drugs and biologic active material into ultrafine colloidal solid capsules is reviewed here as for instance: Immunoactive material; Fluorescent indicators in body fluids; Controlled and sustained release systems Nonspecific drug targeting of the first-order (passage through endothelial tissues); Second-order targeting (a specific transparenchymal migration), and a highly specific targeting of the third-order (transcellular passage, especially lysosomal transports). Examples for some of these applications are given. It can be shown that such ultrafine vesiculated capsules offer some advantages when applied parenterally, but also partly for oral application. In the future, still more studies are necessary finally to clarify the importance and practical use of such ultrafine targeting carriers.
Animals↗
The implications of resistance to antiviral agents for herpesvirus drug targets and drug therapy.
Antiviral drug resistance is an area of increasing clinical importance in treatment of a number of viruses including herpes simplex virus (HSV) and human cytomegalovirus (CMV). Work with these herpesviruses illustrates the value of studies of drug resistance. Novel aspects of drug mechanisms, such as a CMV gene product that contributes to ganciclovir phosphorylation, can be identified via drug resistance mutations. Drug targets such as the HSV DNA polymerase that are involved in drug recognition can be dissected by sequencing of drug-resistance mutations, which can point to alternate therapeutic strategies. Analysis of virus mutants in animal models and in patient populations can help assess the value of viral proteins such as the HSV thymidine kinase and ribonucleotide reductase as drug targets and the pathogenic potential of drug resistant mutants. Such studies reveal a broad spectrum of alterations conferring resistance and emphasize the importance of heterogeneous populations of virus in resistance and pathogenesis and the need to develop alternate therapies.
Animals↗
Proteomic approaches for the identification of cell cycle-related drug targets.
Drugs affecting the cell cycle provide insights into mechanisms underlying cancer and suggest strategies for ablating uncontrolled growth. Essential to an understanding of the activity of such compounds is the identification of the set of proteins affected, either directly or indirectly, by the drug. The combination of novel technologies for stable isotope protein tagging, chromatographic separation, tandem mass spectrometry, and data processing is an extremely powerful means for providing such identifications and, in addition, for establishing a proteome-wide profile of all proteins whose abundance levels or phosphorylation state are affected by the drug.
Animals↗
Drug target validation and identification of secondary drug target effects using DNA microarrays.
We describe here a method for drug target validation and identification of secondary drug target effects based on genome-wide gene expression patterns. The method is demonstrated by several experiments, including treatment of yeast mutant strains defective in calcineurin, immunophilins or other genes with the immunosuppressants cyclosporin A or FK506. Presence or absence of the characteristic drug 'signature' pattern of altered gene expression in drug-treated cells with a mutation in the gene encoding a putative target established whether that target was required to generate the drug signature. Drug dependent effects were seen in 'targetless' cells, showing that FK506 affects additional pathways independent of calcineurin and the immunophilins. The described method permits the direct confirmation of drug targets and recognition of drug-dependent changes in gene expression that are modulated through pathways distinct from the drug's intended target. Such a method may prove useful in improving the efficiency of drug development programs.
Calcineurin↗
[Molecular-target drug].
Cancer metastasis involves the complicated steps of tumor growth, angiogenesis, invasion and adhesion. At present new drugs targeting particular molecule (s) responsible for such cancer progression and metastasis have been developed in clinics. Major endpoints for cancer treatment should be prolongation of survival and maintenance of QOL. However, clinical development of such molecular-target based drugs is associated with difficulties in evaluating the efficacy in phase I/II studies prior to entering phase III study, because many of the targeted drugs seem cytostatic rather than cytocidal to tumors. New approaches incorporating technologies of genomics and proteomics may provide an expanding repertoire of molecular targeted therapeutics for clinical evaluation. In this review, the significance and problems of biomarkers available for clinical evaluation of molecular targeted drugs are discussed.
Angiogenesis Inhibitors↗
Receptor-mediated targeted drug or toxin delivery.
