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PubMedDate not supplied

Comblike complexes of bacterial poly(gamma,d-glutamic acid) and cationic surfactants.

The ability of microbally produced poly(gamma,d-glutamic acid) to form stable polyelectrolyte-opposite charged surfactant complexes was investigated. A sonicated sample of polyacid with a molecular weight about 10(5) Da and a content of d enantiomer higher than 90% was used in this study. Nearly stoichiometric complexes of poly(gamma,d-glutamate) anions and alkyltrimethylammonium cations bearing linear alkyl chains with even numbers of carbon atoms from 12 up to 22 were "synthesized" by precipitation from equimolar mixtures of aqueous solutions of the two components. All complexes were found to adopt stratified supramolecular structures made of alternating layers of poly(gamma,d-glutamate) and surfactant with a periodicity increasing from 3.2 up to 4.3 nm according to the length of the alkyl side chain. No definite evidence indicative of the conformation adopted by the main chain in these complexes could be afforded. In all cases, the alkyl chains are in an extended conformation and oriented normal or nearly normal to the layer planes. Polymethylene chains with more than 16 carbon atoms were partially crystallized in the complexes in a separated paraffinic phase, whereas no crystallinity was detected for shorter lengths. The crystallized paraffinic phases were found to melt reversibly at temperatures between 40 and 70 degrees C. This process was found to happen with a concomitant expansion-contraction that amounts between 2 and 8% of the long period of the structure but without significant alteration of the layered arrangement.

Gram-Positive Bacteria↗
PubMed2000

A new IS4 family insertion sequence, IS4Bsu1, responsible for genetic instability of poly-gamma-glutamic acid production in Bacillus subtilis.

Certain Bacillus subtilis strains, such as B. subtilis (natto) starter strains for the manufacture of natto (fermented soybeans), produce capsular poly-gamma-glutamate (gammaPGA). In B. subtilis (natto), gammaPGA synthesis is controlled by the ComP-ComA two-component regulatory system and thereby induced at the beginning of the stationary growth phase. We have found a new insertion sequence (IS), designated IS4Bsu1, in the comP gene of a spontaneous gammaPGA-negative mutant of B. subtilis (natto) NAF4. IS4Bsu1 (1,406 bp), the first IS discovered in B. subtilis, encodes a putative transposase (Tpase) with a predicted M(r) of 34,895 (374 residues) which displays similarity to the Tpases of IS4 family members. Southern blot analyses have identified 6 to 11 copies of IS4Bsu1, among which 6 copies were at the same loci, in the chromosomes of B. subtilis (natto) strains, including NAF4, three commercial starters, and another three gammaPGA-producing B. subtilis (natto) strains. All of the eight spontaneous gammaPGA(-) mutants, which were derived from five independent NAF4 cultures, had a new additional IS4Bsu1 copy in comP at six different positions within 600 bp of the 5'-terminal region. The target sites of IS4Bsu1 were determined to be AT-rich 9-bp sequences by sequencing the flanking regions of IS4Bsu1 in mutant comP genes. These results indicate that IS4Bsu1 transposes by the replicative mechanism, in contrast to other IS4 members that use the conservative mechanism, and that most, if not all, of spontaneous gammaPGA(-) mutants appear to have resulted from the insertion of IS4Bsu1 exclusively into comP. The presence of insertion hot spots in comP, which is essential for gammaPGA synthesis, as well as high transposition activity, would account for the high frequency of spontaneous gammaPGA(-) mutation by IS4Bsu1 in B. subtilis (natto).

Bacillus subtilis↗
PubMed1987

Increased therapeutic efficacy of cis-platinum complexes of poly-L-glutamic acid against a murine carcinoma.

