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In order to prepare ecologically and biologically safety physical cross-linked hydrogel of a-PVA/NaCl/H(2)O system, we prepared blend hydrogel of natural polymeric binders like gelatin and starch in above system, and effect of these binder additives were evaluated on terbutaline release kinetics. Terbutaline (1%) hydrogels of a-PVA(7%)/NaCl(11%)/H(2)O and a-PVA(7%)/H(2)O system (Cyclic FT process) were prepared along with various concentrations of gelatin and soluble starch by feed-mixture dissolving method. In case of a-PVA/NaCl/H(2)O system only one cycle gelation was done at -20 degrees C for 24 h. On the other hand 3 cycles were done by freezing at -30 degrees C for 16 h followed by thawing at room temperature for 8 h. Drug release was done by paddle method (USP type II) with a rotation of 50 rpm at 37 degrees C in distilled water. Swelling of the gel was done at 37 degrees C for 45 h and melting temperatures of the gel were also studied using the upside-down test tube method. Comparatively lower values of release rate, diffusion coefficient and kinetic constant were found from the blend hydrogel of a-PVA/starch/NaCl/H(2)O system. When % cumulative release was plotted vs. square root of time it showed straight lines, which indicated Higuchi Matrix Dissolution Model. Inclusion of starch binder increased the degree of swelling compared with that of gelatin. 15 h was found as equilibrium swelling time. A Fickian swelling of this blend hydrogel system indicated the swelling controlled Fickian diffusion type of drug release. Melting temperatures of the blend hydrogels were characteristically higher (94-95 degrees C) than that of cyclic FT (72-76 degrees C), resulting a thermostable hydrogel for biological system. SEM morphological studies of gel surface indicated the well-developed interpenetrating macromolecular network structure like fish net in starch blend gel prevails over other hydrogel studied here. Gelatin has got characteristic tunnel (200 microm in diameter) inside the macromolecular network that contributes this system higher release kinetics than that of starch.
New and emerging drug delivery systems for traditional drugs and the products of biotechnology are discussed, and the role of the pharmacist in ensuring the appropriate use of these systems is outlined. Advantages of advanced drug delivery systems over traditional systems are the ability to deliver a drug more selectively to a specific site; easier, more accurate, less frequent dosing; decreased variability in systemic drug concentrations; absorption that is more consistent with the site and mechanism of action; and reductions in toxic metabolites. Four basic strategies govern the mechanisms of advanced drug delivery: physical, chemical, biological, and mechanical. Oral drug delivery systems use natural and synthetic polymers to deliver the product to a specific region in the gastrointestinal tract in a timely manner that minimizes adverse effects and increases drug efficacy. Innovations in injectable and implantable delivery systems include emulsions, particulate delivery systems, micromolecular products and macromolecular drug adducts, and enzymatic-controlled delivery. Options for noninvasive drug delivery include the transdermal, respiratory, intranasal, ophthalmic, lymphatic, rectal, intravaginal, and intrauterine routes as well as topical application. Rapid growth is projected in the drug delivery systems market worldwide in the next five years. Genetic engineering has mandated the development of new strategies to deliver biotechnologically derived protein and peptide drugs and chemoimmunoconjugates. The role of the pharmacist in the era of advanced drug delivery systems will be broad based, including administering drugs, compounding, calculating dosages based on pharmacokinetic and pharmacodynamic monitoring, counseling, and research. The advent of advanced drug delivery systems offers pharmacists a new opportunity to assume an active role in patient care.
The design, synthesis and properties of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers as carriers of anticancer drugs are reviewed. Macromolecular therapeutics based on HPMA copolymers are biocompatible, preferentially accumulate in tumors, and possess a higher anticancer efficacy than low molecular weight drugs. Novel designs of HPMA copolymer carriers resulted in long-circulating conjugates and gene and oligonucleotide delivery systems. HPMA copolymer based macromolecular therapeutics were active against numerous cancer models and are in clinical trials. The data obtained indicated that macromolecular therapeutics activated different signaling pathways and possessed a different mechanism of action than free drugs. This bodes well for the success of future research aimed at identification of new intracellular molecular targets as a basis for the design of the second generation of macromolecular therapeutics.
