Polysuccinimide Research Articles

Reversible response of poly(aspartic acid) hydrogels to external redox and pH stimuli

A redox- and pH-responsive poly(aspartic acid) (PASP) hydrogel is synthesised by cross-linking cysteamine modified polysuccinimide (PSI) with non-cleavable cross-linker 1,4-diaminobutane followed by the hydrolysis of the resultant PSI gel to a PASP hydrogel. The hydrogel showed a remarkable change in its degree of swelling as a function of external pH because of the polyelectrolyte character of the network. In addition to pH-dependent swelling, the thiolation of the polymer rendered redox responsive behaviour to poly(aspartic acid). The degree of swelling could be tuned in a reversible manner by immersing the hydrogel in reducing or oxidising media. The elastic modulus of the hydrogel was also strongly affected by the presence of reducing or oxidising agents. Moreover, the gel strength could be improved via oxidation. The reversible response of the degree of swelling and the elastic modulus was induced through the thiol–disulphide transformation inside the hydrogel proven using a new analytical method. Consequently, a dual responsive hydrogel is obtained with redox-tunable cross-link density.

Synthesis, micellization and characterization of novel amphiphilic β-cyclodextrin/poly(L-aspartate) copolymer

A novel amphiphilic β-cyclodextrin/poly(L-aspartate)(β-CD-PASP) copolymer was prepared by ring-opening polymerization of polysuccinimide(PSI). This copolymer bears β-CD units along the macromolecular chain and the structure was characterized by infrared(IR) and proton nuclear magnetic resonance(1H NMR). The molecular weight of the copolymer was determined by gel permeation chromatography(GPC). The copolymer micelle were prepared by direct dissolution method. The critical micelle concentration(CMC) of the copolymer micelle was measured by flourescence technique with pyrene as probe. The size distribution of micelle was characterized on a dynamic laser light scattering particle size analyzer and its shape was observed by transmission electron microscopy(TEM). The results show that the copolymer could self-assemble into micelle with a low CMC, and the effective diameter of the micelle was 116.3 nm. The methotrexate(MTX)-loaded micelle were prepared and the drug loading content(DLC) was 22.86%. The MTX-loaded copolymer exhibited a better water-solubility than the free drug.

One-Pot Syntheses and Cell Imaging Applications of Poly(amino acid) Coated LaVO4:Eu3+ Luminescent Nanocrystals

For successful biological applications of luminescent nanocrystals, surface functionalization is very essential. It is very important to develop the facile synthetic methods to gain access to obtaining water-stable and biocompatible NPs with appropriate functional groups as well as high luminescence efficiency. Herein, a green and facile one-pot hydrothermal strategy was developed for the preparation of poly(amino acid) coated LaVO4:Eu(3+)-PASP luminescent nanocrystals by employing the hydrolysis of polysuccinimide (PSI) to polyaspartic acid (PASP) to provide a general platform for the surface modification. Because of the enriched carboxylic groups in the PASP coating, these as-prepared nanoparticles (NPs) demonstrated good water-stability, biocompatibility, and bioconjugatability. Due to their strong red luminescence and good bioconjugatability, the antibody bioconjugated LaVO4:Eu(3+)-PASP NPs were successfully used as the biomarkers for cancer cell specific luminescence imaging. The results indicate that these NPs have the potential to act as luminescent probes for luminescence assay and in vitro imaging.

Preparation and swelling properties of “click” hydrogel from polyaspartamide derivatives using tri-arm PEG and PEG-co-poly(amino urethane) azides as crosslinking agents

Copper-assisted azide-alkyne cycloaddition (CuAAC) became a very interesting tool lately for synthesizing biocompatible polymer-based materials such as hydrogels or microgels under mild conditions. As our previous works, modified polyaspartamides with pendent alkyne or azide groups are synthesized by successful ring-opening aminolysis reaction of the polysuccinimide (PSI) using “click” functional amine compounds and ethanolamine. In this work, 3-arm poly(ethylene glycol) (PEG) and 3-arm PEG-co-poly(amino urethane), PEG-(PAU)3, were modified with 3-azido-1-propionic acid (APrA) to obtain the corresponding azido-terminal polymeric crosslinkers, and used to prepare hydrogels with alkynated polyaspartamide via click chemistry. The obtained click hydrogels were transparent and physically strong probably due to highly efficient and homogeneous click reaction. The hydrogel from PEG-(PAU)3 was also pH-sensitive caused by its amino urethane groups in the structure. The hydrogels were characterized by the in-situ gelation and swelling behavior, in vitro cytotoxicity, and morphology. These novel hydrogels have potentials for bioapplications in the fields of drug delivery and tissue engineering.

