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PubMed2004

Interactions of poly(amino acids) in aqueous solution with charged model surfaces--analysis by colloidal probe.

Biomolecules in a confined solution environment may be subject to electrostatic forces with a range up to 100 nm, while van der Waals interaction will account for shorter-range forces. The response of two model poly(amino acids)--poly-L-lysine and poly-L-glutamic acid--has been investigated for a silica/Si-oxide surface at pH 6. The model amino acids were adsorbed, or covalently coupled, to colloidal probes consisting of a microsphere attached to a force-sensing lever. The methodology was based on sensing interaction between the probe and a flat surface through carrying out force versus distance analysis with a scanning force microscope. The results were analyzed within the framework of the conventional DLVO theory. The outcomes illustrate both repulsive and attractive long-range interactions that will hinder, or promote, colloidal biospecies in solution entering the region of attractive short-range interactions at the physical interface. Large 'snap-on' distances were observed for some systems and have been ascribed to compression of the 'soft' functionalized layers. Those observations and measurements of adhesion provided insight into conformation of the adsorbed species and strength of attachment. The results have implications for the efficacy of methods and devices that seek to exploit the properties of micro/nano-fluidic systems.

Data Interpretation, Statistical↗
PubMed2001

Water-soluble poly-(L-glutamic acid)-Gly-camptothecin conjugates enhance camptothecin stability and efficacy in vivo.

The therapeutic efficacy of 20(s)-camptothecin (CPT) is limited in humans by the instability of the active lactone form due to preferential binding of the carboxylate to serum albumin and by difficulty in formulation. Formation of an ester bond with an amino acid via the hydroxyl group at carbon 20 of CPT stabilizes the lactone. Linking CPT to a high molecular weight (MW) anionic polymer enhances solubility and improves distribution to the tumor through enhanced permeability and retention (EPR effect). Poly-(L-glutamic acid) (PG) is an anionic homo-polymer that can theoretically bind one molecule of a drug via the gamma carboxylic acid of each monomeric subunit. It has been used to make a water-soluble PG-paclitaxel conjugate currently in Phase II clinical trials that contains 37% paclitaxel by weight and is administered in a 10 min infusion without pre-medication. We evaluated the anti-tumor activity of PG conjugates of CPT after a single intraperitoneal injection using subcutaneous murine B-16 melanoma tumor growth as an indicator. Interposition of a glycine (gly) linker allowed CPT loading up to 50% w/w on the polymer. Increasing the PG MW from 33 to 49 kDa enhanced the efficacy without altering the maximum tolerated dose (MTD). In athymic mice bearing ectopic human colon or lung tumors, efficacy was enhanced compared to free camptothecin. Thus, as with paclitaxel, conjugation of CPT to PG enhanced pharmaceutical properties and preclinical efficacy.

Animals↗
PubMed2005

In vitro enzymatic degradation of nanoparticles prepared from hydrophobically-modified poly(gamma-glutamic acid).

Amphiphilic poly(gamma-glutamic acid) (gamma-PGA) was prepared by the introduction of L-phenylalanine ethylester (L-PAE) as a side chain. This gamma-PGA-graft-L-PAE formed monodispersed nanoparticles in water. The particle size of the gamma-PGA nanoparticles could be controlled by the degree of L-PAE grafting. The hydrolytic degradation and enzymatic degradation by gamma-glutamyl transpeptidase (gamma-GTP) of these gamma-PGA nanoparticles was studied by gel permeation chromatography (GPC) and scanning electron microscopy (SEM). The hydrolysis ratio of gamma-PGA was found to decrease upon increasing the hydrophilicity of the gamma-PGA. The degradation of the gamma-PGA backbone by gamma-GTP resulted in a dramatic change in nanoparticle morphology. With increasing time, the gamma-PGA nanoparticles reduced in size and finally disappeared completely.Time-course of the changes in the morphology of the gamma-PGA nanoparticles following incubation with gamma-glutamyl transpeptidase.

Biodegradation, Environmental↗
PubMedDate not supplied

Noninvasive visualization of in vivo drug delivery of poly(L-glutamic acid) using contrast-enhanced MRI.