Quantitative analysis of chromatin electrophoretic mobility (mu) in agarose gels provides a measure of three structural parameters: average surface electrical charge density, which is proportional to the gel-free mu (mu 0), effective radius (Re), and particle deformability [Fletcher, T. M., Krishnan, U., Serwer, P., & Hansen, J. C. (1994) Biochemistry 33, 2226-2233]. To determine whether the intramolecular conformational changes associated with salt-dependent chromatin folding influence these electrophoretic parameters, defined oligonucleosomes were reconstituted from monodisperse tandemly repeated 5S DNA and varying amounts of histone octamers. These oligonucleosomes were subjected to both quantitative agarose gel electrophoresis and analytical velocity ultracentrifugation in buffers containing 0-2 mM MgCl2. Ionic conditions that caused a 40% increase in the oligonucleosome sedimentation coefficient (s20,w) also caused both a 30% decrease in Re and a 60% decrease in the magnitude of the mu 0. Furthermore, the Mg(2+)-dependent changes in s20,w, Re, and mu 0 each exhibited the same nonlinear dependence on the degree of nucleosome saturation of the DNA. These data demonstrate that quantitative agarose gel electrophoresis can be used to detect and characterize the process of chromatin folding. In addition, they suggest that this approach can be used for characterization of the conformational dynamics of many other types of macromolecular assemblies, including those systems that are not yet amenable for study by more traditional quantitative biophysical techniques.
Inflammatory edema is associated with vascular macromolecular leakage. Various patterns of vascular macromolecular leakage may be produced depending on the severity and nature of the inflammatory stimulus resulting in transient and/or sustained increases in macromolecular permeability. Inflammatory stimuli which cause endothelial cell damage or destruction induces non-specific increases in macromolecular permeability in all injured microvessels. In the absence of endothelial cell injury, macromolecular permeability is increased in inflammation subsequent to the formation of inter-endothelial cell gaps in capillaries and venules. Various inflammatory mediators including histamine-type agents, immune complexes, and activated leukocytes induce venular large junctional gap formation. Individual, simultaneous, or sequential mediator effects could explain the various patterns of venular macromolecular leakage found in inflammation. The formation of endothelial cell junctional gaps in capillaries cannot be attributed to any known inflammatory mediator. The classical static small pore/large pore model of the microvascular membrane cannot explain the increased extravasation of macromolecules in inflammation. A dual static/variable large pore system would best describe macromolecular transport under normal and inflammatory conditions.
Evidence for the presence of an enkephalinergic system in the ganglia of the pond snail, Lymnaea stagnalis, has been obtained with 3 experimental approaches. Scatchard analysis with [3H]etorphine reveals a monophasic high-affinity opiate binding site (Kd 2.3 nM) which is naloxone-sensitive. Immunocytochemical localization of Met- and Leu-enkephalin-like substances as well as alpha-MSH- and ACTH-like materials was demonstrated within specific populations of neurons. Substances with Met- and Leu-enkephalin and Met-enkephalin sulfoxide RIA reactivities were detected also in HPLC fractions corresponding to the retention times of authentic enkephalin standards. Together, the results provide strong evidence for the presence of enkephalinergic mechanisms in the nervous system of Lymnaea stagnalis. Additionally, the report provides indirect evidence for the existence of a macromolecular opioid precursor. This enkephalinergic system shows striking similarities to opioid mechanisms found in vertebrates and bespeaks a common evolutionary origin.
The virion of Leishmania RNA virus is predicted to be composed of a 742-amino-acid major capsid protein and a small percentage of capsid-polymerase fusion molecules. Recently, the capsid protein alone was expressed and shown to spontaneously assemble into viruslike particles. Since the major structural protein of the virion shell self-assembles into viruslike particles when expressed in the baculovirus expression system, assembly of the virion can be studied by mutational analysis and expression of a single open reading frame. In this study, several deletions and one addition of the capsid protein of Leishmania RNA virus LRV1-4 were generated. These mutants show different degrees of assembly. Assembly domains are being identified such that the capsid protein may be used as a macromolecular packaging and delivery system for Leishmania species.
