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Self-assembly of block copolymers has recently drawn great attention due to its remarkable performance and wide variety of applications in biomedicine, biomaterials, microelectronics, photoelectric materials, catalysts, etc. Poly(amino acid)s (PAAs), formed by introducing synthetic amino acids into copolymer backbones, are able to fold into different secondary conformations when compared with traditional amphiphilic copolymers. Apart from changing the chemical composition and degree of polymerization of copolymers, the self-assembly behaviors of PAAs could be controlled by their secondary conformations, which are more flexible and adjustable for fine structure tailoring. In this article, we summarize the latest findings on the variables that influence secondary conformations, in particular the regulation of order-to-order conformational changes and the approaches used to manage the self-assembly behaviors of PAAs. These strategies include controlling pH, redox reactions, coordination, light, temperature, and so on. Hopefully, we can provide valuable perspectives that will be useful for the future development and use of synthetic PAAs.
Assuntos
Aminoácidos , Polímeros , Polímeros/química , Conformação Molecular , Polimerização , MicelasRESUMO
Polymers of basic amino acids function as polycationic compounds under physiological conditions and exhibit intriguing biological properties, such as antimicrobial and antiviral activities, immunopotentiating ability, and DNA-binding activity. Poly(ε-L-lysine) (ε-PL) produced by some strains of Streptomyces spp. is a cationic homopolymer of L-lysine linking between ε-amino and α-carboxylic acid functional groups and has been used as a food preservative based on its biocompatibility and biodegradability. An ε-PL-producing strain of Streptomyces sp. USE-33 was found to secrete a novel polycationic substance into its culture broth along with ε-PL. High-performance liquid chromatography analyses and one- and two-dimensional 1H and 13C nuclear magnetic resonance (NMR) experiments, accompanied by NMR titration studies, revealed that the secreted substance was poly[ß-(L-diaminopropionyl-L-diaminopropionic acid)], PAP, characterized by an isopeptide backbone linking between the ß-amino and α-carboxylic acid groups of L-α,ß-diaminopropionic acid (L-Dpr) with pendent L-Dpr residues. PAP had a molecular weight of 500 to 1400, and copolymers composed of the two amino acids L-Dpr and L-lysine were not detected in the producer strain USE-33. The strain coproduced high levels of the two poly(amino acid)s in the presence of glycerol, citrate, and ammonium sulfate at pH 4.0 in a two-stage cultivation procedure. PAP exhibited strong inhibitory activities against several yeasts and weaker activities against bacteria than ε-PL. PAP may share a number of biological functions with ε-PL, and the use of PAP along with ε-PL has potential as a specific and advanced material for technical applications in various fields.Key points⢠Novel cationic poly(amino acid) was found in an ε-PL-producing Streptomyces species.⢠The l-α,ß-diaminopropionic acid polymer was characterized by a comb-like structure.⢠The novel poly(amino acid), PAP, exhibited antibacterial and antifungal activities.
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Streptomyces , Fermentação , Polilisina , Polímeros , beta-Alanina/análogos & derivadosRESUMO
Cancer metastasis that is resistant to conventional therapies has become a major cause of patient death. Recent reports indicate that the neutrophil extracellular trap (NET) is closely associated with cancer distant metastases, and the cell-free DNA of NETs has been identified as the ligand of the transmembrane protein CCDC25 of cancer cells, acting as a chemokine to induce cancer cell migration to distant organs. In this work, we present the poly(aspartic acid) based-cationic materials to interfere with the interaction between NET-DNA and CCDC25, and furthermore to inhibit NET-DNA-mediated cancer cell chemotaxis and migration. Because of a stronger binding affinity to DNA and favorable retention in the liver, nanoparticulate poly(aspartic acid) derivatives (cANP) efficiently reduce the level of hepatic NET-DNA infiltration, leading to a significant suppression of cancer metastases in mice and several human metastatic models. Moreover, the cANP exhibits no toxicity to organs of animals during the entire treatment. Thus, this work suggests a strategy for controlling cancer metastases, which will benefit patients in clinics.
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Armadilhas Extracelulares , Neoplasias , Humanos , Animais , Camundongos , Armadilhas Extracelulares/metabolismo , Neutrófilos , Aminoácidos/metabolismo , DNA/metabolismo , Fígado/metabolismo , Neoplasias/patologiaRESUMO
A series of novel poly(amino acid)s materials were designed to prepare drug-loaded nanoparticles by physical encapsulation and chemical bonding. The side chain of the polymer contains a large number of amino groups, which effectively increases the loading rate of doxorubicin (DOX). The structure contains disulfide bonds that showing a strong response to the redox environment, which can achieve targeted drug release in the tumor microenvironment. Nanoparticles mainly present spherical morphology with the suitable size for participating in systemic circulation. cell experiments demonstrate the non-toxicity and good cellular uptake behavior of polymers. In vivo anti-tumor experiments shows nanoparticles could inhibit tumor growth and effectively reduce the side effects of DOX.
