Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “MACROMOLECULAR SYSTEMS”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources
PubMed1996

Macromolecular carrier systems for targeted drug delivery: pharmacokinetic considerations on biodistribution.

This review article describes the current status and future perspectives of site-specific drug delivery by means of macromolecular carrier systems. Basic aspects and recent advances of targeted delivery of 1) conventional drugs, 2) protein drugs, and 3) gene medicines including antisense oligonucleotides and plasmid DNA, are reviewed from a pharmacokinetic perspective. Successful in vivo application of macromolecular carrier systems requires pharmacokinetic considerations at whole body, organ, cellular and subcellular levels. The integration of simultaneous research progress in the multidisciplinary fields such as biochemistry, cell and molecular biology, pharmacology, and pharmacokinetics will accelerate the emergence of marketed drugs with macromolecular carrier systems.

Animals↗
PubMed1996

[Development of drug delivery systems for macromolecular drugs].

With a rapid progress in biotechnology, a variety of endogenous macromolecular substances have become a novel class of therapeutic agents. This review will focus on the development of delivery systems for macromolecular drugs. Current status and future perspectives in this research field are reviewed mainly based on the results obtained in our laboratory. First of all, we studied pharmacokinetic characteristics of macromolecules in relation to their physicochemical properties such as molecular weight and electric charge. Based on this information, we first developed macromolecular prodrugs as a delivery system for low molecular weight drugs. An antitumor antibiotic, mitomycin C (MMC) were covalently conjugated with dextran and various types of macromolecular prodrug of MMC were developed for tumor targeting. Secondly, delivery systems for protein drugs such as soybean trypsin inhibitor, uricase, and recombinant superoxide dismutase (SOD) were developed. In particular, successful targeting of SOD to the liver, kidney and blood circulation was achieved by chemical modification of the protein drug. Finally, we have been trying to develop delivery systems for nucleic acid drugs involving antisense oligonucleotides and plasmid DNA. Prior to the development of delivery systems, we found that the pharmacokinetics of the nucleic acid drugs are decided by their physicochemical properties as polyanions even if these materials contain genetic information. Several approaches were tested to control the in vivo behavior of the oligonucleotides and plasmid DNA based on the finding. Thus, we have established the strategy for rational design of delivery systems for various types of macromolecular drugs based on the pharmacokinetic considerations. This methodology can be a formidable tool for the development of clinically applicable macromolecular drugs.

Antibiotics, Antineoplastic↗
PubMed2004

CLIMS: crystallography laboratory information management system.

Macromolecular crystallography requires simple yet effective means of organizing and managing the large amounts of data generated by crystallization experiments. There are several freely available web-based Laboratory Information Management Systems (LIMS) that assist in these tasks. These, however, rely on the limited user interfaces allowed in HTML-based web pages. To address this limitation, a new LIMS for protein crystallization, which features a novel rich graphical user interface (GUI) to a relational database, has been developed. This application, which is called CLIMS (Crystallography LIMS), assists in all aspects of protein-crystallization projects: protein expression, handling, crystallization optimization, visualization of results and preliminary diffraction data. Extensive use of templates, particularly for commercial screens and common optimization grid screens, exploits the redundancy in experimental setups. The crystallization tray is the central focus of the graphical interface, thus facilitating rapid visualization and annotation of results. CLIMS was developed specifically to cater for the needs of individual laboratories requiring an intuitive and robust system for managing crystallization experiments and is freely available.

Computer Graphics↗
PubMed2003

Lytic transglycosylases in macromolecular transport systems of Gram-negative bacteria.

The cell wall of Gram-negative bacteria is essential for the integrity of the bacterial cell but also imposes a physical barrier to trans-envelope transport processes in which DNA and/or proteins are taken up or secreted by complex protein assemblies. The presence of genes encoding lytic transglycosylases in macromolecular transport systems (bacteriophage entry, type II secretion and type IV pilus synthesis, type III secretion, type IV secretion) suggests an important role for these specialised cell-wall-degrading enzymes. Such enzymes are capable of locally enlarging gaps in the peptidoglycan meshwork to allow the efficient assembly and anchoring of supramolecular transport complexes in the cell envelope. In this review, current knowledge on the role and distribution of these specialised murein-degrading enzymes in diverse macromolecular transport systems is summarised and discussed.

Amino Acid Sequence↗
PubMed1996

Synthesis of transferrin-mitomycin C conjugate as a receptor-mediated drug targeting system.