Thermal Stability and Decomposition Kinetics of Polysuccinimide

The thermal stability and decomposition kinetics of polysuccinimide (PSI) were investigated using analyzer DTG-60 under high purity nitrogen atmosphere at different heating rates (3, 6, 9, 12 K/min). The thermal decomposition mechanism of PSI was determined by Coats-Redfern method. The kinetic parameters such as activation energy (E), pre-exponential factor (A) and reaction order (n) were calculated by Flynn-Wall-Ozawa and Kissinger methods. The results show that the thermal decomposition of PSI under nitrogen atmosphere mainly occurs in the temperature range of 619.15-693.15 K, the reaction order (n) was , the activation energy (E) and pre-exponential factor (A) were obtained to be 106.585 kJ/mol and 4.644 × 109 min-1, the integral and differential forms of the thermal decomposition mechanism of PSI were found to be and , respectively. The results play an important role in understanding the thermodynamic properties of polysuccinimide.

Graft polymerization of p-dioxanone onto polyhydroxyethylaspartamide through ring-opening polymerization using organometallic and enzyme catalysts

The grafting of poly(p-dioxanaone) (PPDO) onto β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) was achieved, first, by synthesis of polysuccinimide (PSI) from DL-aspartic acid through thermal condensation polymerization, and then, followed by aminolysis of PSI to form PHEA with hydroxyl end groups, and finally the PPDO was grafted onto PHEA through these hydroxyl end groups by ring-opening polymerization (ROP) of PDO in the presence of tin octoate [Sn(Oct)2] and Candida Antarctica Lipase B (Novozyme 435) catalysts. Evidence of grafting was obtained by comparing Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray diffraction (XRD) analysis, polarized optical microscopy (POM), proton nuclear magnetic resonance (1H–NMR) spectroscopy, and solubility characteristics of PHEA with PPDO-grafted copolymers (PHEA-g-PPDO). The FT-IR spectroscopic analysis reveals the formation of ester linkage between PPDO and hydroxyl end groups of PHEA. TGA analysis shows a quite different thermal profile for grafted polymers. DSC and XRD results reveal the existence of graft copolymer in two different crystalline forms. POM shows banded spherulitic morphology for the graft copolymers. The grafting of PPDO was further confirmed by 1H–NMR. Eventhough, graft copolymer was obtained by both these methods, the graft copolymer obtained by enzyme catalyzed ROP shows higher crystalline order, better spherulitic morphology, and solubility characteristics than that of the graft polymer obtained by organometal catalyzed ROP.

Study on the Polyaspartic Acid Derivative Synthesis and the Scale Inhibition Performance of Calcium Carbonate

Intermediate vector polysuccinimide (PSI) was prepared by polymerization of malefic acid and ammonia at 180°Cin this article. Hydrophilic polyaspartic acid (PASP) derivative was prepared from amino-sulfonic and PSI; Lipophilic PASP derivative was prepared from PSI and diisopropylamine. Their scale inhibition rates of calcium carbonate were evaluated by static scale experiments. The inhibition rate of calcium carbonate was 90.2% when n(amino-sulfonic): n(PSI) =1:14 and the dosage of pharmaceutical was 12mg / L. The inhibition rate of calcium carbonate was 87.6% when n(diisopropylamine):n(PSI)=1:8 and the dosage of pharmaceutical was 15mg /L. The calcium carbonate that collected from static state experiments was analysised by scanning electron microscope (SEM). The results showed that polyaspartic acid derivatives were synthesized which had the best overall performance when n (amino-sulfonic): n (PSI) = 1:14.

