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PubMed2004

Tumor targeting based on the effect of enhanced permeability and retention (EPR) and the mechanism of receptor-mediated endocytosis (RME).

This review is focused on the macromolecular drug carrier systems by the effect of enhanced permeability and retention (EPR) and the mechanism of receptor-mediated endocytosis (RME). The effect of EPR is thought to be useful for the targeting of the macromolecular drugs to the tumor tissues on a vasculolymphatic level. The RME reveals the selective recognition, high affinity binding, and immediate internalization for the ligand on a cellular level. In the receptor, recognizing transferrin, a level of expression on the tumor cells is higher than that on the normal cells. We have used serum albumin and transferrin as drug carriers to deliver mitomycin C (MMC) to the tumor tissues and into the tumor cells. The properties of the conjugates of MMC to serum albumin and transferrin were examined in vitro and in vivo. We concluded that MMC could be delivered to the tumor tissue and cells by the use of albumin and transferrin as drug carriers.

Animals↗
PubMed1972

Studies on the localization of the cardiac glycoside receptor.

The purpose of this study was to see whether the receptor for cardiac glycosides might be localized upon or within the plasma membrane of digitalis-sensitive cells. Ouabain and digoxin were joined covalently to several large protein molecules. These macromolecular conjugates are too large to enter intact cells; consequently, any pharmacologic or biochemical effects which they display should arise from interaction with a cell surface receptor. Conjugates were tested in several cardiac glycoside-sensitive systems: (a), contractility response of isolated cardiac muscle; (b), active (86)Rb(+) uptake by red cells; (c), enzymatic activity of isolated myocardial microsomal (Na(+) + K(+))-activated adenosine triphosphatase (ATPase); and (d), enzymatic activity of solubilized red cell (Na(+) + K(+))-activated ATPase. Results demonstrated that in all of these systems, the macromolecular-glycoside conjugates were 100- to 1000-fold less active than the free glycosides. Careful chromatographic examination of the various conjugates revealed that they contained a small but persistent free cardiac glycoside contaminant. The amount of this species ranged from 0.1 to 1.0% of the total macromolecule-bound glycoside, and its presence fully explains the levels of biologic activity observed with the conjugates. To try to minimize steric factors which could interfere with glycoside-receptor interaction, digoxin and ouabain were also coupled to macromolecule via long, flexible polyamide side-chains. These extended chain conjugates, in which the cardiac glycoside potentially lay some 30 A removed from the surface of the macromolecule, also exhibited negligible digitalis-like effects when tested upon isolated cardiac muscle, red cell (86)Rb(+) uptake, and enzymatic activity of cardiac microsomal (Na(+) + K(+))-ATPase. However, the extended chain conjugates were fully active when examined with the solubilized red cell (Na(+) + K(+))-ATPase system. To further ensure that the chemical reactions used to couple macromolecule to glycoside did not inactivate the drug, all conjugates were subjected to extensive proteolytic digests exhibited full pharmacologic activity. Digoxin was also coupled to the tripeptide alanylglycylglycine, and the resulting conjugate was fully active. Taken together, these results suggest that if the receptor(s) for cardiac glycosides is associated with the plasma membrane, then it may lie deep within it.

Adenosine Triphosphatases↗
PubMed1991

The use of macromolecular protease inhibitors to study liposome-cell interactions.

A method is introduced that quantitates the release of a high molecular weight compound from small unilamellar vesicles. The technique is based on the liposomal encapsulation of trypsin inhibitor from bovine lung. Because liposomes are impermeable to all components of the test system (inhibitor, enzyme, macromolecular substrate), only the free inhibitor released from disturbed liposomes is measured. Using this technique, the exit of the macromolecular solute from liposomes induced by erythrocyte ghosts was studied. The results were compared with the leakage of a low molecular weight fluorescent marker. They indicate that, especially during the first hours of incubation, ghost-induced release of solutes is dependent on their size.

Animals↗
PubMed1990

Macromolecular binding equilibria in the lac repressor system: studies using high-pressure fluorescence spectroscopy.