The new approach to the treatment of cancer or to immunomodulation is drug targeting. Cellular uptake of drugs bound to a targeting carrier or to a targetable polymeric carrier is mostly restricted to receptor-mediated endocytosis. Factors that influence the efficiency of receptor-mediated uptake of targeted drug conjugate are the affinity of the targeting moieties, the affinity and nature of the target antigen, density of the target antigen, the epitope of the target antigen, the type of cell target, the rate of endocytosis, the route of internalization of the ligand-receptor complex, the ability of the drug or toxin to release from its targeted carrier, the ability of the drug or toxin to escape from a vesicular compartment into the cytosol, the affinity of the carrier to the drug and the concentration of the carrier. Targeted chemotherapy is also significantly influenced by the antigenic modulation and/or immunoselection of tumor cells. The binding of drug (toxin) to targetable polymeric carrier considerably decreases unwanted side toxicity.
Journal Article↗
Cyclin-dependent protein kinases as therapeutic drug targets for antimalarial drug development.
Cyclin-dependent protein kinases (CDKs) have been attractive drug targets for the development of anticancer therapies due to their direct and crucial role in the regulation of cellular proliferation. Following this trend, CDKs have been pursued as potential drug targets for several other diseases. Structure-based drug design programmes have focused on the plasmodial CDKs to develop new candidate antimalarial compounds. This review discusses the most recent advances relating to three Plasmodium falciparum CDKs (PfPK5, PfPK6 and Pfmrk) as they are developed as antimalarial drug targets. CDKs are highly conserved, and focus must be placed upon the amino acid differences between human and plasmodial CDKs in order to develop specific inhibitors. Comparisons of the active sites of human and parasite CDKs reveal sequence and potential structural variations. Using sequence analysis, molecular modelling and in vitro drug screening, it is possible to identify and develop inhibitors that specifically target the plasmodial CDKs. These efforts are aimed at identifying new classes of CDK inhibitors that may be exploited for antimalarial drug development.
Amino Acid Sequence↗
Combination of a drug targeting the cell with a drug targeting the virus controls human immunodeficiency virus type 1 resistance.
Combinations of drugs targeting viral proteins have been used to limit or control drug resistance, which is the most important cause of treatment failure in HIV-1-infected individuals. We suggest an alternative approach, namely to target cellular proteins, which are less prone to mutations than viral proteins. Here we show that simultaneous inhibition of a cellular protein (by hydroxyurea) and a viral protein (by ddI) produces a consistent and sustained suppression of HIV-1 for as long as 40 weeks in the absence of virus rebound. We identified the mechanism to explain this lack of rebound: although the combination of the two drugs did not prevent the emergence of mutant viral strains resistant to didanosine (ddI) in these patients, the mutants were still sensitive to standard doses of ddI in the presence of hydroxyurea. These in vivo results were consistent with our in vitro observations: HIV-1 molecular clones resistant to ddI were rendered sensitive to this drug (at concentrations routinely achievable in vivo) after addition of hydroxyurea. This phenomenon can be explained by the observation that hydroxyurea decreases the level of dATP, the cellular competitor of ddI. A low level of dATP favors the incorporation of ddI, even if the viral reverse transcriptase is resistant to this nucleoside analog. This is a novel mechanism of control of resistance and it explains the efficacy of a treatment that is well tolerated, simple, and inexpensive.
Acquired Immunodeficiency Syndrome↗
Targeted drug delivery to mammalian mitochondria in living cells.
Mitochondrial dysfunction causes or contributes to a large number of human disorders including neuromuscular and neurodegenerative diseases, diabetes, ischaemia-reperfusion injury and cancer. Increasing efforts are being made towards mitochondria-directed pharmacological intervention, leading to the emergence of 'mitochondrial medicine' as a new field of biomedical research. The identification of new molecular mitochondrial drug targets in combination with the development of methods for selectively delivering biologically active molecules to the site of mitochondria will eventually launch new therapies for the treatment of mitochondria-related diseases, based either on the selective protection, repair or eradication of cells. This review discusses the need for the development of mitochondria-specific drug and DNA delivery systems, and evaluates the currently employed strategies for mitochondrial drug targeting, including some of their potential therapeutic applications.