Cis-diamminedichloroplatinum(II) (cis-DDP) and cis diamminediaquoplatinum(II) nitrate (cis-aq) were complexed to poly-L-glutamic acid (PG) of Mr 13,000 or 58,000. Soluble complexes were formed by mixing the platinum(II) compounds with the PG preparations in water at a molar ratio of one platinum(II) to 5 glutamyl residues of the PG. Compared to free cis-DDP, the complexes were about 2 to 6 times less cytotoxic to F9 embryonal carcinoma cells in vitro. In vivo studies with this tumor indicated that when administered i.p. one day after the tumor cells, the complexes were somewhat less active than cis-DDP. However, in comparison to the free drug which, due to its toxicity, was effective only within a very narrow dose range, the complexes were much less toxic, manifesting a wide therapeutic range in which no mortality occurred either from the tumor or as a result of the toxic effects of the drug. Cis-DDP and cis-aq complexes of PG Mr-58,000 were somewhat more toxic than the complexes of PG Mr, 13,000. The in vivo anti-tumor activity of most complexes was superior to that of free cis-DDP when tested in mice carrying high tumor loads. Due to their wide therapeutic range, the complexes could be given at high drug doses resulting in increased life span of the tumor-bearing mice. Moreover, 3 repeated injections of these high doses did not cause death from toxicity and resulted in partial or total eradication of advanced tumors.

Animals↗
PubMed2006

Partial poly(glutamic acid) <--> poly(aspartic acid) exchange in layer-by-layer polyelectrolyte films. Structural alterations in the three-component architectures.

Layer-by-layer (LBL) polyelectrolyte films were constructed from poly(L-glutamic acid) (PGA) and poly(L-aspartic acid) (PAA) as polyanions, and from poly(L-lysine) (PLL) as the polycation. The terminating layer of the films was always PLL. According to attenuated total reflection Fourier transform infrared measurements, the PGA/PLL and PAA/PLL films, despite their chemical similarity, had largely different secondary structures. Extended beta-sheets dominated the PGA/PLL films, while alpha-helices and intramolecular beta-sheets dominated the PAA/PLL films. The secondary structure of the polyelectrolyte film affected the adsorption of human serum albumin (HSA) as well. HSA preserved its native secondary structure on the PGA/PLL film, but it became largely deformed on PAA/PLL films. Both PGA and PAA were able to extrude to a certain extent the other polyanion from the films, but the structural consequences were different. Adding PAA to a (PGA/PLL)5-PGA film resulted in a simple exchange and incorporation: PGA/PLL and PAA/PLL complexes coexisted with their unaltered secondary structures in the mixed film. The incorporation of PGA into a (PAA/PLL)5-PAA film was up to 50% and caused additional beta-structure increase in the secondary structure of the film. The proportions of the two polyanions were roughly the same on the surfaces and in the interiors of the films, indicating practically free diffusion for both polyanions. The abundance of PAA/PLL and PGA/PLL domains on the film surfaces was monitored by the analysis of the amide I region of the infrared spectrum of a reporter molecule, HSA, adsorbed onto the three-component polyelectrolyte films.

Adsorption↗
PubMed1999

Development of a hepatocyte-specific prostaglandin E(1) polymeric prodrug and its potential for preventing carbon tetrachloride-induced fulminant hepatitis in mice.

A polymeric prodrug of prostaglandin E(1) (PGE(1)) was synthesized using galactosylated poly(L-glutamic acid hydrazide) (Gal-HZ-PLGA) as a biodegradable and targetable carrier to hepatocytes. Poly(L-glutamic acid hydrazide) was prepared by reacting poly(gamma-benzyl-L-glutamate) with hydrazine monohydrate, followed by reaction with 2-imino-2-methoxyethyl-1-thiogalactosides to obtain Gal-HZ-PLGA after i.v. injection. (111)In-labeled galactosylated poly(L-glutamic acid hydrazide) ((111)In-Gal-HZ-PLGA) rapidly accumulated in the liver in a dose-dependent manner, whereas (111)In-poly(L-glutamic acid hydrazide) did not, indicating the involvement of a galactose-specific mechanism in the uptake of (111)In-Gal-HZ-PLGA. Fractionation of liver cells revealed that (111)In-Gal-HZ-PLGA was preferentially taken up by liver parenchymal cells. After being taken up by the liver, (111)In-Gal-HZ-PLGA was gradually degraded, and radioactive metabolites with low molecular weight were detected within 10 min after injection. Then, PGE(1) or [(3)H]PGE(1) was coupled to Gal-HZ-PLGA via a hydrazone bond under mild conditions to obtain PGE(1) conjugate. After i.v. injection, [(3)H]PGE(1) conjugate was rapidly taken up by the liver (more than 80% of the dose). After injection of the conjugate, (3)H radioactivity remained in the liver, representing about 70% of the dose, even at 24 h, whereas little radioactivity remained in the organ at 1 h after the injection of free [(3)H]PGE(1). Finally, its pharmacological activity was examined in mice with fulminant hepatitis induced by peritoneal injection of carbon tetrachloride. The i.v. injection of PGE(1) conjugate at a dose of 1 mg (0.074 mg PGE(1))/kg effectively inhibited the increase of plasma glutamic pyruvic transaminase activity, whereas twice this dose (0.15 mg/kg) of free PGE(1) had little effect. These results suggest that the PGE(1) conjugate is an excellent polymeric prodrug of PGE(1) for hepatitis therapy.