Assuntos
Nanopartículas , Neoplasias , Humanos , Sistemas de Liberação de Medicamentos , Preparações de Ação Retardada/farmacologia , Aminoácidos , Sistemas de Liberação de Fármacos por Nanopartículas , Doxorrubicina/farmacologia , Doxorrubicina/química , Polímeros/química , Portadores de Fármacos/química , Nanopartículas/química , Oxirredução , Concentração de Íons de Hidrogênio , Microambiente TumoralRESUMO
Enhancing tissue permeability and achieving drug aggregation is the key to targeted tumor therapy. A series triblock copolymers of poly(ethylene glycol)-poly(L-lysine)-poly(L-glutamine) were synthesized by ring-opening polymerization, and charge-convertible nano-delivery system was constructed by loading doxorubicin (DOX) with 2-(hexaethylimide) ethanol on side chain. In normal environment (pH = 7.4), the zeta potential of the drug-loaded nanoparticle solution is negative, which is conducive to avoiding the identification and clearance of nanoparticles by the reticulo-endothelial system, while potential-reversal can be achieved in the tumor microenvironment, which effectively promotes cellular uptake. Nanoparticles could effectively reduce the distribution of DOX in normal tissues and achieve targeted aggregation at tumor sites, which can effectively improve the antitumor effect, while would not causing toxicity and damage to normal body.
Assuntos
Nanopartículas , Neoplasias , Humanos , Aminoácidos , Sistemas de Liberação de Medicamentos , Preparações de Ação Retardada , Doxorrubicina/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Concentração de Íons de Hidrogênio , Portadores de Fármacos/química , Microambiente TumoralRESUMO
Introduction: As the special modality of cell death, immunogenic cell death (ICD) could activate immune response. Phototherapy in combination with chemotherapy (CT) is a particularly efficient tumor ICD inducing method that could overcome the defects of monotherapies. Methods: In this study, new dual stimuli-responsive micelles were designed and prepared for imaging-guided mitochondrion-targeted photothermal/photodynamic/CT combination therapy through inducing ICD. A dual-sensitive methoxy-polyethylene glycol-SS-poly(L-γ-glutamylglutamine)-SS-IR780 (mPEG-SS-PGG-SS-IR780) polymer was synthesized by grafting IR780 with biodegradable di-carboxyl PGG as the backbone, and mPEG-SS-PGG-SS-IR780/paclitaxel micelles (mPEG-SS-PGG-SS-IR780/PTXL MCs) were synthesized by encapsulating PTXL in the hydrophobic core. Results: In-vivo and -vitro results demonstrated that the three-mode combination micelles inhibited tumor growth and enhanced the therapeutic efficacy of immunotherapy. The dual stimuli-responsive mPEG-SS-PGG-SS-IR780/PTXL MCs were able to facilitate tumor cell endocytosis of nanoparticles. They were also capable of promoting micelles disintegration and accelerating PTXL release. The mPEG-SS-PGG-SS-IR780/PTXL MCs induced mitochondrial dysfunction by directly targeting the mitochondria, considering the thermo- and reactive oxygen species (ROS) sensitivity of the mitochondria. Furthermore, the mPEG-SS-PGG-SS-IR780/PTXL MCs could play the diagnostic and therapeutic roles via imaging capabilities. Conclusion: In summary, this study formulated a high-efficiency nanoscale platform with great potential in combined therapy for tumors through ICD.
Assuntos
Micelas , Nanopartículas , Morte Celular Imunogênica , Indóis/química , Fototerapia/métodos , Nanopartículas/química , Mitocôndrias , Linhagem Celular TumoralRESUMO
The drug-amino acid co-amorphous systems and amorphous solid dispersions (ASDs) are promising methods to address the poor water solubility of poorly water-soluble drugs. However, some amino acids might not be perfect co-formers for co-amorphous systems, and the relatively low drug-loading of many ASDs is one of the main disadvantages of ASDs. Thus, poly-l-lysine and polyglutamic acid were selected as the co-formers, ball milled with basic mebendazole, neutral tadalafil and acidic valsartan at different weight ratios (from 3:1 to 1:3) to prepare poly (amino acid)-based ASDs, aiming to combine the advantages of co-amorphous systems (high drug-loading) and ASDs (relatively high Tg and high physical stability). All the mixtures were converted into amorphous after milling. The powder dissolution studies showed that drug-poly (amino acid) ASDs improved the dissolution rate of the drug in different ways and to different degrees. Moreover, the two poly (amino acid)s enhanced the physical stability of amorphous drugs. It is worthy to mention that the salt formation between the drug and the poly (amino acid) does not necessarily mean better performance compared to non-salt forming systems, and salt formation is also not a prerequisite for the formation of promising drug-poly (amino acid) ASDs.