Design of polyanionic nanocarriers based on modified poly (aspartic acid)s for oral administration: synthesis and characterization

This study designed a series of polyanionic nanocarriers based on biodegradable and biocompatible poly (aspartic acid)s for oral administration. First, polysuccinimide (PSI) was synthesized from L-aspartic acid using acid-catalyzed bulk thermal polycondensation and acid-catalyzed thermal polycondensation in a mixture of mesitylene/sulfolane. PSI-C16 was then synthesized by aminolysis with nucleophile, hexadecylamine to react with PSI known as nucleophilic addition. Finally, a series of partially esterified poly (aspartic acid)s was produced by alkaline treatment to afford an amphiphilic polyanion, poly (sodium aspartate-g-hexadecyl aspartate) (Na-PASP-g-C16-PASP). 1HNMR, FTIR, DSC and GPC were utilized to demonstrate and characterize the polymers. The synthesized polyanion could be self-assembled into the nano-scaled micelles and be independent of pH in phosphoric buffer solutions. The hydrodynamic diameter and zeta potential were measured using the dynamic light scattering (DLS) method, and the critical micelle concentration (CMC) was determined using the fluorescence spectrophotometer. The micellar morphologies were examined using transmission electron microscopy (TEM), and atomic force microscopy (AFM) to present the nano-dimensional sphere. The stability of size transition at different pH levels, from strong acid to alkaline, proved that the micelles could stably transport from the stomach to intestinal lumen prior to arriving in the epithelium of the small intestine.

PH-Sensitive Amphiphilic Biodegradable Graft Co-Polymer Aggregates Based on Polyaspartamide for Intracellular Delivery

A biodegradable, pH-sensitive amphiphilic co-polymer, o-(2-aminoethyl)-o’-methylpolyethylene glycol/1-(3-aminopropyl)imidazole/lactic acid oligomers-g-polyaspartamide (MPEG/API/LAs-g-PASPAM), was synthesized. The hydrophobic biodegradable poly (lactic acid) (PLA), the hydrophilic MPEG and the pH-sensitive API were successfully introduced into the biodegradable polysuccinimide (PSI) backbone by grafting. In its synthesis, the feed ratio of MPE to PLA was varied to provide different amphiphilic balances. FT-IR and 1H-NMR spectroscopy were used to identify the chemical structure of the MPEG/API/LAs-g-PASPAM co-polymers synthesized. Tens to a few hundreds of nanometer-scaled aggregates, appropriate for intracellular drug-carrier applications, were developed in the simulated buffer solution, and their self-assembling behavior was significantly affected by the environmental pH. The size and morphology of self-aggregates were investigated using dynamic light scattering and transmission electron microscopy. The buffering effect was observed in the endosomal pH range. The drug loading and release experiments were conducted for a series of co-polymer aggregate systems, and it was noted that the release behavior was mostly governed by diffusion. The biodegradable kinetics was also studied to ascertain the drug-release mechanism.

Polysuccinimide graft copolymer nano aggregates encapsulating magnetites for imaging probe

Polysuccinimide (PSI) grafted with methylpoly(ethylene glycol) (MPEG) was synthesized and employed to encapsulate pre-synthesized magnetite using a co-precipitation method. This encapsulation was stabilized by the chemical bonding between PSI and magnetite via the introduction of a bridging compound, 3-aminopropylethoxysi- lane (APS). The morphology and properties of the magnetite-encapsulated polymer particles were widely character- ized to investigate their applications as potential magnetic resonance (MR) imaging probes. The Fourier transform infrared and Fourier transform nuclear magnetic resonance spectroscopy confirmed the successful synthesis of the MPEG-g-PSI- and APS-coated magnetites in addition to X-ray diffraction of their crystalline structure. The size and distribution of the pure and polymer-coated magnetite aggregates were examined using transmission electron microscopy and light scattering analysis. The magnetite-encapsulated aggregates prepared in this study showed excellent superparamagnetic and biocompatible properties that enabled their successful use as MR imaging probes.