Biomedical imaging is valuable for noninvasive investigation of in vivo drug delivery with polymer conjugates. It can provide real-time information on pharmacokinetics, biodistribution, and drug delivery efficiency of the conjugates. Noninvasive visualization of in vivo drug delivery of polymer conjugates with contrast-enhanced magnetic resonance imaging (MRI) was studied with paramagnetically labeled poly(L-glutamic acid) in an animal tumor model. Poly(L-glutamic acid) is a biocompatible and biodegradable drug carrier for diagnostics and therapeutics. Poly(L-glutamic acid)-1,6-hexanediamine--(Gd-DO3A) conjugates with molecular weights of 87, 50, and 28 kDa and narrow molecular weight distributions were prepared and studied in mice bearing MDA-MB-231 human breast cancer xenografts. Contrast-enhanced MRI resulted in real-time and three-dimensional visualization of blood circulation, pharmacokinetics, biodistribution, and tumor accumulation of the conjugates, and the size effect on these pharmaceutics properties. The conjugate of 28 kDa rapidly cleared from the circulation and had a relatively lower tumor accumulation. The conjugates with higher molecular weights exhibited a more prolonged blood circulation and higher tumor accumulation. The difference between the conjugates of 87 and 50 kDa was not significant. Contrast-enhanced MRI is effective for noninvasive real-time visualization of in vivo drug delivery of paramagnetically labeled polymer conjugates.

Animals↗
PubMed2002

Depletion of free 30S ribosomal subunits in Escherichia coli by expression of RNA containing Shine-Dalgarno-like sequences.

We have constructed synthetic coding sequences for the expression of poly(alpha,L-glutamic acid) (PLGA) as fusion proteins with dihydrofolate reductase (DHFR) in Escherichia coli. These PLGA coding sequences use both GAA and GAG codons for glutamic acid and contain sequence elements (5'-GAGGAGG-3') that resemble the consensus Shine-Dalgarno (SD) sequence found at translation initiation sites in bacterial mRNAs. An unusual feature of DHFR-PLGA expression is that accumulation of the protein is inversely related to the level of induction of its mRNA. Cellular protein synthesis was inhibited >95% by induction of constructs for either translatable or untranslatable PLGA RNAs. Induction of PLGA RNA resulted in the depletion of free 30S ribosomal subunits and the appearance of new complexes in the polyribosome region of the gradient. Unlike normal polyribosomes, these complexes were resistant to breakdown in the presence of puromycin. The novel complexes contained 16S rRNA, 23S rRNA, and PLGA RNA. We conclude that multiple noninitiator SD-like sequences in the PLGA RNA inhibit cellular protein synthesis by sequestering 30S small ribosomal subunits and 70S ribosomes in nonfunctional complexes on the PLGA mRNA.

Base Sequence↗
PubMedDate not supplied

Multivalent conjugates of poly-gamma-D-glutamic acid from Bacillus licheniformis with antibody F(ab') and glycopeptide ligands.

Poly-gamma-D-glutamic acid from Bacillus licheniformis is a water-soluble, nontoxic, nonimmunogenic exopolymer. Using synthetic linkers, the alpha-carboxylate side chains of PGA were conjugated to an exposed thiol side chain of an antibody F(ab') fragment, Mc109F4. Analysis of the PGA-Mc109F4 conjugate by gel filtration HPLC revealed a mixture of multivalent conjugates. The PGA-Mc109F4 conjugate retained biological activity, but showed a lower binding affinity to target BCL3B3 cells than free Mc109F4 F(ab')(2) by flow cytometry, and a lower efficacy for BCL3B3 growth inhibition than free Mc109F4 F(ab')(2). PGA was also conjugated with the free amino group of glycopeptide antibiotic vancomycin. The PGA-vancomycin conjugate showed slightly lower antibacterial activity than free vancomycin versus susceptible Bacillus subtilis, but slightly higher activity versus intrinsically resistant Leuconostoc mesenteroides.

Antibodies, Neoplasm↗
PubMed2002

Poly(glutamic acid) poly(ethylene glycol) hydrogels prepared by photoinduced polymerization: Synthesis, characterization, and preliminary release studies of protein drugs.

