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1.
J Mater Chem B ; 9(41): 8594-8603, 2021 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-34705008

RESUMEN

Peptide dendrimers have a broad application in biomedical science due to their biocompatibility, diversity, and multifunctionality, but the precision synthesis of high-molecule weight peptide dendrimers remains challenging. We here report the facile and liquid-phase synthesis of molecular level precision and amino-acid built-in polylysine (PLL) dendrimers with molecular weights as high as ∼60 kDa. Three types of polyhedral oligosilsesquioxane (POSS)-cored PLL dendrimers with phenylalanine, tyrosine, or histidine as building blocks were synthesized. The precise structures of the dendrimers were confirmed by MALDI-TOF MS, GPC, and 1H NMR spectroscopy. The interior functionalized peptide dendrimers improved the encapsulation capability of SN38 and sustained the release profiles. Enhanced molecular interactions between the peptide dendrimers and drugs were explored by both NMR experiments and computer simulations. The peptide dendrimer/SN38 formulations showed potent antitumor activity against multiple cancer cell lines. We believe that this strategy can be applied to the synthesis of tailor-made functional peptide dendrimers for drug-specific delivery and other diverse biomedical applications.


Asunto(s)
Aminoácidos/química , Antineoplásicos/química , Dendrímeros/química , Sistemas de Liberación de Medicamentos , Péptidos/química , Polilisina/química , Aminoácidos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dendrímeros/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Irinotecán/química , Irinotecán/farmacología , Estructura Molecular , Peso Molecular , Péptidos/síntesis química , Péptidos/farmacología , Polilisina/síntesis química , Polilisina/farmacología , Células Tumorales Cultivadas
2.
ACS Appl Bio Mater ; 4(5): 4310-4318, 2021 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-35006843

RESUMEN

Developing strategies to optimize double-stranded RNA (dsRNA) delivery remains a significant challenge in improving RNA interference (RNAi) in insects. Nanoformulations may provide an avenue for the safe and effective delivery of dsRNA. We investigated nanoparticle-mediated gene silencing using biodegradable polymers, poly-l-lysine (PLL), and polyphenol (-)-epigallocatechin gallate (EGCG) for dsRNA delivery into Spodoptera frugiperda (Sf9) cells. Negatively charged cores were formed by EGCG and dsRNA complexes, and PLL was used to encapsulate the cores. The nanoparticles were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), scanning transmission electron microscopy (STEM), and energy-dispersive spectrometry (EDS) analysis. The stability of the nanoparticles was assessed by incubating them in nuclease-containing Sf9 cell conditioned media. The effectiveness of the nanoparticles was investigated in Sf9 cells stably expressing the luciferase gene. The results revealed that the nanoparticles formed were small and spherical. The PLL/EGCG/dsRNA nanoparticles exhibited better stability compared to that of PLL/dsRNA or naked dsRNA. Nanoparticles prepared with dsRNA targeting the luciferase gene induced an efficient knockdown (66.7%) of the target gene. In Sf9 cells, nanoparticles prepared with Cy3- or CyPHer-5E-labeled dsRNA showed higher cellular uptake and endosomal escape, respectively, than the naked dsRNA. The improvement in uptake and cytosolic delivery may have helped to increase the knockdown efficiency. In Sf9 cells, the nanoparticles prepared with dsRNA targeting the inhibitor of apoptosis gene induced apoptosis by knocking down its expression. In conclusion, we demonstrate that PLL/EGCG/dsRNA nanoparticles are stable, highly efficient, and effective in dsRNA delivery and knockdown of the target gene.


Asunto(s)
Materiales Biocompatibles/química , Catequina/química , Nanopartículas/química , Polilisina/química , ARN Bicatenario/química , Spodoptera/genética , Animales , Materiales Biocompatibles/síntesis química , Catequina/síntesis química , Silenciador del Gen , Ensayo de Materiales , Tamaño de la Partícula , Polilisina/síntesis química , ARN Bicatenario/genética , Spodoptera/citología
3.
Biomater Sci ; 8(13): 3611-3627, 2020 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-32515439