Efficient transdermal drug delivery of large hydrophilic drugs is challenging. Here we report that the short synthetic peptide, ACSSSPSKHCG, identified by in vivo phage display, facilitated efficient transdermal protein drug delivery through intact skin. Coadministration of the peptide and insulin to the abdominal skin of diabetic rats resulted in elevated systemic levels of insulin and suppressed serum glucose levels for at least 11 h. Significant systemic bioavailability of human growth hormone was also achieved when topically coadministered with the peptide. The transdermal-enhancing activity of the peptide was sequence specific and dose dependent, did not involve direct interaction with insulin and enabled penetration of insulin into hair follicles beyond a depth of 600 microm. Time-lapse studies suggested that the peptide creates a transient opening in the skin barrier to enable macromolecular drugs to reach systemic circulation.
Nonspecific interactions between individual macro-molecules and their immediate surroundings ("background interactions") within a medium as heterogeneous and highly volume occupied as the interior of a living cell can greatly influence the equilibria and rates of reactions in which they participate. Background interactions may be either repulsive, leading to preferential size-and-shape-dependent exclusion from highly volume-occupied elements of volume, or attractive, leading to nonspecific associations or adsorption. Nonspecific interactions with different constituents of the cellular interior lead to three classes of phenomena: macromolecular crowding, confinement and adsorption. Theory and experiment have established that predominantly repulsive background interactions tend to enhance the rate and extent of macromolecular associations in solution, whereas predominantly attractive background interactions tend to enhance the tendency of macromolecules to associate on adsorbing surfaces. Greater than order-of-magnitude increases in association rate and equilibrium constants attributable to background interactions have been observed in simulated and actual intracellular environments.
Polyethylene glycol (PEG, 4%)-precipitated macromolecular IgG isolated from the sera of 20 patients with systemic lupus erythematosus (SLE) and 15 control subjects was analyzed for its IgG isotype concentration by single radial immunodiffusion. PEG precipitates from SLE sera had higher mean levels of IgG1, IgG2 and IgG3 and lower IgG4 than PEG precipitates isolated from normal sera although only the IgG2 levels were significantly different. Using an anti-complementary assay there was a significant correlation between the ability of parent sera to fix complement and the absolute levels of PEG precipitable IgG1, IgG2 and IgG3. These data suggest that the ability of immune complexes in the sera of patients with SLE to fix complement is dependent on their IgG subclass composition.
Dendrimers are synthetic, highly branched, mono-disperse macromolecules of nanometer dimensions. Started in the mid-1980s, the research investigations into the synthetic methodology, physical and chemical properties of these macromolecules are increasing exponentially with growing interest in this field. Potential applications for dendrimers are now forthcoming. Properties associated with these dendrimers such as uniform size, water solubility, modifiable surface functionality and available internal cavities make them attractive for biological and drug-delivery applications.
Cellular motile systems as diverse as muscle and the mitotic spindle have been compared by their specific power output: the maximum power they develop per unit of engine volume. Striated muscles and flagella have high specific output; their performance is comparable to that of typical automobile engines. The cytokinetic furrow and the mitotic spindle have very much lower specific power output. The furrow's output is 7,000 times lower than muscle and the spindle's is 300,000 times lower. Different macromolecules have been used to generate power in systems with similar output (muscles and flagella) and, conversely, the same macromolecular motor has been used in systems with very different output (muscles and cytokinetic furrows). The common feature amid this diversity is adaptation to a particular biological role, which specific power output reflects very well. High values are found where a powerful, compact engine should be advantageous, while low values are found where precision, not power, matters most.