A class of new biodegradable hydrogels based on poly(ethylene glycol) methacrylate-graft-poly(glutamic acid) and poly(ethylene glycol) dimethacrylate was synthesized by photoinduced polymerization. Because all the polymeric constituents were highly hydrophilic, crosslinking could be performed in aqueous solutions. This type of crosslinked hydrogel was prepared by modifying a select number of acidic side-groups on poly(glutamic acid) with poly(ethylene glycol) methacrylate. These modified chains were then crosslinked in the presence of poly(ethylene glycol) dimethacrylate under a photoinduced polymerization at a wavelength of 365 nm. Swelling experiments were conducted to study the crosslinking density, pH-responsive behavior, and degradation of the hydrogel. Results showed that the degree of swelling of this type of hydrogels increased as the crosslinker concentration (or density) was reduced. Because of the presence of acidic side chains on poly(glutamic acid), swelling behavior was found to be pH-responsive, increasing at high pH in response to the increase in the amount of ionized acidic side chains. The degradation rate of these hydrogels also varied with pH. More rapid degradation was observed under stronger alkaline conditions because of the hydrolysis of the ester bonds between the crosslinker and the polymer backbone. Practically useful degradation rates could be achieved for such hydrogels under physiological conditions. Drug release rates from these hydrogels were found to be proportional to the protein molecular weight and the crosslinker density; increasing at lower protein molecular weight or crosslinker density. The preliminary findings presented in this article suggest that this class of biodegradable hydrogels could be an attractive avenue for drug delivery applications. The specific photoinduced crosslinking chemistry used would permit hydrogels to be synthesized in existence of the entrapped macromolecular drugs including peptides, proteins, and cells. In addition, the rapid feature of this polymerization procedure along with the ability to perform hydrogel synthesis and drug loading in an aqueous environment would offer great advantages in retaining drug activity during hydrogel synthesis.

Biocompatible Materials↗
PubMedDate not supplied

Poly(l-glutamic acid) Gd(III)-DOTA conjugate with a degradable spacer for magnetic resonance imaging.

The clinical application of macromolecular Gd(III) complexes as MRI contrast agents is impeded by their slow excretion and potential toxicity due to the release of Gd(III) ions caused by the metabolism of the agents. A polymer Gd(III) chelate conjugate with a cleavable spacer has been designed to solve this problem. Poly(l-glutamic acid)-cystamine-[Gd(III)-DOTA] was prepared by the conjugation of DOTA to PGA (MW = 50,000) via cystamine, a cleavable disulfide spacer, followed by the complexation with GdCl(3). A Gd(III) DOTA chelate derivative was readily released from the polymer conjugate in the incubation with cysteine, an endogenous plasma thiol. The conjugate produced significant MRI blood pool contrast enhancement in nude mice bearing OVCAR-3 human ovarian carcinoma xenographs. Less significant contrast enhancement was observed for a small molecular contrast agent, Gd(DTPA-BMA). The pharmacokinetic MRI study showed that the Gd(III) chelate from the conjugate accumulated in the urinary bladder in a similar kinetic pattern to Gd(DTPA-BMA), suggesting that the chelate was released by the endogenous thiols and excreted through renal filtration. The preliminary results suggest that this novel design has a great potential to solve the safety problem of macromolecular MRI contrast agents.

Animals↗
PubMedDate not supplied

Paclitaxel and water-soluble poly (L-glutamic acid)-paclitaxel, induce direct chromosomal abnormalities and cell death in a murine metastatic melanoma cell line.

The purpose of this study was to demonstrate the effects of paclitaxel and water-soluble poly (L-glutamic acid)-paclitaxel (PG-TXL), on chromosome morphology, telomeric associations, and induction of cell death in a murine melanoma cell line (K-1735 clone X-21). Murine melanoma cells were treated with various concentrations (0.1 microgram, 1.0 microgram, 4.0 micrograms, and 8.0 micrograms/ml) of paclitaxel alone, PG alone, or PG-TXL for 2 hr and 4 hr and harvested immediately without recovery. We found that: (1) the frequency of metaphases with telomeric associations increased, (2) metaphases had clumped and distorted chromosome morphology, (3) cells accumulated in metaphase (mitotic arrest), and (4) cell death had been induced. Cells treated with PG-TXL showed more such abnormalities than did cells treated with either paclitaxel or PG alone. Our preliminary results indicate that PG-TXL may be superior to paclitaxel alone in inducing cytotoxic effects, and these effects could be mediated by various chromosomal abnormalities in cancer cells.