Novel solvent-free synthesis and modification of polyaspartic acid hydrogel

Polyaspartic acid (PASP) hydrogel, a hydrolysis derivative of polysuccinimide (PSI), has been previously synthesized by using organic solvents such as dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO), making the process environmentally and economically unattractive. The present paper presents a “green” synthesis, without using organic solvents. It demonstrates that hydrolysis and modification can be combined with in situ cross-linking. Introducing an aqueous soluble cross-linker, experimental results would broaden the application area of PASP at significantly reduced preparation cost, whilst moreover improving the required properties. The PASP hydrogel obtained by this method has a 600 g g−1 water-swelling ratio against 420 g g−1 as obtained by the conventional method using DMF. To reduce the ionic strength sensitivity of the hydrogel, sulfo-groups from, e.g. taurine, can be grafted onto the main chain of PASP and produce a modified PASP hydrogel with a 300 g g−1 water-swelling ratio in a 0.9% sodium chloride solution, against only 80 g g−1 for the non-grafted PASP hydrogel.

Thermo‐ and pH‐Responsive Polymersomes of Poly(α,β‐N‐substituted‐DL‐aspartamide)s

AbstractMaterials that can respond to multiple stimuli, such as temperature and pH changes, are of considerable interest for applications in drug delivery systems. Notably, α,β‐[poly(2‐hydroxyethyl)‐DL‐aspartamide] is a potentially useful material for such applications. This study investigated the temperature and pH responsiveness of polymers structurally similar to α,β‐[poly(2‐hydroxyethyl)‐DL‐aspartamide], namely, poly(α,β‐N‐substituted‐DL‐aspartamide)s, in aqueous media. These polymers were derived from polysuccinimide (PSI), which was first synthesized via acid‐catalyzed bulk polycondensation of L‐aspartic acid (L‐ASP) in the presence of 85% o‐phosphoric acid under N2. Two primary amino alcohols, 4‐aminobutanol (4AB) and 6‐aminohexanol (6AH), were then respectively utilized to modify PSI to form poly (α,β‐N‐substituted‐DL‐aspartamide)s via aminolysis. Different ratios of these two amino alcohols were used to modify the polymer to produce a series of copolymers with lower critical solution temperatures ranging from 53–28°C when dispersed in aqueous media. Moreover, the properties of the poly(α,β‐N‐ substituted‐DL‐aspartamide)s in aqueous solution were affected by pH changes. The morphology of the particles formed by these amphiphilic polymers was observed using scanning electronic microscopy and transmission electronic microscopy, and the particles were found to be polymersomes with shell and hollow core structures and diameters of 0.5–1 μm. Other properties of this series of self‐assembly copolymers were also characterized. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012

Top-down Synthesis of Versatile Polyaspartamide Linkers for Single-Step Protein Conjugation to Materials

Materials used in various biological applications are often modified with proteins to regulate biomolecular and cellular adhesion. Conventional strategies of protein conjugation accompany monovalent bifunctional protein linkers, which present several limitations in molecular synthesis and protein conjugation. Herein, we present a new strategy of preparing multivalent polyaspartamide linkers in a simple top-down manner, and also demonstrate that the resulting polymer linkers allow us to readily conjugate proteins to both organic and inorganic materials. The top-down synthesis of polyaspartamide linkers was performed by partially opening succinimidyl ring moieties of polysuccinimide (PSI) with the controlled number of nucleophiles reactive to photo-cross-linked hydrogel or gold-coated inorganic materials: (1) Poly(2-hydroxyethyl-co-2-methacryloxyethyl aspartamide) (PHMAA) presenting methacrylate was used to micropattern fibronectin or collagen on a hydrogel in order to regulate cell adhesion and growth area on a micrometer scale. (2) Poly(2-hydroxyethyl-co-2-mercaptoethyl aspartamide) (PHMCA) presenting thiol functional groups was used to link fibronectin to a gold-coated silicon microelectromechanical probe designed to measure cell traction force. Overall, these multivalent polyaspartamide protein linkers will greatly assist efforts to analyze and regulate the cellular adhesion to and phenotypic activities of a wide array of substrates and devices.