RESUMEN

The limited regenerative capacity of the CNS poses formidable challenges to the repair of spinal cord injury (SCI). Two key barriers to repair are (i) the physical gap left by the injury, and (ii) the inhibitory milieu surrounding the injury, the glial scar. Biomaterial implantation into the injury site can fill the cavity, provide a substrate for cell migration, and potentially attenuate the glial scar. We investigated the biological viability of a biocompatible and biodegradable poly-ε-lysine based biomaterial, Proliferate®, in low and high cross-linked forms and when coated with IKVAV peptide, for SCI implantation. We demonstrate altered astrocyte morphology and nestin expression on Proliferate® compared to conventional glass cell coverslips suggesting a less reactive phenotype. Moreover Proliferate® supported myelination in vitro, with myelination observed sooner on IKVAV-coated constructs compared with uncoated Proliferate®, and delayed overall compared with maintenance on glass coverslips. For in vivo implantation, parallel-aligned channels were fabricated into Proliferate® to provide cell guidance cues. Extensive vascularisation and cellular infiltration were observed in constructs implanted in vivo, along with an astrocyte border and microglial response. Axonal ingrowth was observed at the construct border and inside implants in intact channels. We conclude that Proliferate® is a promising biomaterial for implantation following SCI.


Asunto(s)
Materiales Biocompatibles/química , Enfermedades del Sistema Nervioso Central/terapia , Polilisina/química , Prótesis e Implantes , Traumatismos de la Médula Espinal/terapia , Animales , Materiales Biocompatibles/síntesis química , Células Cultivadas , Polilisina/síntesis química , Ratas , Ratas Sprague-Dawley
4.
Int J Nanomedicine ; 15: 3023-3038, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32431499

RESUMEN

INTRODUCTION: Advanced tumor-targeted theranostic nanoparticles play a key role in tumor diagnosis and treatment research. In this study, we developed a multifunctional theranostic platform based on an amphiphilic hyaluronan/poly-(N-ε-carbobenzyloxy-L-lysine) derivative (HA-g-PZLL), superparamagnetic iron oxide (SPIO) and aggregation-induced emission (AIE) nanoparticles for tumor-targeted magnetic resonance (MR) and fluorescence (FL) dual-modal image-guided photodynamic therapy (PDT). MATERIALS AND METHODS: The amphiphilic hyaluronan acid (HA) derivative HA-g-PZLL was synthesized by grafting hydrophobic poly-(N-ε-carbobenzyloxy-L-lysine) (PZLL) blocks onto hyaluronic acid by a click conjugation reaction. The obtained HA-g-PZLLs self-assembled into nanoparticles in the presence of AIE molecules and SPIO nanoparticles to produce tumor-targeted theranostic nanoparticles (SPIO/AIE@HA-g-PZLLs) with MR/FL dual-modal imaging ability. Cellular uptake of the theranostic nanoparticles was traced by confocal laser scanning microscopy (CLSM), flow cytometry and Prussian blue staining. The intracellular reactive oxygen species (ROS) generation characteristics of the theranostic nanoparticles were evaluated with CLSM and flow cytometry. The effect of PDT was evaluated by cytotoxicity assay. The dual-mode imaging ability of the nanoparticles was evaluated by a real-time near-infrared fluorescence imaging system and magnetic resonance imaging scanning. RESULTS: The resulting theranostic nanoparticles not only emit red fluorescence for high-quality intracellular tracing but also effectively produce singlet oxygen for photodynamic tumor therapy. In vitro cytotoxicity experiments showed that these theranostic nanoparticles can be efficiently taken up and are mainly present in the cytoplasm of HepG2 cells. After internalization, these theranostic nanoparticles showed serious cytotoxicity to the growth of HepG2 cells after white light irradiation. DISCUSSION: This work provides a simple method for the preparation of theranostic nanoparticles with AIE characteristics and MR contrast enhancement, and serves as a dual-modal imaging platform for image-guided tumor PDT.