Macromolecular conjugates of mitomycin C (MMC) were synthesized by binding an active ester of glutarylated MMC (MMC-G-OSu) to human holo-transferrin (TF). Water-soluble TF-MMC conjugates (TF-G-MMC) were obtained in a good yield (> 95%) by this method. The MMC content of the conjugate increased (0.82-9.49 MMC/w%) with increasing amounts of MMC-G-OSu added to the conjugation mixture. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed no aggregation in these conjugates. 125I-TF-G-MMC was bound specifically to the TF receptor on Sarcoma 180 cells; the measurement of equilibrium binding of the 125I-labeled conjugate resulted in a saturation isotherm. The amount of conjugate specifically bound to the TF receptor decreased as the MMC content of the conjugate increased. However, it was found that the conjugate with an MMC content below 10 mol MMC/mol TF still retains a binding activity of more than half that of TF. Therefore, when an optimal chemical modification was chosen, TF could be used as a tumor specific drug carrier.

Animals↗
PubMed2001

Duration time of a one-dimensional random walk as a function of the energies of the intermediate states: application for dissociation and relaxation processes in DNA hybrids.

Kinetic parameters of macromolecular systems are important for their function in vitro and in vivo. These parameters describe how fast the system dissociates (the characteristic dissociation time), and how fast the system reaches equilibrium (characteristic relaxation time). For many macromolecular systems, the transitions within the systems are described as a random walk through a number of states with various free energies. The rate of transition between two given states within the system is characterized by the average time which passes between starting the movement from one state, and reaching the other state. This time is referred to as the mean first-passage time between two given states. The characteristic dissociation and relaxation times of the system depend on the first-passages times between the states within the system. Here, for a one-dimensional random walk we derived an equation, which connects the mean first-passage time between two states with the free energies of the states within the system. We also derived the general equation, which is not restricted to one-dimensional systems, connecting the relaxation time of the system with the first-passage times between states. The application of these equations to DNA branch migration, DNA structural transitions and other processes is discussed.

DNA↗
PubMed2006

Quantitative acid hydrolysis of DE-310, a macromolecular carrier system for the camptothecin analog DX-8951f.

DE-310 is a novel macromolecular prodrug of the topoisomerase-I inhibitor DX-8951. DX-8951 is covalently linked to carboxymethyl dextran polyalcohol (CM-Dex-PA) via a Gly-Gly-Phe-Gly (GGFG) tetrapeptide spacer. The present study was conducted to identify the portions of DX-8951 linked to DE-310, as well as to quantify the number of DX-8951 molecules associated with DE-310. Two different structures terminated with either glycolaldehyde (CM-GA-GGFG-DX-8951) or glycerol (CM-Glr-GGFG-DX-8951) are obtained when the polymer backbone is fragmented with 1 M HCl. The two products, i.e., CM-GA-GGFG-DX-8951 and CM-Glr-GGFG-DX-8951, indicate linkage of GGFG-DX-8951 with carboxymethyl (CM) group at C-2 and C-4 position of the glucose units, respectively. In the present study, CM-GA-GGFG-DX-8951 was reduced to CM-ethyleneglycol (EG)-GGFG-DX-8951 in order to improve stability prior to HPLC analysis. Hydrolysis results revealed that the amount of CM-GA-GGFG-DX-8951 liberated was 84.7 nmol/mg DE-310 and the amount of CM-Glr-GGFG-DX-8951 was 71.8 nmol/mg DE-310. Considering the ratio of generation between CM-GA-GGFG-DX8951 and CM-Glr-GGFG-DX8951, it suggested that slightly larger amount of GGFG-DX-8951 was linked to carboxymethyl groups at the C-2 position of glucose units in DE-310. The sum of the amounts of CM-GA-GGFG-DX-8951 and CM-Glr-GGFG-DX-8951 agrees well with the amount of G-DX-8951 produced from DE-310 by alpha-chymotrypsin treatment (157.5 nmol/mg DE-310). The data indicate that the established hydrolysis give a quantitative evaluation of the DX-8951 linked to DE-310.

Acids↗
PubMedDate not supplied

Drug delivery systems for the future.

Parenteral drug delivery systems have the potential to make drugs both safer and more effective. While research in this field has been active for over 30 years, the current fiscal constraints of health care delivery add a greater degree of urgency to finding a working system. The three competing technologies currently under development include prodrug or zymogen-like systems, simple soluble macromolecular systems, and complex particulate multicomponent systems. In this review, the advantages, disadvantages, and areas for further development of these three basic technology systems are compared and contrasted; the biophysical constraints are considered; and a model solution system using surface modified nanocrystalline ceramics is described.