Assuntos
Aminoácidos , Lisina , Aminoácidos/química , Estabilidade de Medicamentos , Solubilidade , Lisina/química , Água , Liberação Controlada de FármacosRESUMO
Polymers have always played a critical role in the development of novel drug delivery systems by providing the sustained, controlled and targeted release of both hydrophobic and hydrophilic drugs. Among the different polymers, polyamides or poly(amino acid)s exhibit distinct features such as good biocompatibility, slow degradability and flexible physicochemical modification. The degradation rates of poly(amino acid)s are influenced by the hydrophilicity of the amino acids that make up the polymer. Poly(amino acid)s are extensively used in the formulation of chemotherapeutics to achieve selective delivery for an appropriate duration of time in order to lessen the drug-related side effects and increase the anti-tumor efficacy. This review highlights various poly(amino acid) polymers used in drug delivery along with new developments in their utility. A thorough discussion on anticancer agents incorporated into poly(amino acid) micellar systems that are under clinical evaluation is included.
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Chiral aggregation-induced emission luminogens (AIEgens) are the new-generation chiral sensors that regulate chiral signals from the molecular level to the macroscopic assembly. Expanding applications of chiral AIEgens and in-depth understanding of their chiral recognition in biological systems are meaningful. Herein, two star chiral AIEgens, consisting of tetraphenylethene (TPE) as core and poly(N-acryloyl-L(D) valine) (PLV or PDV) as arms, were precisely synthesized via atom transfer radical polymerization (ATRP) technique and named TPE-PLV and TPE-PDV. They possessed typical AIE characteristics and exhibited an increase in concentration-dependent fluorescence intensity. The two AIEgens were pH-responsive and had strong AIE-related emission in acidic solution. Importantly, AIEgens can enter the living cells by ATP dependent endocytosis, then light them up. The interactions between the AIEgens and living human hepatocarcinoma (HepG2) cells revealed that the internalization process of TPE-PLV and TPE-PDV was both chiral-dependent and pH-responsive. This novel strategy for synthesizing poly(amino acid)s functionalized AIEgens could inspire the development of promising fluorescent materials with chirality.
Assuntos
Aminoácidos , Corantes Fluorescentes , Humanos , Concentração de Íons de Hidrogênio , PolimerizaçãoRESUMO
Degradable polymers (DPs) - "green materials" of the future, have an innumerable use in biomedicine, particularly in the fields of tissue engineering and drug delivery. Among these kind of materials naturally occurring polymers - proteins which constituted one of the most important "bricks of life" - α-amino acids (AAs) are highly suitable. A wide biomedical applicability of proteins is due to special properties such as a high affinity with tissues and releasing AAs upon biodegradation that means a nutritive potential for cells. Along with these positive characteristics proteins as biomedical materials they have some shortcomings, such as batch-to-batch variation, risk of disease transmission, and immune rejection. The last limitation is connected with the molecular architecture of proteins. Furthermore, the content of only peptide bonds in protein molecules significantly restricts their material properties. Artificial polymers with the composition of AAs are by far more promising as degradable biomaterials since they are free from the limitations of proteins retaining at the same time their positive features - a high tissue compatibility and nutritive potential. The present review deals with a brief description of different families of AA-based artificial polymers, such as poly(amino acid)s, pseudo-poly(amino acid)s, polydepsipeptides, and pseudo-proteins - relatively new and broad family of artificial AA-based DPs. Most of these polymers have a different macromolecular architecture than proteins and contain various types of chemical links along with NH-CO bonds that substantially expands properties of materials destined for sophisticated biomedical applications.