Asunto(s)
Medios de Contraste/química , Imagen por Resonancia Magnética , Nanopartículas/química , Imagen Óptica , Fotoquimioterapia , Nanomedicina Teranóstica , Animales , Línea Celular Tumoral , Femenino , Fluorescencia , Células Hep G2 , Humanos , Ácido Hialurónico/síntesis química , Ácido Hialurónico/química , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/ultraestructura , Polilisina/síntesis química , Polilisina/química , Espectroscopía de Protones por Resonancia Magnética , Especies Reactivas de Oxígeno/metabolismo , Espectroscopía Infrarroja por Transformada de Fourier
5.
J Mater Chem B ; 8(12): 2418-2430, 2020 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-32115589

RESUMEN

Bioreducible cationic polymers have gained considerable attention in gene delivery due to their low cytotoxicity and high efficiency. In the present work, we reported a cationic polymer, poly(disulfide-l-lysine)-g-agmatine (denoted as SSL-AG), and evaluated its ability to transfer pEGFP-ZNF580 plasmid (pZNF580) into human umbilical vein endothelial cells (HUVECs). This SSL-AG polymeric carrier efficiently condensed pZNF580 into positively charged particles (<200 nm) through electrostatic interaction. This carrier also exhibited excellent buffering capacity in the physiological environment, good pDNA protection against enzymatic degradation and rapid pDNA release in a highly reducing environment mainly because of the responsive cleavage of disulfide bonds in the polymer backbone. The hemolysis assay and in vitro cytotoxicity assay suggested that the SSL-AG carrier and corresponding gene complexes possessed both good hemocompatibility and great cell viability in HUVECs. The cellular uptake of the SSL-AG/Cy5-oligonucleotide group was 3.6 times that of the poly(l-lysine)/Cy5-oligonucleotide group, and its mean fluorescence intensity value was even higher than that of the PEI 25 kDa/Cy5-oligonucleotide group. Further, the intracellular trafficking results demonstrated that the SSL-AG/Cy5-oligonucleotide complexes exhibited a high nucleus co-localization rate (CLR) value (36.0 ± 2.8%, 3.4 times that of the poly (l-lysine)/Cy5-oligonucleotide group, 1.6 times that of the poly(disulfide-l-lysine)-g-butylenediamine/Cy5-oligonucleotide group) at 24 h, while the endo/lysosomal CLR value was relatively low. This suggested that SSL-AG successfully delivered plasmid into HUVECs with high cellular uptake, rapid endosomal escape and efficient nuclear accumulation owing to the structural advantages of the bioreducible and agmatine groups. In vitro transfection assay also verified the enhanced transfection efficiency in the SSL-AG/pZNF580 group. Furthermore, the results of CCK-8, cell migration and in vitro/vivo angiogenesis assays revealed that pZNF580 delivered by SSL-AG could effectively enhance the proliferation, migration and vascularization of HUVECs. In a word, the SSL-AG polymer has great potential as a safe and efficient gene carrier for gene therapy.


Asunto(s)
Agmatina/química , Técnicas de Transferencia de Gen , Polilisina/química , Agmatina/síntesis química , Agmatina/farmacología , Animales , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Masculino , Ratones , Tamaño de la Partícula , Polilisina/síntesis química , Polilisina/farmacología , Propiedades de Superficie
6.
ACS Appl Mater Interfaces ; 11(40): 36939-36948, 2019 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-31513367

RESUMEN

Stimuli-responsive biomaterials supply a promising solution to adapt to the complex physiological environment for different biomedical applications. In this study, a dynamic UV-triggered pH-responsive biosurface was constructed on titania nanotubes (TNTs) by loading photoacid generators, diphenyliodonium chloride, into the nanotubes, and grafting 2,3-dimethyl maleic anhydride (DMMA)-modified hyperbranched poly(l-lysine) (HBPLL) onto the surface. The local acidity was dramatically enhanced by UV irradiation for only 30 s, leading to the dissociation of DMMA and thereby the transformation of surface chemistry from negatively charged caboxyl groups to positively charged amino groups. The TNTs-HBPLL-DMMA substrate could better promote proliferation and spreading of rat bone mesenchymal stem cells (rBMSCs) after UV irradiation. The osteogenic differentiation of rBMSCs was enhanced because of the charge reversal in combination with the titania-based substrates.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/efectos de la radiación , Nanotubos/química , Titanio/farmacología , Rayos Ultravioleta , Fosfatasa Alcalina/metabolismo , Animales , Compuestos de Bifenilo/química , Adhesión Celular/efectos de los fármacos , Adhesión Celular/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Masculino , Anhídridos Maleicos/síntesis química , Anhídridos Maleicos/química , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de la radiación , Nanotubos/ultraestructura , Compuestos Onio/química , Polilisina/síntesis química , Polilisina/química , Ratas Sprague-Dawley , Propiedades de Superficie
7.
Int J Biol Macromol ; 140: 423-428, 2019 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-31381925