Acute Disease↗
PubMed1983

Structural bases for public idiotypic specificities of monoclonal antibodies directed against poly(Glu60Ala30Tyr10) and poly(Glu60Ala40) random copolymers.

NH2-terminal amino acid sequences of heavy and light chains of seven poly(Glu60Ala30Tyr10) (GAT) specific hybridoma products derived from DBA/2 and (DBA/2 X BALB/c)F1 hybrid mice and those of BALB/B polyclonal antibodies have been determined over the first 40 residues. Comparison of these sequences with those of nine other GAT or poly(Glu60Ala40) (GA) specific hybridoma products previously reported allowed the following conclusions. (i) Sequences of hybridoma H and L chains are present in the pool of polyclonal antibodies. (ii) The public CGAT (or pGAT) idiotypic specificities are strictly confined to antibodies exhibiting limited heterogeneity with regard to both the variable heavy (VH) and the variable kappa (V kappa) sequences that may be accounted for by one and two germ-line genes, respectively. (iii) The public idiotypic specificities GA-1, expressed by some anti-GAT and most anti-GA antibodies, make use of the same (or similar) VH germ-line genes as the CGAT or pGAT antibodies but possess a distinctive V kappa sequence. (iv) Antibodies expressing neither of the alternative public specificities mentioned above appear to be more heterogeneous and express VH and V kappa sequences that were found to differ from the basic structures defining the CGAT (pGAT) or GA-1 correlates. It is concluded that CGAT (or pGAT) and GA-1 public idiotypic specificities are germ-line markers of both VH and V kappa regions, an observation in agreement with previously reported serological data.

Animals↗
PubMedDate not supplied

Paclitaxel-loaded poly(gamma-glutamic acid)-poly(lactide) nanoparticles as a targeted drug delivery system against cultured HepG2 cells.

The study was to develop paclitaxel-loaded formulations using a novel type of self-assembled nanoparticles that was composed of block copolymers synthesized from poly(gamma-glutamic acid) and poly(lactide) via a simple coupling reaction. The nanoparticles (the NPs) were prepared with various feed weight ratios of paclitaxel to block copolymer (the P/BC ratio). The morphology of all prepared nanoparticles was spherical and the surfaces were smooth. Increasing the P/BC ratio significantly increased the drug loading content of the prepared nanoparticles, but remarkably reduced the drug loading efficiency. The release rate of paclitaxel from the NPs decreased significantly as the P/BC ratio increased. For the potential of targeting liver cancer cells, galactosamine was further conjugated on the prepared nanoparticles (the Gal-NPs) as a targeting moiety. It was found that the activity in inhibiting the growth of HepG2 cells (a liver cancer cell line) by the Gal-NPs was comparable to that of a clinically available paclitaxel formulation, while the NPs displayed a significantly less activity. This may be attributed to the fact that the Gal-NPs had a specific interaction with HepG2 cells via ligand-receptor recognition. Cells treated with distinct paclitaxel formulations resulted in arrest in the G2/M phase. The arrest of cells in the G2/M phase was highly suggestive of interference by paclitaxel with spindle formation and was consistent with the morphological findings presented herein. In conclusion, the active targeting nature of the Gal-NPs prepared in the study may be used as a potential drug delivery system for the targeted delivery to liver cancers.