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Aminoácidos/química , Depsipeptídeos/química , Polímeros/química , Materiais Biocompatíveis , Engenharia TecidualRESUMO
The interaction of PEGylated poly(amino acid)s with their biological targets depends on their chemical nature and spatial arrangement of their building blocks. The synthesis, self-assembly, and DNA complexation of ABC terblock copolymers consisting of poly(ethylene glycol), (PEG), poly(l-lysine), and poly(l-leucine), are reported. Block copolymers are produced by a metal-free, living ring-opening polymerization of respective amino acid N-carboxyanhydrides using amino-terminated PEG as macroinitiator: (PEG-b-p(l-Lys)x -b-p(l-Leu)y , PEG-b-p(l-Leu)x -b-p(l-Lys)y , and PEG-b-p((l-Lys)x -co-p(l-Leu)y ). Sizes of self-assembled nanoparticles depend on the formation method. The nanoprecipitation method proves useful for copolymers with the poly(l-lysine) block protected as trifluoroacetate, effective diameters range between 92 and 132 nm, while direct dissolution in distilled water is suitable for the deprotected copolymers, yielding effective diameters between 52 and 173 nm. Critical micelle concentration (CMC) analyses corroborate particle size analyses and show a distinct impact of the molecular architecture; the lowest CMC (8 µg mL-1 ) is observed when the poly(l-leucine) segment forms the C-block and the hydrophilic, disassembly driving poly(l-lysine) segment is short. DNA complexation, evaluated by gel motility and RiboGreen analyses, depends strongly on the molecular architecture. A more efficient DNA complexation is observed when poly(l-lysine) and poly(l-leucine) form individual blocks as opposed to them forming a copolymer.
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Técnicas de Transferência de Genes , Nanopartículas/química , Polímeros/química , Cátions , Polietilenoglicóis/químicaRESUMO
The poly(amino acid)s based biomaterials have attracted great research attention over the past few decades because of their biocompatibility, biodegradability and well designability. Although much progress has achieved in the synthesis and biomedical applications of poly(amino acid)s, the synthesis of luminescent poly(amino acid)s has been rarely reported. In this work, novel amphiphilic luminescent poly(amino acid)s with aggregation-induced emission (AIE) feature have been synthesized by a new approach of controlling N-carboxy anhydride (NCA) ring-opening polymerization, in which hydrophobic 2-(4-aminophenyl)-3-(10-hexadecyl-4H-phenothiazin-3-yl)acrylonitrile (Phe-NH2) with AIE feature was used as initiator and hydrophilic oligomeric glycol functionalized glutamate (OEG-glu) NCA was acted as monomer. The successful synthesis of final Phe-OEG-Pglu polymers was confirmed by different characterization techniques. Phe-OEG-Pglu polymers possess amphiphilic properties and can self-assemble into luminescent polymeric nanoparticles (LPNs). Based on cellular imaging experiments, we demonstrated that Phe-OEG-Pglu LPNs have great potential for bio-imaging applications due to their attractive properties including strong fluorescence intensity, great water dispersibility, excellent biocompatibility and high cellular uptake efficiency.
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Aminoácidos/química , Luminescência , Nanopartículas , Polimerização , PolímerosRESUMO
The redox capacity, as well as the aurophilicity of the terminal thiol side groups, in poly(Cysteine) lend a unique characteristic to this poly(amino acid) or polypeptide. There are two major application fields for this polymer: (i) biomedical applications in drug delivery and surface modification of biomedical devices and (ii) as coating for electrodes to enhance their electrochemical sensitivity. The intended application determines the synthetic route for p(Cysteine). Polymers to be used in biomedical applications are typically polymerized from the cysteine N-carboxyanhydride by a ring-opening polymerization, where the thiol group needs to be protected during the polymerization. Advances in this methodology have led to conditions under which the polymerization progresses as living polymerization, which allows for a strict control of the molecular architecture, molecular weight and polydispersity and the formation of block copolymers, which eventually could display polyphilic properties. Poly(Cysteine) used as electrode coating is typically polymerized onto the electrode by cyclic voltammetry, which actually produces a continuous, pinhole-free film on the electrode via the formation of covalent bonds between the amino group of Cysteine and the carbon of the electrode. This resulting coating is chemically very different from the well-defined poly(Cysteine) obtained by ring-opening polymerizations. Based on the structure of cysteine a significant degree of cross-linking within the coating deposited by cyclic voltammetry can be assumed. This manuscript provides a detailed discussion of the ring-opening polymerization of cysteine, a brief consideration of the role of glutathione, a key cysteine-containing tripeptide, and examples for the utilization of poly(Cysteine) and poly(Cysteine)-containing copolymers, in both, the biomedical as well as electrochemical realm.