Animals↗
PubMedDate not supplied

Preparation of nanoparticles composed of chitosan/poly-gamma-glutamic acid and evaluation of their permeability through Caco-2 cells.

In this study, a novel nanoparticle system for paracellular transport was prepared using a simple and mild ionic-gelation method upon addition of a poly-gamma-glutamic acid (gamma-PGA) solution into a low-molecular-weight chitosan (low-MW CS) solution. The particle size and the zeta potential value of the prepared nanoparticles can be controlled by their constituted compositions. The results obtained by the TEM and AFM examinations showed that the morphology of the prepared nanoparticles was spherical in shape. Evaluation of the prepared nanoparticles in enhancing intestinal paracellular transport was investigated in vitro in Caco-2 cell monolayers. It was found that the nanoparticles with CS dominated on the surfaces could effectively reduce the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers. After removal of the incubated nanoparticles, a gradual increase in TEER was noticed. The confocal laser scanning microscopy observations confirmed that the nanoparticles with CS dominated on the surface were able to open the tight junctions between Caco-2 cells and allowed transport of the nanoparticles via the paracellular pathways.

Caco-2 Cells↗
PubMed1998

Hemostatic capability of rapidly curable glues from gelatin, poly(L-glutamic acid), and carbodiimide.

The hemostatic capability of rapidly curable glues composed of gelatin and poly(L-glutamic acid) (PLGA) was compared with that of the conventional fibrin glue. The hydrogels produced from mixed gelatin and PLGA aqueous solution within several seconds by addition of water-soluble carbodiimide (WSC) was applied to the dog spleen injured by needle pricking. The WSC-catalyzed gelatin-PLGA glues exhibited higher hemostatic capability than the fibrin glue. The total amount of bleeding from the injured spleen until hemostasis when the gelatin-PLGA hydrogel glues were applied was significantly smaller than that of the fibrin glue application. The gelatin-PLGA glue application enhanced the success rate of complete hemostasis to a significantly greater extent than the fibrin glue, while the frequency of glue applications until achieving complete hemostasis decreased. The gelatin PLGA hydrogels strongly adhered to the surface of dog spleen, whereas the fibrin hydrogel was easily detached from the spleen surface. It was concluded that this strong adhesion mechanically suppressed the bleeding, leading to enhanced hemostasis by the rapidly curable gelatin-PLGA glues.

Animals↗
PubMed2002

Direct observation of the multistep helix formation of poly-L-glutamic acids.

The helix formation dynamics of poly-L-glutamic acids (PGAs) were observed by the microsecond-resolved Fourier transform infrared (FTIR) and circular dichroism (CD) spectroscopies. The helix formation of 34-residue PGA from random coil at pH (or pD for FTIR) 8.0 was initiated by a pH jump to 4.9 using the rapid solution mixer whose mixing dead time is 50 micros. The amide I' line in the time-resolved FTIR spectra exhibited the fast (<100 micros) increase of the total helical content. The time-resolved CD spectra of the same process also showed the fast (<150 micros) formation of short helical segments (5 +/- 1 residues), which was followed by the slower (<1 ms) elongation of the short helices to longer helices (>10 residues). Similar dynamics were observed for the same pH jump of approximately 190-residue PGA, although there were additional steps that made the helix formation of approximately 190-residue PGA more complex. The observed multistep helix formation is likely caused by the strong hydrogen-bonding interactions between the protonated side chains of PGAs.

Circular Dichroism↗
PubMed1993

[Studies of two conjugates of monoclonal antibody (HIM6) and cytosine arabinoside].