This review article describes three aspects of polymeric drugs. The general mechanism of the EPR (enhanced permeability and retention) effect and factors involved in the effect are discussed, in view of the advantages of macromolecular therapeutics for cancer treatment, which are based on the highly selective EPR-related delivery of drug to tumor. Also described are advantages of more general water-soluble polymeric drugs as primary anticancer agents, using SMANCS as an example. Last, SMANCS/Lipiodol is discussed with reference to the type of formulation for arterial injection with most pronounced tumor selective delivery, as well as its advantages, precautions, and side effects from the clinical standpoint.
Estradiol-3-benzoate (EB), an ester derivative of the main oestrogen hormone estradiol, was chemically modified and bound to poly(alpha,beta-(N-2-hydroxyethyl-DL-aspartamide))-poly(alpha,beta-(N-2-aminoethyl-DL-aspartamide)) copolymer (PAHA). EB was first converted to estradiol-3-benzoate-17-(benzotriazole-1-carboxylate), which readily reacted with amino groups in PAHA affording the polymer-drug conjugate PAHA-EB. In PAHA-EB estradiol moiety was covalently bound to the polymeric carrier by carbamate linkage, through non-toxic ethylenediamine spacer. The synthesized compound is a potential hydrosoluble estradiol prodrug.
This paper describes an original methodology for determining macromolecular antigen levels by polarization of fluorescence. it involves the use of fluorescent derivatives of Fab fragments of a monoclonal antibody (Mr 50,000), whose fluorescence polarization rises significantly when it combines with a macromolecular antigen. An experimental system (Fab anti-aldosterone and aldosterone--bovine serum albumin (BSA)) is studied to test this methodology, which was then used to develop an immunoassay for human immunoglobulin M (IgM), using anti-mu chain Fabs. In the two assays, the binding stoichiometry of Fab/antigen was 10/1 and 8/1 for aldosterone--BSA and IgM, respectively. The lower limit of detection of the IgM assay was 0.8 microgram/ml and thus it was applicable to clinical detection of IgM concentrations.
The specialized structure and function of the lymphatics has stimulated considerable interest in both site-specific drug delivery to the lymph and lymphoid tissue, and delivery to the systemic circulation via lymphatic transport mechanisms. In this review, drug access to the lymphatic system from the vasculature or interstitium after parenteral administration, and from the gastrointestinal tract after enteral administration, is discussed. Macromolecular and lipophilic prodrug approaches to lymphatic delivery and the use of microparticulate systems such as microspheres, liposomes, and colloidal carbon are also examined and discussed.
The possibility of isolating lactic whey proteins (LWP) in the form of insoluble complexes (IC) with apple pectin was studied. The effect of pH, ionic strength (mu, NaCl), temperature (T degree C), pectin weight fraction (X3%) and the total concentration of macromolecular components in the system (Ws) on isolation has been considered. The process has been characterized by LWP yield in the composition IC--P, percentage and the extent of protein concentration in the concentrated phase (IC)--F. The mixing of lactic whey with a pectin solution usually yielded an IC (10% less than or equal to X3 less than or equal to 90%). The dependence of P on X3 is of an extreme nature with a maximum of 85% at X3 = 60%. The following conditions correspond to the maximum LWP yield (90%) in the complex composition: pH 3.4, mu = 0.01, T = 5-20 degrees C, X3 = 60%, Ws = 0.5%. At compositions of the system corresponding to the maximum P value (X3 = 60%) practically all the LWP fractions are present in the concentrated phase. If X3 much greater than 60% or X3 much less than 60% alpha-lactalbumin is practically absent in the concentrated phase. Usually, minimum F values (2.5-4.0) correspond to maximum protein yield at X3 = 60%. At X3 greater than 70% and X3 less than 50% F values may be considerably higher (20 times and more). A decrease in the pectin methylation degree from 56.7% down to 15.4% does not affect F. The maximum protein yield (94%) occurs when low methylated pectin is used. The character of the dependence of F on X3 is explained according to similar processes of complex gel formation and the processes of gel formation in polymer solutions.