Antineoplastic Agents, Phytogenic↗
PubMed1985

Modulation of locomotor activity of polymorphonuclear cells by cationic substances and cationic lysosomal fractions from human neutrophils.

Seven cationic substances--human and egg-white lysozyme, RNase, protamine, histone, poly-L-lysine and poly-L-arginine; five cationic lysosomal fractions from human polymorphonuclears (PMNs); RNA; poly-L-glutamic acid; DNA; heparin; endotoxin; mastocytotropic agent compound 48/80; and cytochalasin B were tested for the influence on chemotaxis and random migration of human PMNs using under-agarose migration and Boyden chambers with two filters and [51Cr]PMNs. The above substances were either preincubated with PMNs, added to chemoattractants, or used instead of chemoattractants. In under-agarose migration method chemotaxis was inhibited by 11-35% when egg-white lysozyme, protamine, heparin, endotoxin, or compound 48/80 was added to the cells. High concentration of cytochalasin B inhibited chemotaxis by 73%. Cationic fractions I and V and low concentration of cytochalasin B enhanced chemotaxis by 11%, 41%, and 30%, respectively. When human and egg-white lysozyme, DNA, or cytochalasin B was added to the chemoattractants, motility of PMNs was inhibited. Cationic fractions II and V from human PMNs, when used as chemoattractants, enhanced cellular motility by 143-167%. Random migration was enhanced by heparin and inhibited by cytochalasin B and by cationic fractions from human PMNs. These findings suggest that various cationic and anionic substances and cationic fractions from human PMNs have heterogeneous influence on random migration and chemotactic activity of human PMN. Analysis relating chemotaxis to phagocytosis and to intracellular bactericidal activity (ICBA) has shown several patterns. Protamine, poly-L-lysine, poly-L-arginine, and agent compound 40/80 all inhibit chemotaxis and enhance phagocytosis and ICBA; cationic fractions II and V enhanced all three functions, whereas cytochalasin B suppressed phagocytosis and ICBA and had concentration-dependent modulatory influence on chemotaxis. It implies diverse mechanisms of action and possible impact on inflammatory reactions.

Chemotaxis↗
PubMed2005

Preparation and characterization of biodegradable nanoparticles based on poly(gamma-glutamic acid) with l-phenylalanine as a protein carrier.

The objective of the present study was to prepare nanoparticles composed of poly(gamma-glutamic acid) (gamma-PGA) and l-phenylalanine ethylester (l-PAE) in order to evaluate the possibility of using these nanoparticles as protein carriers. Novel amphiphilic graft copolymers composed of gamma-PGA as the hydrophilic backbone and l-PAE as the hydrophobic segment were successfully synthesized by grafting l-PAE to gamma-PGA using water-soluble carbodiimide (WSC). Due to their amphiphilic properties, the gamma-PGA-graft-l-PAE copolymers were able to form nanoparticles. The size of the gamma-PGA nanoparticles was measured by photon correlation spectroscopy (PCS) and showed a monodispersed size distribution with a mean diameter ranging from 150 to 200 nm. The solvents selected to prepare the gamma-PGA nanoparticles by a precipitation and dialysis method affected the particle size distribution. To evaluate the feasibility of vehicles for these proteins, we prepared protein-loaded gamma-PGA nanoparticles by surface immobilization and encapsulation methods. Ovalbumin (OVA) was used as a model protein and was immobilized onto the gamma-PGA nanoparticles or encapsulated into the inner core of these nanoparticles. Moreover, these OVA-encapsulated gamma-PGA nanoparticles could be preserved by freeze-drying process. The results of cytotoxicity tests showed that the gamma-PGA and gamma-PGA nanoparticles did not cause any relevant cell damage. It is expected that biodegradable gamma-PGA nanoparticles can immobilize proteins, peptides, plasmid DNA and drugs onto their surfaces and/or into the nanoparticles. These nanoparticles are potentially useful in pharmaceutical and biomedical applications.

Cell Proliferation↗
PubMed2005

Physicochemical properties of cross-linked poly-gamma-glutamic acid and its flocculating activity against kaolin suspension.