Antibodies, Monoclonal↗
PubMed2004

DE-310, a novel macromolecular carrier system for the camptothecin analog DX-8951f: potent antitumor activities in various murine tumor models.

DE-310 is a novel macromolecular conjugate composed of DX-8951f, a camptothecin analog, and a carboxymethyldextran polyalcohol carrier, which are covalently linked via a peptidyl spacer. In a murine Meth A (fibrosarcoma) solid tumor model, once daily x 5 treatments (qd x 5) with DX-8951f at the maximum tolerated dose (MTD) were required to shrink the tumor, and DX-8951f (qd x 5) at 1/4 MTD was required to inhibit tumor growth. A single treatment (qd x 1) with DE-310 at the MTD or 1/4 MTD shrank the tumor, with no body weight loss occurring at 1/4 MTD. Even at 1/16 MTD, DE-310 inhibited tumor growth. In a long-term assay, Meth A solid tumors disappeared in mice treated with DE-310 (qd x 1) at the MTD and 1/2 MTD, and all 6 mice remained tumor-free on the 60th day after administration. Repeated injection (4 times) on schedules of every 3 days, 7 days or 14 days demonstrated that multiple treatment with DE-310 produced greater tumor growth delay than a single treatment with DE-310. Against 5 human tumor (colon and lung cancer) xenografts in mice, DE-310 (qd x 1) was as effective as DX-8951f administered once every 4 days, 4 times. The life-prolonging activity of DE-310 was assessed in lung (3LL, Lewis lung carcinoma) and liver (M5076, histiocytoma) metastasis models. Against 3LL, DE-310 (qd x 1) at the MTD to 1/3 MTD significantly prolonged survival, with an increase in life span (ILS) of 4.8- to 1.6-fold, respectively, over that in untreated control mice. Also, DE-310 (qd x 1) significantly prolonged survival in the liver metastasis model of M5076. These results demonstrate that DE-310 is a promising agent for the treatment of cancer.

Animals↗
PubMed1995

Simulating the folding of small proteins by use of the local minimum energy and the free solvation energy yields native-like structures.

Assuming that the protein primary sequence contains all information required to fold a protein into its native tertiary structure, we propose a new computational approach to protein folding by distributing the total energy of the macromolecular system along the torsional axes. We further derive a new semiempirical equation to calculate the total energy of a macromolecular system including its free energy of solvation. The energy of solvation makes an important contribution to the stability of biological structures. The segregation of hydrophilic and hydrophobic domains is essential for the formation of micelles, lipid bilayers, and biological membranes, and it is also important for protein folding. The free energy of solvation consists of two components: one derived from interactions between the atoms of the protein, and the second resulting from interactions between the protein and the solvent. The latter component is expressed as a function of the fractional area of protein atoms accessible to the solvent. The protein-folding procedure described in this article consists of two successive steps: a theoretical transition from an ideal alpha helix to an ideal beta sheet is first imposed on the protein conformation, in order to calculate an initial secondary structure. The most stable secondary structure is built from a combination of the lowest energy structures calculated for each amino acid during this transition. An angular molecular dynamics step is then applied to this secondary structure. In this computational step, the total energy of the system consisting of the sum of the torsional energy, the van der Waals energy, the electrostatic energy, and the solvation energy is minimized. This process yields 3-D structures of minimal total energy that are considered to be the most probable native-like structures for the protein. This method therefore requires no prior hypothesis about either the secondary or the tertiary structure of the protein and restricts the input of data to its sequence. The validity of the results is tested by comparing the crystalline and computed structures of four proteins, i.e., the avian and bovine pancreatic polypeptide (36 residues each), uteroglobin (70 residues), and the calcium-binding protein (75 residues); the C alpha-C alpha maps show significant homologies and the position of secondary structure domains; that of the alpha helices is particularly close.

Animals↗
PubMed1967

Some fundamental molecular mechanisms of contractility in fibrous macromolecules.

The fundamental molecular mechanisms of contractility and tension development in fibrous macromolecules are developed from the point of view of the principles of polymer physical chemistry. The problem is treated in a general manner to encompass the behavior of all macromolecular systems irrespective of their detailed chemical structure and particular function, if any. Primary attention is given to the contractile process which accompanies the crystal-liquid transition in axially oriented macromolecular systems. The theoretical nature of the process is discussed, and many experimental examples are given from the literature which demonstrate the expected behavior. Experimental attention is focused on the contraction of fibrous proteins, and the same underlying molecular mechanism is shown to be operative for a variety of different systems.