RESUMEN

Penicillin G acylase (PGA) from Providencia rettgeri PX04 (PrPGA) was utilized to synthesize ß-lactam antibiotics. Poly-lysine supported cross-linked enzyme aggregates (PL-CLEAs) were prepared using PGA. Addition of poly-lysine significantly increased retention of PGA activity in CLEAs, with a decrease in the synthesis/hydrolysis (S/H) ratio. PL-CLEAs with 0.56 mg/mL poly-lysine retained 83% of free PGA activity, and displayed a higher S/H ratio than that of the free enzyme. Both PL-CLEAs and CLEAs exhibited high pH and thermal stabilities. PL-CLEAs possessed the best stability profile, and the lowest α value [(kcat/Km)Ps/(kcat/Km)AD], and was most effective at amoxicillin synthesis. A >94% yield of amoxicillin was achieved using a D-HPGME/6-APA ratio of 1.2:1 (240 mM, 200 mM), with fed-batch addition of D-HPGME. PL-CLEAs displayed excellent operational stability during amoxicillin synthesis. Over 97% of initial conversion was retained after twenty rounds of catalysis. PL-CLEAs exhibited greater potency than CLEAs in practical catalysis, permitting a higher concentration of reactants.


Asunto(s)
Antibacterianos/química , Penicilina Amidasa/química , Polilisina/química , beta-Lactamas/química , Antibacterianos/síntesis química , Catálisis , Reactivos de Enlaces Cruzados/síntesis química , Reactivos de Enlaces Cruzados/química , Estabilidad de Enzimas , Enzimas Inmovilizadas/química , Hidrólisis , Cinética , Polilisina/síntesis química , Providencia/química , Resistencia betalactámica/genética , beta-Lactamas/síntesis química
8.
Molecules ; 24(8)2019 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-30991689

RESUMEN

We developed a tumor-targeted contrast agent based on linear polylysine (PLL) by conjugating a small molecular imaging agent, fluorescent molecule and targeting agent amino phenylboronic acid onto the amino groups of polylysine, which can specifically target monosaccharide sialic acid residues overexpressing on the surface of tumor cell membranes. Further, 3,4,5,6-Tetrahydrophthalic anhydride (DCA) was attached to the free amino groups of the polylysine to change to a negative charge at physiology pH to lower the cytotoxicity, but it soon regenerated to a positive charge again once reaching the acidic intratumoral environment and therefore increased cell uptake. Laser confocal microscopy images showed that most of the polymeric contrast agents were bound to the cancer cell membrane. Moreover, the tumor targeting contrast agent showed the same magnetic resonance imaging (MRI) contrasting performance in vitro as the small molecule contrast agent used in clinic, which made it a promising tumor-targeting polymeric contrast agent for cancer diagnosis.


Asunto(s)
Medios de Contraste , Imagen por Resonancia Magnética , Neoplasias/diagnóstico por imagen , Animales , Medios de Contraste/síntesis química , Medios de Contraste/química , Medios de Contraste/farmacología , Perros , Células Hep G2 , Humanos , Células de Riñón Canino Madin Darby , Microscopía Confocal , Neoplasias/metabolismo , Neoplasias/patología , Polilisina/síntesis química , Polilisina/química , Polilisina/farmacología
9.
J Nanobiotechnology ; 16(1): 80, 2018 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-30316298