High hydrostatic pressure coupled with fluorescence polarization has been used to investigate protein subunit interactions and protein-operator association in lac repressor labeled with a long-lived fluorescent probe. On the basis of observation of a concentration-dependent sigmoidal decrease in the dansyl fluorescence polarization, we conclude that application of high hydrostatic pressure results in dissociation of the lac repressor tetramer. The 2-fold decrease in the rotational relaxation time and the high-pressure plateau are consistent with a tetramer to dimer transition. The volume change for tetramer dissociation to dimer is -82 +/- 5 mL/mol. The dissociation constant calculated from the data taken at 4.5 degrees C is 4.3 +/- 1.3 nM. The tetramer dissociation constant increases by a factor of 3 when the temperature is raised from 4.5 to 21 degrees C. A very small effect of inducer binding on the subunit dissociation is observed at 4.5 degrees C; the Kd increases from 4.5 to 7.1 nM. At 21 degrees C, however, inducer binding stabilizes the tetramer by approximately 0.8 kcal/mol. Pressure-induced monomer formation is indicated by the curves obtained upon raising the pH to 9.2. The addition of IPTG shifts the pressure transition to only slightly higher pressures at this pH, indicating that the stabilization of the tetramer by inducer is not as marked as that observed at pH 7.1. From the decrease in the polarization of the dansyl repressor-operator complexes, we also conclude that the application of pressure results their dissociation and that the volume change is large in absolute value (approximately 200 mL/mol). The lac repressor-operator complex is more readily dissociated upon the application of pressure than the tetramer alone, indicating that operator binding destabilizes the lac repressor tetramer.

Dansyl Compounds↗
PubMed1992

Specific macromolecular interactions between tau and the microtubule system.

The microtubule-associated protein Tau, a major component of brain microtubules, shares common repeated C-terminal sequences with the high molecular-weight protein MAP-2. It has been shown that tau peptides V187-G204 and V218-G235, representing two main repeats, induced brain tubulin assembly in a concentration-dependent fashion. The specific roles of these repeats in the interaction of tau with microtubules, and its antigenic nature were investigated using synthetic tau peptides and site-directed monoclonal antibodies. Tau peptides appeared to compete with MAP-2 incorporation into assembled microtubules. The interactions of the tau fragments with beta-tubulin peptides bearing the tau binding domain on tubulin were analyzed by fluorescence spectroscopy. The specificity of the binding was further demonstrated by the reactivity of tau and the tau peptides with a monoclonal anti-idiotypic antibody produced after immunization with the beta-II(422-434) tubulin peptide, as assessed by enzyme-linked immunoassay. Western blots confirmed the interaction of tau with the monoclonal antibody. In addition, immunoassays revealed a competition between the MAP-reacting monoclonal antibody and the tubulin peptide beta-II(422-434) for their interaction with the tau molecule.

Amino Acid Sequence↗
PubMedDate not supplied

Combined use of polycationic peptide and biodegradable macromolecular polymer as a novel gene delivery system: a preliminary study.

Plasmid(p) DNA was condensed by polycationic peptide polylysine (PLL) to be a core and then encapsulated in biodegradable monomethoxy (polyethyleneglycol)-poly(lactide-co-glycolide)-monomethoxy (poly-ethylene glycol) (PELGE) to form core-shell nanoparticles as a novel gene delivery system PPD (PELGE-PLL-DNA). Nanoparticles formed from PPD had several complementary properties such as improved biocompatibility, decreased cytotoxicity, enhanced pDNA integrity, and the characteristic of lysosomal escape as PLGA nanoparticles. The results demonstrated the potential of this PPD as an efficient gene delivery system.

Cell Line, Tumor↗
PubMed1975

Macromolecular synthesis in Streptomyces antibioticus: in vitro systems for aminoacylation and translation from young and old cells.

In vitro systems for the aminoacylation of transfer ribonucleic acid (tRNA) and for polypeptide synthesis have been constructed from young (12-h cultures, not producing actinomycin) and old (48-h cultures, producing actinomycin) cells of Streptomyces antibioticus. When Escherichia coli aminoacyl-tRNA synthetases were used to acylate S. antibioticus tRNA's, it was observed that, per absorbance unit of tRNA, the tRNA's from 48-h cells had a lower ability to accept the amino acids, leucine, serine, pheynlalanine, methionine, and valine than did the tRNA's from 12-h cells. Individual differences were observed between aminoacyl-tRNA synthetases from 12-h cells and those from 48-h cells with respect to the rate and extent of aminoacylation of E. coli tRNA with the five amino acids listed above. In vitro systems for the synthesis of polyphenylalanine have been constructed from 12- and 48-h cells. Ribsomes and soluble enzymes from 12-h cells are more efficient than those from 48-h cells in supporting polyphenylalanine synthesis, and, although the activity of both systems can be stimulated by the addition of E. coli tRNA, the higher level of incorporation observed in the unstimulated 12-h system (ribosomes and soluble enzymes) is maintained. Indeed, the difference in capacity for polyphenylalanine synthesis between in vitro systems from 12- and 48-h cells is greater when the systems are maximally stimulated by E. coli tRNA. Cross-mixing experiments reveal that enzymes from 48-h cells support a slightly higher level of polyphenylalanine synthesis than enzymes from 12-h cells with ribosomes from either cell type, and that the ribosomes are the primary agents responsible for the decreased efficiency of the in vito system from 48-h cells are compared with that from 12-h cells. To determine whether ribosome-associated factors were responsible for the relative inefficiency of the ribosomes from 48-h cells in translation, salt-washed ribosomes from 12- and 48-h cells were examined for their abilities to catalyze polyphenylalanine synthesis. Even after salt washing, ribosomes from 12-h cells were about five times higher in specific activity (counts per minute of polyphenylalanine synthesized per absorbance at 260 nm of ribosomes) than equivalent amounts of ribosomes from 48-h cells. Analysis of the proteins of salt-washed ribosomes of the two cell types by acrylamide gel electrophoresis suggests that the relative amounts of individual proteins present on ribosomes from 12-h cells are different from the amounts present on ribosomes from 48-h cells. These results are discussed in terms of the regulation of translation in S. antibioticus.