Animals↗
In-vitro evaluation of khaya and albizia gums as compression coatings for drug targeting to the colon.
Khaya and albizia gums were evaluated as compression coatings for target drug delivery to the colon using indometacin (a water insoluble drug) and paracetamol (a water soluble drug) as model drugs. The core tablets were compression-coated with 300 and 400 mg of 100% khaya gum, 100% albizia gum and a mixture of khaya and albizia gum (1:1). Drug release studies were carried out in 0.1(M) HCl (pH 1.2) for 2 h, Sorensen's buffer (pH 7.4) for 3 h and then in phosphate-buffered saline (pH 6.8) or in simulated colonic fluid for the rest of the experiment to mimic the physiological conditions from the mouth to colon. The results indicated that khaya and albizia gums were capable of protecting the core tablet in the physiological environment of the stomach and small intestine, with albizia gum showing greater ability than khaya gum. The release from tablets coated with the mixture of khaya and albizia gums was midway between the two individual gums, indicating that there was no interaction between the gums. Studies carried out using rat caecal matter in phosphate-buffered saline at pH 6.8 (simulated colonic fluid) showed that the gums were susceptible to degradation by the colonic bacterial enzymes, leading to release of the drug. The results demonstrate that khaya gum and albizia gum have potential for drug targeting to the colon.
Acetaminophen↗
Gene expression analysis as an aid to the identification of drug targets.
Many drug targets are components of complex signalling pathways, and in order to understand the true biological consequences of modulating these targets it is necessary to understand the biology of the system in great detail. Genomics research can contribute some of the tools to achieve this, for example through the use of cDNA microarrays. Since activation of signalling pathways leads to mRNA expression, microarray technology can be used to provide a detailed quantitative assessment of the consequences of this activation, often providing a completely new biological perspective on well established cellular systems. This review will discuss some of the results obtained using mRNA profiling of yeast and mammalian cells to analyse signalling pathways of relevance to inflammation and cancer, and will point towards the future applications of this exciting approach to drug target evaluation.
Animals↗
Dextrins as potential carriers for drug targeting: tailored rates of dextrin degradation by introduction of pendant groups.
There is a recognised need to identify new biodegradable polymers suitable for development as targetable drug carriers. The aim of this study was to determine the rate of degradation of two dextrin fractions (Mw 15.5 and 51 KDa) by alpha-amylase and liver lysosomal enzymes (tritosomes). Also experiments were conducted to discover whether backbone modification by succinolyation (1-34 mol%) or pendant group incorporation (e.g. doxorubicin) could be used to tailor the rate of polymer degradation. Dextrin (alpha-1,4 polyglucose) is a natural polymer used clinically as a peritoneal dialysis solution and as a controlled drug delivery formulation. Size exclusion chromatography (SEC) showed that dextrin was degraded rapidly (within 20 min) by rat plasma and porcine pancreatic alpha-amylase. In contrast over 48 h no degradation was observed in the presence of tritosomes. The rate of alpha-amylase degradation of succinoylated dextrins (Mw approximately 51 KDa) was dependant on the degree of modification (dextrin >1>5>15>34 mol% succinoylation). Dextrin-doxorubicin conjugates were prepared from the 15 and 34 mol% succinoylated intermediates to have a doxorubicin loading of 8 and 12 wt.%, respectively. These doxorubicin conjugates were more stable than their parent intermediates, and SEC showed an apparently higher molecular weight. The drug conjugates did however degrade slowly over 7 days to release oligosaccharide-doxorubicin species. This fundamental study demonstrates the possibility of controlling the rate of dextrin enzymolysis by backbone modification and thus affords the potential to rationally design dextrin-drug conjugates for specific applications as targetable carriers.