RESUMEN

BACKGROUND: Engineered inorganic nanoparticles (NPs) are essential components in the development of nanotechnologies. For applications in nanomedicine, particles need to be functionalized to ensure a good dispersibility in biological fluids. In many cases however, functionalization is not sufficient: the particles become either coated by a corona of serum proteins or precipitate out of the solvent. We show that by changing the coating of magnetic iron oxide NPs using poly-L-lysine (PLL) polymer the colloidal stability of the dispersion is improved in aqueous solutions including water, phosphate buffered saline (PBS), PBS with 10% fetal bovine serum (FBS) and cell culture medium, and the internalization of the NPs toward living mammalian cells is profoundly affected. METHODS: A multifunctional magnetic NP is designed to perform a near-infrared (NIR)-responsive remote control photothermal ablation for the treatment of breast cancer. In contrast to the previously reported studies of gold (Au) magnetic (Fe3O4) core-shell NPs, a Janus-like nanostructure is synthesized with Fe3O4 NPs decorated with Au resulting in an approximate size of 60 nm mean diameter. The surface of trisoctahedral Au-Fe3O4 NPs was coated with a positively charged polymer, PLL to deliver the NPs inside cells. The PLL-Au-Fe3O4 NPs were characterized by transmission electron microscopy (TEM), XRD, FT-IR and dynamic light scattering (DLS). The unique properties of both Au surface plasmon resonance and superparamagnetic moment result in a multimodal platform for use as a nanothermal ablator and also as a magnetic resonance imaging (MRI) contrast agent, respectively. Taking advantage of the photothermal therapy, PLL-Au-Fe3O4 NPs were incubated with BT-474 and MDA-MB-231 breast cancer cells, investigated for the cytotoxicity and intracellular uptake, and remotely triggered by a NIR laser of ~ 808 nm (1 W/cm2 for 10 min). RESULTS: The PLL coating increased the colloidal stability and robustness of Au-Fe3O4 NPs (PLL-Au-Fe3O4) in biological media including cell culture medium, PBS and PBS with 10% fetal bovine serum. It is revealed that no significant (< 10%) cytotoxicity was induced by PLL-Au-Fe3O4 NPs itself in BT-474 and MDA-MB-231 cells at concentrations up to 100 µg/ml. Brightfield microscopy, fluorescence microscopy and TEM showed significant uptake of PLL-Au-Fe3O4 NPs by BT-474 and MDA-MB-231 cells. The cells exhibited 40 and 60% inhibition in BT-474 and MDA-MB-231 cell growth, respectively following the internalized NPs were triggered by a photothermal laser using 100 µg/ml PLL-Au-Fe3O4 NPs. The control cells treated with NPs but without laser showed < 10% cell death compared to no laser treatment control CONCLUSION: Combined together, the results demonstrate a new polymer gold superparamagnetic nanostructure that integrates both diagnostics function and photothermal ablation of tumors into a single multimodal nanoplatform exhibiting a significant cancer cell death.


Asunto(s)
Compuestos Férricos/química , Oro/química , Nanopartículas de Magnetita/química , Polímeros/química , Nanomedicina Teranóstica/métodos , Muerte Celular , Línea Celular Tumoral , Fluorescencia , Humanos , Hipertermia Inducida , Nanopartículas de Magnetita/ultraestructura , Fototerapia , Polilisina/síntesis química , Polilisina/química , Electricidad Estática , Temperatura , Difracción de Rayos X
10.
J Am Chem Soc ; 140(38): 11992-12000, 2018 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-30156838

RESUMEN

High transfection efficiency and low cytotoxicity are the two key factors to be considered in the design of gene carriers. Herein, a novel and versatile gene carrier (PLL-RT) was prepared by introducing "molecular string" RT (i.e., p-toluylsulfonyl arginine) onto the polylysine backbone. The introduction of RT string contributed to the formation of multiple interactions between the polycationic gene carriers and cell membrane or DNA, as well as adopting α-helix conformation, all of which would be beneficial to enhance the gene transfection. In addition, RT string grafted onto other polycations such as hyperbranced PEI25k and dendrimer PAMAM could also acquire improved transfection efficiency and low cytotoxicity. Moreover, PLL-RT presented significant tumor inhibition effect in vivo. This work provided an effective strategy for constructing novel gene carriers with high transfection and low cytotoxicity.


Asunto(s)
ADN/genética , Técnicas de Transferencia de Gen , Polilisina/análogos & derivados , Tosilarginina Metil Éster/análogos & derivados , Animales , Cardiolipinas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , ADN/metabolismo , Endocitosis/fisiología , Endosomas/metabolismo , Femenino , Humanos , Membranas Artificiales , Ratones Endogámicos BALB C , Conformación Molecular , Neoplasias/terapia , Tamaño de la Partícula , Polilisina/síntesis química , Polilisina/metabolismo , Polilisina/toxicidad , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/uso terapéutico , Tosilarginina Metil Éster/síntesis química , Tosilarginina Metil Éster/metabolismo , Tosilarginina Metil Éster/toxicidad
11.
Int J Nanomedicine ; 13: 3625-3640, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29983558