Acylation↗
PubMed1979

Clearance of macromolecular and particulate substances from the cerebrospinal fluid system of the rat.

Arachnoid villi in the intracranial dural sinuses constitute the principal sites for absorption of proteins and particulates from the cerebrospinal fluid (CSF) system. Although arachnoid villi in the rat are morphologically less complex than those found in other mammals, their resistance to CSF outflow, as assessed by a graded series of contstant flow manometric infusions, is similar to that found in other species. Moreover, inulin and polystyrene beads, when infused into the spinal subarachnoid space of rats, are rapidly cleared from the CSF system into intracranial dural sinuses. Inulin appeared in sinus blood 3 minutes after onset of infusion and reached concentrations 26 times greater than those found in the systemic circulation; particulate matter in the form of 0.5 micrometer polystyrene beads showed similar efflux characteristics. Hence, the CSF system of the rat is functionally similar to that found in other mammalian species, with arachnoid villi constituting a major efflux route for clearance of macromolecular and particulate substances.

Absorption↗
PubMed2000

Gd-DTPA relaxivity depends on macromolecular content.

Gd-DTPA T(1) relaxivity of water protons was measured at 1.5 T and room temperature as a function of macromolecular content in model systems. Gd-DTPA relaxivity was found to increase with macromolecular concentration. The results of this study indicate that the Gd-DTPA relaxivity in tissue extracellular compartment could be as much as 30-70% higher than that of Gd-DTPA in saline. Quantitative MR analyses that use T(1) as an estimation of local Gd-DTPA concentration require a priori determination of the Gd relaxivity in tissue.

Animals↗
PubMed2005

Snake venom serine proteinases: sequence homology vs. substrate specificity, a paradox to be solved.

Snake venom glands synthesize a variety of serine proteinases capable of affecting the haemostatic system. They act on macromolecular substrates of the coagulation, fibrinolytic, and kallikrein-kinin systems, and on platelets to cause an imbalance of the haemostatic system of the prey. In this review we describe their biochemical/biophysical characteristics, biological activities as well as aspects of their evolution and structure-activity relationship.

Amino Acid Sequence↗
PubMed1982

Role of macromolecular binding site of thrombin molecule in excitation of anticoagulation system.

The reaction of anticoagulation system upon perfusion of humorally isolated (with retained innervation) carotid sinus of a rabbit by alpha-,beta/gamma-, DIP-alpha-thrombin and prethrombin I was studied. DIP-alpha-thrombin without clotting activity was shown to initiate like alpha-thrombin the reflex reaction of anticoagulation system characterized by a sharp increase in non-enzymatic fibrinolysis (by 225%) and total fibrinolytic activity of blood (by 51%). Prethrombin I (thrombin precursor) is also capable of exciting the function of anticoagulation system characterized by an increase in non-enzymatic fibrinolysis (by 82%) and total fibrinolytic activity (by 36%). Furthermore, perfusion of prethrombin I or alpha-thrombin at almost the same molar concentrations resulted in the similar degree of anticoagulation system effector reaction. Reflex response of anticoagulation system was not observed upon perfusion of carotid sinus by beta/gamma-thrombin that has high esterase but little if any clotting activity that appears to be due to molecular changes in the macromolecular binding site region. These data support the suggestion that the effect of anticoagulation system excitation is due to interaction of the macromolecular binding site in the structure of alpha-thrombin with anticoagulation system chemoreceptors.

Animals↗
PubMed1988

The basement membrane and associated structures in the murine endolymphatic sac.

The ultrastructure of the basement membrane of the murine endolymphatic sac was studied under various experimental conditions in labyrinthectomized and ethacrynic acid-treated animals and was compared with normal anatomy. The basement membrane was clearly visualized after staining with ruthenium red or dialyzed iron. The basement membrane of the murine sac consists of two different layers: the lamina rara and the lamina densa. It demarcates the border between the epithelial cells and the subepithelial connective tissue. Our findings suggest that the basement membrane acts as a physical support to the epithelium in the endolymphatic sac. The basement membrane also shows a dynamic capacity to form a new basement membrane, with the result that the lateral intercellular space between contiguous epithelial cells may be integrated with the subepithelial space. This system is believed to act as a macromolecular and bulk water transport system. In the subepithelial space, collagen, reticular and elastic fibrils are found having a close relationship to the basement membrane. The elastic fibres are presumed to play a role in the pressure-regulating mechanism in the endolymphatic sac.