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Different types of amphiphilic macromolecular structures have been developed within recent decades to prepare the polymer particles considered as drug delivery systems. In the present research the series of amphiphilic block-copolymers containing poly(glutamatic acid) as hydrophilic, and polyphenylalanine as hydrophobic blocks was synthesized and characterized. Molecular weights for homo- and copolymers were determined by gel-permeation chromatography (GPC) and amino acid analysis, respectively. The copolymers obtained were applied for preparation of polymer particles. The specific morphology of prepared polymerosomes was proved using transmission electron microscopy (TEM). The influence on particle size of polymer concentration and pH used for self-assembly, as well as on the length of hydrophobic and hydrophilic blocks of applied copolymers, was studied by dynamic light scattering (DLS). Depending on different experimental conditions, the formation of nanoparticles with sizes from 60 to 350 nm was observed. The surface of polymersomes was modified with model protein (enzyme). No loss in biocatalytic activity was detected. Additionally, the process of encapsulation of model dyes was developed and the possibility of intracellular delivery of the dye-loaded nanoparticles was proved. Thus, the nanoparticles discussed can be considered for the creation of modern drug delivery systems.
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A drug delivery system to the inner ear using nanoparticles consisting of oligoarginine peptide (Arg8) conjugated to poly(amino acid) (poly(2-hydroxyethyl L-aspartamide; PHEA) was investigated to determine whether the limitations of low drug transport levels across the round window membrane (RWM) and poor transport into inner ear target cells, including hair cells and spiral ganglion, could be overcome. Three types of carrier materials, PHEA-g-C18, PHEA-g-Arg8, and PHEA-g-C18-Arg8, were synthesized to examine the effects of oligoarginine and morphology of the synthesized carriers. Nile red (NR) was used as a fluorescent indicator as well as to model a hydrophobic drug. Compared with PHEA-g-C18-NR nanoparticles, the oligoarginine-conjugated nanoparticles of PHEA-g-C18-Arg8-NR and PHEA-g-Arg8-NR entered into HEI-OC1 cells at significant levels. Furthermore, the strongest fluorescence intensity was observed in nuclei when PHEA-g-C18-Arg8 nanoparticles were used. The high uptake rates of PHEA-g-C18 and PHEA-g-C18-Arg8 nanoparticles were observed in ex vivo experiments using hair cells. After the delivery of PHEA-g-C18-Arg8 nanoparticles with reporter gene transfer, EGFP (enhanced green fluorescent protein) expression was monitored as an indicator of gene delivery. In the inner ear cells, PHEA-g-C18-Arg8 nanoparticles showed comparable or better transfection capabilities than the commercially available Lipofectamine reagent. PHEA-g-C18-Arg8 penetrated in vivo across the RWM of C57/BL6 mice with Nile red staining and GFP expression in various inner ear tissues. In conclusion, PHEA-g-C18-Arg8 nanoparticles were successfully transported into the inner ear through the intratympanic route and are proposed as promising candidates as delivery carriers to address inner ear diseases.
Assuntos
Arginina/administração & dosagem , Portadores de Fármacos/química , Orelha Interna/efeitos dos fármacos , Técnicas de Transferência de Genes , Nanopartículas/química , Animais , Núcleo Celular/metabolismo , Cóclea/patologia , Sistemas de Liberação de Medicamentos , Regulação da Expressão Gênica , Vetores Genéticos/química , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/metabolismo , Células Ciliadas Auditivas/metabolismo , Humanos , Lipídeos/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxazinas/química , Poli-Hidroxietil Metacrilato/análogos & derivados , Poli-Hidroxietil Metacrilato/química , Polímeros/química , Janela da Cóclea/metabolismo , Solventes/químicaRESUMO
INTRODUCTION: Pulmonary delivery is an attractive administration route for therapeutic proteins and peptides. In this context, endocytosis/transcytosis at the distal lung epithelial barrier is an important process in the pulmonary absorption of therapeutic macromolecules. The alveolar epithelium is comprised of type I and type II cells. Understanding the transport mechanisms in these cells is essential for the development of efficient pulmonary delivery systems of therapeutic macromolecules. AREAS COVERED: Endocytic pathways for albumin and insulin in alveolar epithelial cells and possible receptors for the endocytosis are discussed. Strategies to enhance the endocytosis and pulmonary absorption of macromolecules are also discussed, by focusing on the effects of cationic poly(amino acid)s. EXPERT OPINION: Although the surface area occupied by type II cells in alveoli is much smaller than that covered by type I cells, type II cells may significantly contribute to the endocytosis/transcytosis of macromolecules such as albumin. Identification of the receptors involved in the cellular uptake of each macromolecule is prerequisite for the understanding and regulation of its transport into and across alveolar epithelial cells. Establishment of novel in-vitro culture cell models of type I and type II cells would be a great help for the future advance of this research field.