Cross-linked poly-gamma-glutamic acid (C-L gamma-PGA) was prepared with gamma-PGA irradiated with gamma-ray at various kGy values. The physicochemical properties including viscosity and water absorption capacity were compared between C-L gamma-PGA and several typical flocculating agents. The viscosity of C-L gamma-PGA increased with the dose of gamma-irradiation, although the water absorption capacity of C-L gamma-PGA did not, which showed a maximum of 1005.6 ml/g at 20 kGy. Flocculating activity against kaolin suspension was not observed for any of the test compounds when used singly. However, the activity of C-L gamma-PGA markedly increased following the addition of polyaluminum chloride. The activity increased with temperature up to 80 degrees C and remained at 80 degrees C of heat pretreatment for 1 h, but did not at more than 50 degrees C of heat pretreatment for 24 h. The activity was also observed within a pH range of 4.5-10.0. Both the water absorption capacity and flocculating activity of C-L gamma-PGA decreased in parallel with increasing NaCl concentration, suggesting that the flocculating activity of C-L gamma-PGA was associated with its water absorption capacity, rather than viscosity. An investigation of the effects of various cations on the flocculating activity of C-L gamma-PGA showed that only trivalent cations had a synergistic effect. The mechanism of C-L gamma-PGA flocculating activity is discussed based on the results of preliminary experiments.

Adsorption↗
PubMed2005

Preparation of gamma-PGA/chitosan composite tissue engineering matrices.

Gamma-poly(glutamic acid) (gamma-PGA), a hydrophilic and biodegradable polymer, was chosen to modify chitosan matrices to produce a gamma-PGA/chitosan composite biomaterial. Three types of both dense and porous composite matrices containing different amounts of gamma-PGA were fabricated. Chitosan and gamma-PGA matrices were also prepared as controls. Fluorescence staining indicated that chitosan and gamma-PGA were evenly distributed in the composite matrices. SEM micrographs showed that an interconnected porous structure with a pore size of 30-100 microm was present in all porous matrices except the gamma-PGA ones. By increasing the percentage of gamma-PGA from 0% to 20%, the swelling ratio of the matrices was enhanced from 1.6 to 3.2. Similarly, the contact angle of the matrices decreased from 113 degrees to 94 degrees . These data suggested that the surface hydrophilicity, water absorption rate, and swelling ratio were improved by adding gamma-PGA to the matrices. Additionally, the mechanical strength of the porous gamma-PGA/chitosan matrices was about 25-50%, higher than that of the unmodified chitosan matrices. The composite matrices were also examined and found to be an appropriate environment for cell attachment and proliferation. The cell density on the 20% gamma-PGA-modified matrices was almost triple that on the unmodified chitosan matrices on day 5. In summary, the gamma-PGA/chitosan composite matrices, due to their better hydrophilic, cytocompatible, and mechanical properties, are very promising biomaterials for tissue engineering applications.

Absorbable Implants↗
PubMed1991

Differential effects of poly (Glu60, Phe40) (GPhe) on murine TH1 and TH2 cells.

The random amino acid copolymer (Glu60, Phe40)n (GPhe) was previously shown to augment antigen-dependent proliferation of the murine TH2 cell lines DCL-2 and D10.G4.1. In the present study, the addition of GPhe to (Glu36, Lys24, Ala40)n (GLA)-primed BALB/c primary lymph node (1 degree LN) T cell cultures, the source of DCL-2, resulted in significant suppression of both the proliferative and lymphokine response to GLA. Suppression by GPhe of the 1 degree LN response was subsequently shown to be neither antigen- nor haplotype restricted, and was inhibitable by polyclonal anti-GPhe antibodies. Studies were extended to a GLA-reactive T cell hybridoma clone (DL.4G6.1). where significant suppression by GPhe of GLA-stimulated lymphokine production was observed as measured by markedly decreased HT-2 stimulatory activity of the collected supernatants. Subsequent antibody blocking experiments employing the monoclonal anti-murine IL-4 antibody 11B11 revealed that BALB/c GLA-reactive 1 degree LN T cells and DL.4G6.1 did not produce detectable levels of IL-4 in their culture fluids when stimulated by GLA, which suggested that these cells, unlike DCL-2, were TH1-like in nature. The addition of GPhe to the TH1 clones 5.2 and 5.9 resulted in significant suppression of proliferation to homologous antigen (ovalbumin), in contrast to the augmentation observed with the TH2 cell lines DCL-2 and D10.G4.1. It was concluded from these data, that the addition of GPhe to various T cell cultures lead to unusual suppressive and augmenting activities specific for TH1 and TH2 cells, respectively. Although the mechanism for these dichotomous effects of GPhe is as yet undetermined, several possibilities are considered.