Two conjugates (HIM6-PAD-ara C and HIM6-PLGA-ara C) of the anticancer agent cytosine arabinoside (ara C) and monoclonal antibody (HIM6) against human leukocytes were prepared with dextran T-40 and poly-L-glutamic acid as intermediate carriers, respectively. The drug-antibody conjugates maintained most of the original antigen-binding activity of the free antibody. The ratio of positive bound cells was found to be > 90% by an indirect immunofluorescence assay. The cytotoxicities of HIM6-PAD-ara C and HIM6-PLGA-ara C against antibody-reactive human leukemia HL60 cells were lower than those of free ara C and a mixture of ara C and HIM6 (IC50s of HIM6-PAD-ara C, HIM6-PLGA-ara C, ara C and the mixture of ara C and HIM6 were 0.212, 0.102, 0.028 and 0.024 microgram/ml, respectively), but were similar to those of the intermediates PAD-ara C and PLGA-ara C. On the other hand, these two conjugates showed no cytotoxic its against non-target hepatoma cells. These results indicate that the specific cytotoxicity of the conjugate depends on specific binding to the target surface antigen by the monoclonal antibody in the conjugate molecule.

Antibodies, Monoclonal↗
PubMed2005

Multivalent ion/polyelectrolyte exchange processes in exponentially growing multilayers.

We show, in this paper that multivalent ferrocyanide anions can penetrate into exponentially growing (PGA/PAH)n multilayer films whatever the nature of the last deposited layer. These ions are not able to diffuse out of the film when it is brought in contact with a pure buffer solution. However, the contact of this film with a poly(allylamine) (PAH) or a poly(L-glutamic acid) (PGA) solution leads to the release of ferrocyanide ions from the multilayer. It is shown that the release of ferrocyanide anions, when the film is in contact with a PGA solution, is due to the diffusion of the PGA chains into the film so that an exchange between ferrocyanide ions and PGA chains takes place inside the film. On the other hand, PAH chains do not diffuse into PGA/PAH multilayers. When the film is then brought in contact with a PAH solution, the PAH chains from the solution are expected to strongly interact with the ferrocyanide ions and thus induce a diffusion mechanism of the multivalent anions out of the film, the film/solution interface playing the role of a sink for these ions. This work thus shows that interactions between multivalent ions and exponentially growing films are much more complex than expected at first sight and that polyelectrolyte multilayers must be seen as dynamic entities in which diffusion and exchange processes can take place.

Adsorption↗
PubMed2004

Characterization of Bacillus subtilis gamma-glutamyltransferase and its involvement in the degradation of capsule poly-gamma-glutamate.

During early stationary phase, Bacillus subtilis NAFM5 produces capsular poly(gamma-glutamic acid) (gammaPGA, 2x10(6) Da), which contains D- and L-glutamate, and then degrades it during late stationary phase. The gamma-glutamyltransferase (EC 2.3.2.2; GGT) of this strain successively hydrolysed gammaPGA from the amino-terminal end, to yield both D- and L-glutamate. This enzyme was specifically synthesized during the stationary phase through transcriptional activation of the corresponding ggt gene by the ComQXPA quorum-sensing system. A ggt knockout mutant degraded gammaPGA into 1x10(5) Da fragments, but not any further, indicating that the capsule gammaPGA is first internally degraded by an endo-type of gammaPGA hydrolase into 1x10(5) Da intermediates, then externally into glutamates via GGT. Due to its inability to generate the glutamates from the capsule, the ggt mutant sporulated more frequently than the wild-type strain. The results show that B. subtilis GGT has a powerful exo-gamma-glutamyl hydrolase activity that participates in capsule gammaPGA degradation to supply stationary-phase cells with constituent glutamates.

Bacillus subtilis↗
PubMed2006

Layer-by-layer-assembled microfiltration membranes for biomolecule immobilization and enzymatic catalysis.