Animals↗
Lectin-mediated drug targeting: quantification of binding and internalization of Wheat germ agglutinin and Solanum tuberosum lectin using Caco-2 and HT-29 cells.
For the potential use of Wheat germ agglutinin (WGA) and Solanum tuberosum lectin (STL) as auxiliary excipients for targeting drugs to colonocytes, the number of Caco-2 and HT-29-bound lectins was determined by fluorimetry using fluorescein-labelled derivatives of the N-acetylglucosamine-specific lectins. After 1 h of incubation, the WGA-binding capacity of 5 x 10(4) Caco-2 cells was 26.9 +/- 0.5 pmol at 4 degrees C and 27.2 +/- 1.0 pmol at 37 degrees C respectively. In comparison, 19.5 +/- 2.9 pmol (37 degrees C) and 16.7 +/- 0.9 pmol (4 degrees C) WGA were bound within 1 h to 5 x 10(4) HT-29 cells referring to about 80% of the total amount of WGA bound within 4 h of incubation. In contrast, binding of STL to the colon carcinoma cell lines was independent of incubation times and temperatures tested exhibiting a binding rate of 8.4 +/- 0.6 pmol (HT-29) and 9.9 +/- 0.8 pmol (Caco-2) STL/5 x 10(4) cells. As determined by flow cytometry, non-specific binding is lower than 1.0% (WGA) and 3.4% (STL). Uptake and intracellular accumulation of the lectins were investigated by confocal laser scanning microscopy at 4 degrees C and 37 degrees C respectively. A decrease of initially membrane-bound lectins concurrent with increasing cytoplasmic enrichment by time was observed by digital cell image analysis. Due to specific and numerically sufficient adhesion as well as internalization, WGA and STL are anticipated as targeting tools in lectin-mediated drug delivery systems.
Acetylglucosamine↗
Protein kinase C as a drug target: implications for drug or diet prevention and treatment of cancer.
Protein kinase C (PKC) isoforms are serine/threonine kinases involved in signal transduction pathways that govern a wide range of physiological processes including differentiation, proliferation, gene expression, brain function, membrane transport and the organization of cytoskeletal and extracellular matrix proteins. PKC isoforms are often overexpressed in disease states such as cancer. In this review, PKC in a variety of cancers is discussed along with some specific cell biological mechanisms by which PKC exerts its function(s). The PKC family consists of several isoforms comprising three groups: classical, novel and atypical. Although PKC has been investigated for around 2 decades, only recently has the specific function of each isoform started to be elucidated and the isoforms evaluated for use as targets of drug action. Phorbol esters such as the tumor-promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) or diacylglycerol (DAG) activate classical and novel PKC isoforms. Naturally occurring retinoids, antisense oligonucleotides against specific PKC isoforms and specific PKC inhibitors can block this activation. Beta carotene and retinoid derivatives act as anticarcinogenic agents and can antagonize some of the biological actions of phorbol esters and oxidants. Another important area of investigation is the use of antisense oligonucleotides to inhibit specific PKC isoforms. These compounds have proven effective in reducing specific types of cancer in rodents and humans and are currently used in clinical trials. This review examines PKC isoforms as a target of drug action with special emphasis on their use in cancer therapy.
Animals↗
Cellular resistance to topoisomerase-targeted drugs: from drug uptake to cell death.
DNA topoisomerase inhibitors are important antineoplastic agents used in the treatment of both leukemias and solid tumors, such as breast, lung and colon cancers. Their clinical usefulness is limited by both natural and acquired tumor cell resistance, which almost always is multifactorial in nature. The resistance can be due to pretarget events, such as drug accumulation, metabolism and intracellular drug distribution, or due to reduced drug-target interaction. More recently, post-target events, such as macromolecular synthesis, cell cycle progression, DNA repair/recombination and regulation of cell death, have been shown to play an important role in the sensitivity toward topoisomerase inhibitors. The different mechanisms involved in the cellular resistance toward clinically used topoisomerase inhibitors will be reviewed in this article with particular emphasis on post-target events.
Antineoplastic Agents↗