Adenosine Triphosphate↗
PubMed2004

Pharmacokinetics of DE-310, a novel macromolecular carrier system for the camptothecin analog DX-8951f, in tumor-bearing mice.

To improve the distribution of the novel camptothecin analog DX-8951, DE-310, which is composed of DX-8951 covalently linked to a macromolecular carrier by a peptidyl (GGFG) spacer, was designed to exploit the Enhanced Permeability and Retention (EPR) effect. To compare the pharmacokinetics of a single dose of DE-310 with that of DX-8951f in Meth A tumor-bearing mice, the concentrations of conjugated DX-8951 (carrier-bound DX-8951), released DX-8951, and glycyl DX-8951 (G-DX-8951) were determined in plasma, liver, and tumor tissue. The concentrations of conjugated DX-8951 in tumor tissue were lower than those in plasma, with an AUC(0-inf) of 1/6 that of plasma; however, the AUC(0-inf) of released DX-8951 in tumor tissue was 30 times greater than that in plasma. The half-life (t1/2) of conjugated DX-8951, released DX-8951, and G-DX-8951 in plasma, liver, and tumor tissue were 2-3 days. In contrast, after administration of 14C-DX-8951f, the radioactivity in tumor tissue decreased in parallel with the decrease in plasma concentrations, with a t1/2(0.083-3 h) of 0.6 h. These data show that higher levels and longer retention of conjugated DX-8951 and released DX-8951 occur in tumor tissue after the administration of DE-310 to Meth A tumor-bearing mice. These results indicate that DE-310 improves the pharmacokinetic profileof DX-8951f, particularly, its ability to target tumor tissue.

Animals↗
PubMed2006

Clinical perspectives on pulmonary systemic and macromolecular delivery.

The large epithelial surface area, the high organ vascularization, the thin nature of the alveolar epithelium and the immense capacity for solute exchange are factors that led the lung to serve as an ideal administration route for the application of drugs for treatment of systemic disorders. However, the deposition behaviour of aerosol particles in the respiratory tract depends on a number of physical (e.g. properties of the particle), chemical (e.g. properties of the drug) and physiological (e.g. breathing pattern, pulmonary diseases) factors. If these are not considered, it will not be possible to deposit a reproducible and sufficient amount of drug in a predefined lung region by means of aerosol inhalation. The lack of consideration of such issues led to many problems in inhalation drug therapy for many years mainly because physiological background of aerosol inhalation was not fully understood. However, over the last 20 years, there has been considerable progress in aerosol research and in the understanding of the underlying mechanisms of particle inhalation and pulmonary particle deposition. As a consequence, an increasing number of studies have been performed for the lung administration of drugs using a variety of different inhalation techniques. This review describes the physical and in part some of the physiological requirements that need to be considered for the optimization of pulmonary drug delivery to target certain lung regions.

Administration, Inhalation↗
PubMed1988

Interaction of adriamycin with human erythrocyte membranes. Role of the negatively charged phospholipids.

The interaction of the antitumor compound adriamycin with human erythrocyte membranes, used as models of target cell membranes, has been studied using circular dichroism measurements. In order to elucidate the nature of the sites involved in the electrostatic interaction between adriamycin and erythrocyte membranes, its interaction with the following macromolecular systems was studied: phosphatidylserine-containing small unilamellar vesicles (SUV), prepared from total lipid extracts of erythrocytes, sialic acid-depleted erythrocyte ghosts and mucopolysaccharides. We have shown that the interaction between adriamycin and carboxylate groups is very weak and that negatively charged phosphate groups, in the case of membranes, or sulfate groups, in the case of mucopolysaccharides, are responsible for the prime interaction of adriamycin with these macromolecular systems.

Circular Dichroism↗
PubMed2004

Novel buffer systems for macromolecular crystallization.

In protein crystallization, screening is initially performed to obtain an indication of the conditions under which a macromolecule might crystallize. These preliminary conditions are then optimized to produce (in a perfect world) well diffracting crystals; this process of optimization often involves fine grid screening around the initial conditions. An issue in optimization is to find factors which are independent, so as to simplify the analysis of the results of optimization trials. This is necessarily difficult with buffers, as a buffer and its pH range tend to be very highly correlated. Multi-buffer systems for pH modulation are presented which enable a broad pH range to be sampled without changing the chemical composition of the buffering component.

Buffers↗