Animals↗
PubMed2006

Effect of pH on binding of mutagenic heterocyclic amines by the natural biopolymer poly(gamma-glutamic acid).

Poly(gamma-glutamic acid) (gamma-PGA), a nontoxic and biodegradable macropolymer, was evaluated for its efficiency in binding three mutagenic heterocyclic amines (HAs), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-p-2), as affected by pH in a batch mode. The maximum HA sorption was attained for pH 3-7 and decreased sharply for pH less than 3. Binding isotherms obtained at pH 2.5 and 5.5 showed different isotherm shapes that belong to S and L types, respectively. The isotherm data at pH 2.5 were well described by a linear form of the Langmuir equation, while at pH 5.5 it showed two distinct curves, which were precisely fitted as multiple Langmuir curves. The deviation of linearity in Scatchard plot proved the multisite HA sorption. The Brunauer-Emmett-Teller equation also fitted better to isotherm data at pH 5.5, suggesting a multisite sorption caused by multimolecular HA layers on gamma-PGA. High HA sorption levels of 1250, 667, and 1429 mg/g at pH 2.5 and 1429, 909, and 1667 mg/g at pH 5.5 were observed for MeIQ, 4,8-DiMeIQx, and Trp-p-2, respectively. Among the HAs studied, the sorption capacity correlated directly with hydrophobicity of HAs and inversely with the number of methyl groups in HA molecules. The plausible binding mechanism of HAs on gamma-PGA may include a combination of hydrophobic, hydrogen-bonding, ionic, and dipole-dipole interactions.

Adsorption↗
PubMed1990

Inhibition of aminoglycoside-induced nephrotoxicity in rats by polyanionic peptides.

In the present study, we compared poly-L-Asp with poly-L-Glu and poly-D-Glu in vitro and in vivo for their ability to inhibit the GM-induced nephrotoxicity. In vitro, all three polyanions (i) bound GM over a wide range of pH; (ii) displaced GM previously bound to negatively charged phospholipid bilayers at acid pH (i.e. under the conditions prevailing in lysosomes in vivo), and thereby (iii) decreased the inhibitory potency of GM towards lysosomal phospholipase A1. Thus, one was tempted to predict that all three polyanions would have the potential of protecting against AG-induced nephrotoxicity. However, when co-administered to rats with GM, poly-L-Asp and poly-D-Glu completely suppressed the development of lysosomal phospholipidosis, as assessed by biochemical criteria and increased drug accumulation, whereas poly-L-Glu did not offer such protection despite a relatively lower increase in drug accumulation levels. Histoautoradiography also confirmed that poly-L-Asp, but not poly-L-Glu, was a nephroprotectant against the tissue proliferative response induced by GM. Morphologically, poly-L-Asp almost completely and poly-D-Glu totally prevented the accumulation of myeloid bodies in lysosomes. In vitro incubation in the presence of purified lysosomal extracts revealed marked differences in the hydrolysis rate of these peptides (poly-D-Glu:poly-L-Asp:poly-L-Glu = 1:1.2:16.9). Assuming that all three polyanionic peptides are transported and accumulated in lysosomes to the same extent, these results not only suggest that their stability in lysosomes is an essential requisite for protection against lysosomal phospholipidosis, but also strengthen our hypothesis that the site of action of poly-L-Asp is inside the lysosomes but not at the level of the renal membranes. In addition, poly-D-Glu alone or combined with GM induced another type of morphological lesion, not related to AG-induced nephrotoxicity which, to our knowledge, has not yet been described.