Multilayer assemblies of polyelectrolytes, for protein immobilization, have been created within the membrane pore domain. This approach was taken for two reasons: (1) the high internal membrane area can potentially increase the amount of immobilized protein, and (2) the use of convective flow allows uniform assembly of layers and eliminates diffusional limitations after immobilization. To build a stable assembly, the first polyelectrolyte layer was covalently attached to the membrane surface and inside the pore walls. Either poly(L-glutamic acid) (PLGA) or poly(L-lysine) (PLL) was used in this step. Subsequent deposition occurs by multiple electrostatic interactions between the adsorbing polyelectrolyte [poly(allylamine) hydrochloride (PAH) or poly(styrenesulfonate) (PSS)] and the oppositely charged layer. Three-layer membranes were created: PLL-PSS-PAH or PLGA-PAH-PSS, for an overall positive or negative charge, respectively. The overall charge on both the protein and membrane plays a substantial role in immobilization. When the protein and the membrane are oppositely charged, the amount immobilized and the stability within the polyelectrolyte assembly are significantly higher than for the case when both have similar charges. After protein incorporation in the multilayer assembly, the active site accessibility was comparable to that obtained in the homogeneous phase. This was tested by affinity interaction (avidin-biotin) and by carrying out two reactions (catalyzed by glucose oxidase and alkaline phosphatase). Besides simplicity and versatility, the ease of enzyme regeneration constitutes an additional benefit of this approach.

Adsorption↗
PubMed2004

Synthesis of a novel structural triblock copolymer of poly(gamma -benzyl-l-glutamic acid)-b-poly(ethylene oxide)-b-poly(epsilon-caprolactone).

A novel structural triblock copolymer of poly(gamma-benzyl-l-glutamic acid)-b-poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PBLG-PEO-PCL) was synthesized by a new approach in the following three steps: (1) sequential anionic ring opening polymerization (ROP) of ethylene oxide and epsilon-caprolactone with an acetonitrile/potassium naphthalene initiator system to obtain a diblock copolymer CN-PEO-PCL with a cyano end-group; (2) conversion of the CN end-group into NH2 end-group by hydrogenation to obtain NH2-PEO-PCL; (3) ROP of gamma-benzyl-l-glutamate-N-carboxyanhydrides (Bz-l-GluNCA) with NH2-PEO-PCL as macroinitiator to obtain the target triblock copolymer. The structures from CN-PEO precursor to the triblock copolymers were confirmed by FT-IR and 1H NMR spectroscopy, and their molecular weights were measured by gel permeation chromatography. The monomer of Bz-l-GluNCA can react almost quantitatively with the amino end-groups of NH2-PEO-PCL macroinitiator by ROP.

Biocompatible Materials↗
PubMed2004

Human serum albumin self-assembly on weak polyelectrolyte multilayer films structurally modified by pH changes.

Adsorption of proteins onto film surfaces built up layer by layer from oppositely charged polyelectrolytes is a complex phenomenon, governed by electrostatic forces, hydrogen bonds, and hydrophobic interactions. The amounts of the interacting charges, however, both in polyelectrolytes and in proteins adsorbed on such films are a function of the pH of the solution. In addition, the number and the accessibility of free charges in proteins depend on the secondary structure of the protein. The subtle interplay of all these factors determines the adsorption of the proteins onto the polyelectrolyte film surfaces. We investigated the effect of these parameters for polyelectrolyte films built up from weak "protein-like" polyelectrolytes (i.e., polypeptides), poly(L-lysine) (PLL), and poly(glutamic acid) (PGA) and for the adsorption of human serum albumin (HSA) onto these films in the pH range 3.0-10.5. It was found that the buildup of the polyelectrolyte films is not a simple function of the pure charges of the individual polyelectrolytes, as estimated from their respective pKa values. The adsorption of HSA onto (PLL/PGA)n films depended strongly on the polyelectrolyte terminating the film. For PLL-terminated polyelectrolyte films, at low pH, repulsion, as expected, is limiting the adsorption of HSA (having net positive charge below pH 4.6) since PLL is also positively charged here. At high pH values, an unexpected HSA uptake was found on the PGA-ending films, even when both PGA and HSA were negatively charged. It is suggested that the higher surface rugosity and the decrease of the alpha-helix content at basic pH values (making accessible certain charged groups of the protein for interactions with the polyelectrolyte film) could explain this behavior.

Absorption↗