Fabrication of Gene Carrier via Self-assembly of Poly[(dimethylamino)ethyl Methacrylate] and Poly(aspartic acid)-grafted-Poly(ethylene glycol)

A biocompatible complex has been prepared as gene carrier via electrostatic interaction, which is composed of a polycation, that is, poly[(dimethylamino)ethyl methacrylate] end-capped with cholesterol moiety (Chol-PDMAEMA30), along with a polyanion named poly(aspartic acid)-grafted-poly(ethylene glycol) (PASP-g-PEG). The complexes have less cytotoxicity compared to the case of alone Chol-PDMAEMA30 or branched polyethylenimine (PEI) system. In the present study, biocompatible complexes have been prepared as gene carrier via electrostatic interaction, which is composed of a polycation, that is, poly[(dimethylamino)ethyl methacrylate] end-capped with cholesterol moiety (Chol-PDMAEMA30), along with a polyanion named poly(aspartic acid)-grafted-poly(ethylene glycol) (PASP-g-PEG). We first synthesized polysuccinimide (PSI) via condensation polymerization of aspartic acid, and then used PEG-NH2 to react with the partial pentacyclic rings of PSI to yield a kind of graft copolymer polysuccinimide-grafted-poly(ethylene glycol) (PSI-g-PEG). After hydrolysis of the residual succinimide units, a new biodegradable and biocompatible graft copolymer PASP-g-PEG was prepared successfully. Chol-PDMAEMA30 was synthesized via oxyanion-initiated polymerization, as reported in our previous literature. We investigated the interactions between every pair among calf thymus DNA, Chol-PDMAEMA30, and PASP-g-PEG by agarose gel retardation assay. The results indicate that the prepared complexes could completely bind DNA and may become more stable during systemic circulation. The complexes have less cytotoxicity compared to the case of alone Chol-PDMAEMA30 or branched polyethylenimine (PEI) system. Furthermore, the physicochemical properties of the complexes were also investigated by zeta potential, transmission electron microscopy (TEM) and dynamic light scattering (DLS) measurements. These biodegradable and biocompatible polymeric carriers have potential applications in gene delivery.

Dual Kinetic Hydrate Inhibition and Scale Inhibition by Polyaspartamides

Polyaspartamides are a recently developed class of kinetic hydrate inhibitors (KHIs) with good biodegradability, made from polysuccinimide (PSI). Because polyaspartates are well-known biodegradable...

PH-Sensitive Micelles with Cross-Linked Cores Formed from Polyaspartamide Derivatives for Drug Delivery

A series of polyaspartamide derivatives were synthesized by grafting O-(2-aminoethyl)-O'-methylpoly(ethylene glycol) 5000 (MPEG), 1-(3-aminopropyl) imidazole (API), and cinnamate onto polysuccinimide (PSI) with the respective degrees of substitution adjusted by the feed molar ratio. The chemical structure of the prepared polymer was confirmed using FT-IR and (1)H NMR spectroscopy. A new pH-sensitive polymeric micelle based on the synthesized polymer was prepared and characterized, and its pH-sensitive properties were characterized by the measurement of light transmittance and particle sizes at varying pH values. pH-dependent aggregation and deaggregation behavior was clearly observed in the polymer aqueous dispersion system. Photo-cross-linking of the cinnamate branches cross-linked the core of the micelles. The core cross-linked micelles showed high stability over a wider pH range and displayed obvious pH-dependent swelling-shrinking behavior instead of micelle-unimer transition behavior. This micelle system overcame the drawback of the facile disintegration of normal polymeric micelles and showed obvious delayed paclitaxel release in in vitro drug delivery experiments.

POLYASPARTAMIDES GRAFTED WITH 1-(3-AMINOPROPYL)IMIDAZOLE AS LESS TOXIC AND HIGHLY EFFICIENT GENE CARRIERS

通过氨基引发聚丁二酰亚胺(PSI)开环反应,制备了系列侧链含氨乙基和咪唑丙基的聚(L-天冬酰胺)共聚物( P1~P5 ).该系列聚合物不仅具有极低的细胞毒性,而且随侧链中咪唑取代基含量的增加,聚合物在pH 5~8范围内缓冲能力显著提高.通过凝胶电泳、粒径和电位分析等研究了聚合物与质粒DNA的相互作用.结果表明,所有聚合物均可以在较低N/P比有效结合DNA.在N/P比高于5时,形成粒径在100 nm以下、表面电荷为+20 mV左右的稳定复合物纳米粒子.聚合物介导荧光素酶基因(pGL-3)和增强型绿色荧光蛋白基因(pEGFP-C1)体外转染293T细胞和COS-7细胞的结果表明,侧链中引入咪唑取代基显著提高了聚合物的转染能力.通过优化侧链氨基/咪唑取代基比例,获得转染效率最高的聚合物 P4 . P4 介导pGL-3和pEGFP-C1在细胞中的表达与聚乙烯亚胺(PEI)相当、甚至是PEI的2~3倍.