Animals↗
PubMed2006

The "macromolecular tourist": universal temperature dependence of thermal diffusion in aqueous colloidal suspensions.

By performing measurements on a large class of macromolecular and colloidal systems, we show that thermophoresis (particle drift induced by thermal gradients) in aqueous solvents displays a distinctive universal dependence on temperature. For systems of particles interacting via temperature-independent forces, this behavior is strictly related to the solvent thermal expansivity, while an additional, T-independent term is needed to account for the behavior of "thermophilic" (migrating to the warmth) particles. The former relation between thermophoresis and thermal expansion may be exploited to envisage other fruitful studies of colloidal diffusion in inhomogeneous fluids.

Colloids↗
PubMed2003

Emerging trends in oral delivery of peptide and protein drugs.

Most peptide and protein drugs are currently used as parenteral formulations because of their poor oral bioavailability. Development of an effective oral delivery system for these macromolecular drugs requires a thorough understanding of their physicochemical properties, such as molecular weight, hydrophobicity, ionization constants, and pH stability, as well as biological barriers that restrict protein and peptide absorption from the gastrointestinal (GI) tract, including pH variability, enzymatic degradation, and membrane efflux. Various strategies currently under investigation include amino acid backbone modifications, formulation approaches, chemical conjugation of hydrophobic or targeting ligand, and use of enzyme inhibitors, mucoadhesive polymers, and absorption enhancers. However, there is only limited success because of the hostile environment of the GI tract--e.g., strong pH extremes and abundant presence of potent luminal enzymes. This review focuses on the challenges posed by the GI system and how different pharmaceutical approaches can be used to make oral delivery of protein and peptide drugs more feasible. The roles of P-glycoprotein and CYP3A4 in controlling the extent of intestinal absorption and metabolism will also be discussed.

Administration, Oral↗
PubMed2001

Immunological and toxicological implications of short-term studies in animals of pharmaceutical aerosol delivery to the lungs: relevance to humans.

The effects of xenobiotics on the lungs have been studied for many years. In the past 50 years, delivery of drugs to the lungs has been adopted to achieve local effects, specifically for the treatment of asthma. Recently, due to the proximity of the circulating blood supply and to their large surface area, the lungs have been proposed as the port of entry for drugs to obtain systemic effects, particularly for macromolecular compounds of biological origin. Numerous studies regarding drug formulation, delivery systems, and related pharmacokinetics have been reported; however, the concurrent effects of pulmonary delivery of drugs on the physiology of the lung has not been evaluated early in the development process. The prospect of using the lungs for the delivery of biological molecules such as proteins, peptides, and nucleic acids raises the question of the local toxicity of these compounds. Therefore, criteria must be established to study the initial impact of pulmonary drug delivery on the physiology of the lungs. This relates particularly to subtle local and systemic implications of those effects on the transport phenomena that may be contrasted with conventional toxicity studies focused on gross effects.

Administration, Inhalation↗
PubMed2006

Bacteriophage T4 capsid: a unique platform for efficient surface assembly of macromolecular complexes.

We report the first description of a macromolecular complex display system using bacteriophage T4. Decorated with two dispensable outer capsid proteins, Hoc (155 copies) and Soc (810 copies), the 120 nm x 86 nm T4 capsid particle offers a unique binding site-rich platform for surface assembly of hetero-oligomeric complexes. To display the 710 kDa anthrax toxin complex, two bipartite functional fusion proteins, LF-Hoc and LFn-Soc, were constructed. Using a defined in vitro binding system, sequential assembly was performed by first attaching LF-Hoc and/or LFn-Soc to hoc-soc- phage, saturating the Hoc and Soc binding sites. Trypsin-nicked PA63 was then assembled into heptamers through specific interaction with the capsid-exposed LFn domain. EF was then attached to the unoccupied sites of PA63 heptamers, completing the assembly of the tripartite anthrax toxin. Negative electron microscopy showed decoration of each capsid with a layer of heptameric PA63 rings. Up to 229 anthrax toxin complexes, equivalent to a total of 2400 protein molecules and a mass of about 133 MDa (2.7 times the mass of capsid shell), were anchored on a single particle, making it the highest density display reported on any virus. The phage T4 capsid lattice provides a stable biological platform allowing maximum display of large hetero-oligomeric complexes in vitro and offers insights for developing novel vaccines, analysis of protein-protein interactions, and structure determination of complexes.

Antigens, Bacterial↗