RESUMEN

BACKGROUND: Lumbrokinase (LK) is an enzyme complex with antithrombotic, antioxidant, antitumor, and immunomodulatory effects. It has been extensively studied and used in clinical anti-tumor therapy. However, its half-life is short, its bioavailability is low, and its toxicity and side effects are great, which greatly limit its clinical application. Therefore, LK is often combined with other drugs (such as immune agents, hormones, or Chinese herbal medicine) to reduce its dosage and side effects and to improve its anti-tumor effects. METHODS AND RESULTS: Here, we described an LK/paclitaxel (PTX) nanocarrier based on poly(ethylene glycol)-b-(poly(ethylenediamine l-glutamate)-g-poly(ε-benzyoxycarbonyl-l-lysine)-r-poly(l-lysine)) (PEG-b-(PELG-g-(PZLL-r-PLL))). In the present study, LK and PTX were loaded by electrostatic and/or hydrophobic effects under mild conditions, thereby increasing the half-life and bioavailability of the drugs via the sustained release and enhancement of tumor site enrichment by the LK/PTX/PEG-b-(PELG-g-(PZLL-r-PLL)) complex through passive targeting. In this study, using bladder cancer cells (J82 cells) and rat bladder cancer model as the object, the structure of the nanocarrier, the relationship between drugs composition and antitumor properties were systematically studied. CONCLUSION: We propose that the block copolymer PEG-b-(PELG-g-(PZLL-r-PLL)) may function as a potent nanocarrier for augmenting anti-bladder cancer pharmacotherapy, with unprecedented clinical benefits.


Asunto(s)
Albúminas/uso terapéutico , Endopeptidasas/uso terapéutico , Paclitaxel/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Albúminas/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclina B1/metabolismo , Portadores de Fármacos/química , Endopeptidasas/sangre , Endopeptidasas/farmacología , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Lisina/análogos & derivados , Lisina/síntesis química , Lisina/química , Masculino , Microvasos/patología , Peso Molecular , Paclitaxel/sangre , Paclitaxel/farmacología , Polietilenglicoles/síntesis química , Polietilenglicoles/química , Polilisina/análogos & derivados , Polilisina/síntesis química , Polilisina/química , Ratas Sprague-Dawley , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias de la Vejiga Urinaria/sangre , Neoplasias de la Vejiga Urinaria/irrigación sanguínea , Neoplasias de la Vejiga Urinaria/patología
12.
Bioorg Med Chem ; 26(9): 2539-2550, 2018 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-29656988

RESUMEN

Cationic nucleopeptides belong to a family of synthetic oligomers composed by amino acids and nucleobases. Their capability to recognize nucleic acid targets and to cross cellular membranes provided the basis for considering them as novel non-covalent delivery agents for nucleic acid pharmaceuticals. Herein, starting from a 12-mer nucleopeptide model, the number of cationic residues was modulated in order to obtain new nucleopeptides endowed with high solubility in acqueous medium, acceptable bio-stability, low cytotoxicity and good capability to bind nucleic acid. Two candidates were selected to further investigate their potential as nucleic acid carriers, showing higher efficiency to deliver PNA in comparison with RNA. Noteworthy, this study encourages the development of nucleopeptides as new carriers to extend the known strategies for those nucleic acid analogues, especially PNA, that still remain difficult to drive into the cells.


Asunto(s)
Portadores de Fármacos/metabolismo , Ácidos Nucleicos de Péptidos/metabolismo , Polilisina/metabolismo , ARN/metabolismo , Timina/análogos & derivados , Timina/metabolismo , Cationes/síntesis química , Cationes/química , Cationes/metabolismo , Cationes/toxicidad , Línea Celular Tumoral , Permeabilidad de la Membrana Celular , Dicroismo Circular , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Portadores de Fármacos/toxicidad , Humanos , Conformación de Ácido Nucleico , Hibridación de Ácido Nucleico , Ácidos Nucleicos de Péptidos/química , Ácidos Nucleicos de Péptidos/genética , Polilisina/síntesis química , Polilisina/química , Polilisina/toxicidad , ARN/química , ARN/genética , Solubilidad , Temperatura , Timina/síntesis química , Timina/toxicidad , Transfección/métodos
13.
Anal Chem ; 90(5): 3149-3155, 2018 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-29397683