TGA/FTIR/MS study on thermal decomposition of poly(succinimide) and sodium poly(aspartate)

The thermal degradation of sodium polyaspartate (PAspNa) and of its precursor - polysuccinimide (PSI) - was investigated using three different techniques: thermal analysis (TA), Fourier transform infrared spectroscopy (FTIR) and mass spectrometry (MS). These online coupled techniques can comprise a very useful tool for the investigation of the thermal decomposition and its mechanisms and allow having simultaneous information about the decomposition process itself as well as of the evolving substances. PSI and sodium-polyaspartate present complex thermal decomposition processes (two to five stages). Also, thermal stability of PSI is low in comparison to that of PAspNa. Finally, weight losses were 72.53% for PSI and 46.73% in the case of PAspNa.

Fabrication of polymer‐gadolinium (III) complex nanomicelle from poly(ethylene glycol)‐polysuccinimide conjugate and diethylenetriaminetetraacetic acid‐gadolinium as magnetic resonance imaging contrast agents

AbstractMethoxy poly (ethylene glycol)‐graft‐α, β‐poly (aspartic acid) derivatives (mPEG‐g‐PAA‐N3) were synthesized by sequential ring‐opening reaction of polysuccinimide (PSI) with mPEG‐NH2 (MW: 2000 Da), and 1‐azido‐3‐aminopropane, respectively. Then N2‐(hex‐5‐yne)‐diethylenetriamine‐tetra‐t‐butylacetate (DTTA‐der) was conjugated to mPEG‐g‐PAA‐N3 by click cycloaddition. After deprotection of carboxylic groups, mPEG‐g‐PAA‐DTTA macromolecular ligands were obtained. MPEG‐g‐PAA‐(DTTA‐Gd) complex nanomicelles were fabricated from mPEG‐g‐PAA‐DTTA and Gadolinium chloride. The formation of nanomicelles was confirmed by fluorescence spectrophotoscopy and particle size measurements. It was found that all the nanomicelles showed spherical shapes with core‐shell structures and narrow size distributions. Their sizes ranged from 50 to 80 nm, suggesting their passive targeting potential to tumor tissue. With the increase of graft degree (GD) of mPEG, the sizes of mPEG‐g‐PAA‐(DTTA‐Gd) nanomicelles showed a tendency to decrease. Compared with gadopentetate dimeglumine (Gd‐DTPA), mPEG‐g‐PAA‐(DTTA‐Gd) nanomicelles showed essential decreased cytotoxicity to KB cell line and enhanced T1‐weighted signal intensity, especially at low concentration of gadolinium (III), suggesting their great potentials as magnetic resonance imaging contrast agents. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011

Synthesis and characterization of poly(aspartic acid) derivatives conjugated with various amino acids

Novel derivatives of poly(aspartic acid) conjugated with various amino acids and their amphiphilic copolymers were synthesized and characterized. Methyl esters of various amino acids (in their hydrochloride form) were synthesized from the reaction of amino acids with methanol in the presence of chlorotrimethylsilane (TMSCl). Aminolysis reaction onto polysuccinimide (PSI) using various amino acid methyl esters in the presence of catalyst and the followed hydrolysis provided the corresponding amino acid-conjugated poly(aspartic acid) derivatives in high reaction yield. Amino acid—conjugated amphiphilic analogs were also prepared by introducing hydrophobic alkylamine along with amino acid using a similar procedure. The chemical structures of copolymers were confirmed by FT-IR and 1H NMR spectroscopy. The physicochemical properties of amphiphilic copolymers were characterized using dynamic light scattering (DLS), fluorescence spectroscopy and field emission scanning electron microscopy (FE-SEM). In addition, the in vitro cell viability of the copolymers was examined. These polymers have potential applications in the pharmaceutical and cosmetic fields as delivery vehicles for bioactive molecules.