Animals↗
PubMed2003

Poly(L-glutamic acid)-paclitaxel conjugate is a potent enhancer of tumor radiocurability.

PURPOSE: Conjugating drugs with polymeric carriers is one way to improve selective delivery to tumors. Poly (L-glutamic acid)-paclitaxel (PG-TXL) is one such conjugate. Compared with paclitaxel, its uptake, tumor retention, and antitumor efficacy are increased. Initial studies showed that PG-TXL given 24 h before or after radiotherapy enhanced tumor growth delay significantly more than paclitaxel. To determine if PG-TXL-induced enhancement is obtained in a more clinically relevant setting, we investigated PG-TXL effects on tumor cure. METHODS AND MATERIALS: Mice bearing 7-mm-diameter ovarian carcinomas were treated with PG-TXL at an equivalent paclitaxel dose of 80 mg/kg, single dose or 5 daily fractions of radiation or both PG-TXL and radiation. Treatment endpoint was TCD(50) (radiation dose yielding tumor control in 50% of mice). Acute radioresponse of jejunum, skin, and hair was determined for all treatments. RESULTS: PG-TXL dramatically improved tumor radioresponse, reducing TCD(50) of single-dose irradiation from 53.9 (52.2-55.5) Gy to 7.5 (4.5-10.7) Gy, an enhancement factor (EF) of 7.2. The drug improved the efficacy of fractionated irradiation even more, reducing the TCD(50) of 66.6 (62.8-90.4) Gy total fractionated dose to only 7.9 (4.3-11.5) Gy, for an EF of 8.4. PG-TXL did not affect normal tissue radioresponse resulting from either single or fractionated irradiation. CONCLUSION: PG-TXL dramatically potentiated tumor radiocurability after single-dose or fractionated irradiation without affecting acute normal tissue injury. To our knowledge, PG-TXL increased the therapeutic ratio of radiotherapy more than that previously reported for other taxanes, thus, PG-TXL has a high potential to improve clinical radiotherapy.

Adenocarcinoma↗
PubMed2006

Multifunctional conjugation of proteins on/into bio-nanoparticles prepared by amphiphilic poly(gamma-glutamic acid).

The present study focuses on nanoparticles composed of amphiphilic poly(gamma-glutamic acid) (gamma-PGA) as potential protein carriers. Amphiphilic graft co-polymers composed of y-PGA as the hydrophilic backbone and L-phenylalanine ethylester (L-PAE) as the hydrophobic segment were synthesized by grafting L-PAE to y-PGA using water-soluble carbodiimide (WSC). Due to their amphiphilic properties, the gamma-PGA-graft-L-PAE co-polymer formed monodispersed nanoparticles in water. The particle size of the nanoparticles composed of gamma-PGA-graft-L-PAE (gamma-PGA nanoparticles) was about 200 nm and showed a highly negative zeta potential. To evaluate their potential applications as multifunctional protein carrier, we prepared protein-entrapped gamma-PGA nanoparticles by encapsulation, covalent immobilization or physical adsorption methods. For this purpose, 11 different proteins with various molecular weights and isoelectric points (pI values) were used as model proteins. The encapsulation of the protein into the nanoparticles was observed for all tested proteins. The amount of protein covalently immobilized or adsorbed onto the nanoparticles showed different tends based on the molecular weight and pI of each protein. Positively charged proteins could be adsorbed onto the negatively charged nanoparticles by electrostatic interaction. Moreover, it was found that enzyme-encapsulated nanoparticles showed higher enzymatic activity than surface-immobilized nanoparticles. These results indicated that the enzymatic activity of the enzyme-entrapped nanoparticles was significantly affected by the conjugation method, and that encapsulation was the optimal method for the conjugation of proteins and nanoparticles. It is expected that the y-PGA nanoparticle will have great potential as multifunctional carriers in pharmaceutical and biomedical applications, such as drug and vaccine delivery systems.

Biocompatible Materials↗
PubMed2006

Hierarchical ionic self-assembly of rod-comb block copolypeptide-surfactant complexes.

Novel hierarchical nanostructures based on ionically self-assembled complexes of diblock copolypeptides and surfactants are presented. Rod-coil diblock copolypeptide poly(gamma-benzyl-L-glutamate)-block-poly(L-lysine), PBLG-b-PLL (Mn = 25,000 and 8000 for PBLG and PLL, respectively, polydispersity index 1.08), was complexed with anionic surfactants dodecanesulfonic acid (DSA) or dodecyl benzenesulfonic acid (DBSA), denoted as PBLG-b-PLL(DSA)1.0 and PBLG-b-PLL(DBSA)1.0, respectively. The complexation leading to supramolecular rod-comb architectures was studied by transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS), Fourier transform infrared spectroscopy (FTIR), and polarized optical microscopy (POM). PBLG-b-PLL, PBLG-b-PLL(DBSA)1.0, and PBLG-b-PLL(DSA)1.0 self-assemble with alternating PBLG lamellae and PLL-containing lamellae with a periodicity of 27-33 nm. Within the PBLG lamellae, the rod-like PBLG helices pack with a periodicity of ca. 1.3 nm. The internal structure of the PLL-containing lamellae depends on the complexation. For pure PBLG-b-PLL, the PLL chains adopt a random coil conformation and the PLL domains are disordered. For PBLG-b-PLL(DSA)1.0, lamellar self-assembly of periodicity of 3.7 nm within the PLL(DSA)1.0 domains is observed due to crystalline packing of the linear n-dodecyl tails. For PBLG-b-PLL(DBSA)1.0 with branched dodecyl tails, a distinct SAXS reflection is observed, suggesting self-assembly within the PLL(DBSA)1.0 domains with a periodicity of 2.9 nm. However, due to the absence of higher order reflections, the internal structure cannot be conclusively assigned. The efficient plasticization which leads to fluid-like liquid crystallinity in PBLG-b-PLL(DBSA)1.0 and an alpha-helical conformation according to FTIR allows us to suggest that the PLL(DBSA)1.0 domains have a hexagonal internal structure. The interplay of self-assembly at different length scales combined with rod-like liquid crystallinity can open new routes to design functional materials.

Benzenesulfonates↗
PubMed2006

An intranasal vaccine targeting both the Bacillus anthracis toxin and bacterium provides protection against aerosol spore challenge in rabbits.

An intranasal vaccine targeting the Bacillus anthracis toxin and vegetative bacterium was tested for the ability to protect immunized rabbits against aerosol B. anthracis spore exposure. Rabbits were vaccinated intranasally with PA-based vaccines formulated as dry powders with or without chitosan (ChiSys, Archimedes Development Limited), a compound that exhibits muco-adhesive properties, or as a liquid. Formulations also contained MPL adjuvant and PA. Some vaccines contained PA conjugated to a 10-mer peptide of the poly-d-glutamic acid capsule of B. anthracis. Rabbits were immunized on days 0 and 28 and aerosol challenged with an average 250LD50 Ames spores on day 85. Serum antibody was measured before and after challenge. Significant anti-PA serum IgG levels were obtained, particularly with use of ChiSys based formulations. PA-Conj induced significant anti-capsule responses, although a formulation containing free capsule peptide did not. All immunized rabbits survived the challenge, but differences in morbidity, as evidenced by anorexia, between vaccine groups were observed. Only rabbits immunized with PA+PA-Conj appeared normal throughout the post-challenge observation period (14 days), while all that received PA with the free capsule peptide appeared ill at times as evidenced by a failure to eat normally. One negative control rabbit received a lower inhaled spore dose (183LD50) and survived the challenge, although it was anorexic post-challenge. It also had a high level of anti-LF antibodies in its convalescent serum (5400 U/ml), indicating an extensive infection. In contrast, 75% of the immunized rabbits had no LF-specific antibody in their post-challenge sera, and the rest had low levels (< or = 138 U/ml), indicating that infections resulting in toxin production were avoided or greatly reduced. Thus, intranasal immunization with a chitosan-based powder vaccine combining PA and capsule epitopes provided superior protection against B. anthracis infection compared to a single antigen (PA) vaccine, as evidenced by a reduction in morbidity and prevention of death.

Adjuvants, Immunologic↗