RESUMEN

A simple, noncovalent modification strategy was proposed to synthesize poly-l-lysine-black phosphorus (pLL-BP) hybrid. BP nanoflakes were prepared with a water-phase exfoliation method. pLL can adhere to the surface of BP via hydrophobic interaction between butyl chains of pLL and the BP surface as well as the electrostatic interaction between the protonated amino groups on pLL and the negative charge on deprotonated PxOy groups remaining on BP. The as-synthesized pLL-BP hybrid turns out to be an ideal matrix for hemoglobin immobilization and direct electron transfer. Good conductivity and biocompatibility of BP maintain the native structure and the bioactivity of hemoglobin (Hb), facilitating the direct electron transfer between the electroactive center of Hb and electrode. The rate constant ( kET) for direct electron transfer of Hb@pLL-BP is calculated to be 11.24 s-1. The constructed Hb-pLL-BP based enzymatic electrochemical biosensor displays excellent catalytic activity toward the reduction of oxygen and hydrogen peroxide. The electrochemical response toward H2O2 exhibits a linear dependence on hydrogen peroxide concentration ranging between 10 µM and 700 µM. The results demonstrate that the pLL-BP hybrid can act as a biocompatible building block for the construction of novel biofuel cells, bioelectronics, and biosensors.


Asunto(s)
Nanoestructuras/química , Fósforo/química , Polilisina/química , Animales , Técnicas Biosensibles/métodos , Bovinos , Técnicas Electroquímicas/métodos , Hemoglobinas/química , Peróxido de Hidrógeno/análisis , Peróxido de Hidrógeno/química , Interacciones Hidrofóbicas e Hidrofílicas , Proteínas Inmovilizadas/química , Polilisina/síntesis química
14.
Biomed Pharmacother ; 91: 534-545, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28482291

RESUMEN

The purpose of this research was to evaluate the protective effects of insulin-loaded poly(ethylene glycol)-b-poly((2-aminoethyl-l-glutamate)-g-poly(l-lysine)) (PEG-b-P(ELG-g-PLL)) on renal ischemia/reperfusion (I/R) injury in rats with diabetes mellitus. Rats were preconditioned with free insulin or insulin/PEG-b-P(ELG-g-PLL) polyplexes, then subjected to renal I/R. The blood and kidneys were then harvested, Glucose uptake rate, glucose transporter 4 (GULT4) mRNA level, cell membrane GULT4 content and GULT4 expression were measured, the level of serum creatinine and blood urea nitrogen were determined, the activity of superoxide dismutase and inducible nitric oxide synthase, the content of malondialdehyde and nitric oxide, reactive oxygen species (ROS) production and nuclear factor κB (NF-κB) mRNA level, Bcl-2 assaciated x protein (Bax) mRNA and B cell lymphoma/lewkmia-2 (Bcl-2) mRNA level, and the expression of protein 47kDa phagocyte oxidase (p47phox) in renal tissues were measured. Insulin preconditioning improved the recovery of renal function, reduced oxidative stress injury, restored nitroso-redox balance and downregulated the expression of p47phox induced by renal I/R injury, while the application of block copolymer PEG-b-P(ELG-g-PLL) as an insulin nanocarrier significantly enhanced the protective effect of insulin. Block copolymer PEG-b-P(ELG-g-PLL) could be used as a potential nanocarrier for insulin with sustained release and enhanced bioavailability.


Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Insulina/uso terapéutico , Riñón/patología , Polímeros/química , Daño por Reperfusión/tratamiento farmacológico , Animales , Glucemia/metabolismo , Nitrógeno de la Urea Sanguínea , Bovinos , Membrana Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Creatinina/sangre , Preparaciones de Acción Retardada , Diabetes Mellitus/sangre , Diabetes Mellitus/patología , Transportador de Glucosa de Tipo 4/metabolismo , Hipoglucemia/patología , Insulina/farmacología , Riñón/irrigación sanguínea , Masculino , Malondialdehído/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Polietilenglicoles/síntesis química , Polietilenglicoles/química , Polilisina/análogos & derivados , Polilisina/síntesis química , Polilisina/química , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/sangre , Daño por Reperfusión/patología , Superóxido Dismutasa/metabolismo
15.
ACS Comb Sci ; 19(4): 246-254, 2017 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-28276242

RESUMEN

Cationic macromolecular carriers can be effective carriers for small molecular compounds, drugs, epitopes, or nucleic acids. Polylysine-based polymeric branched polypeptides have been systematically studied on the level of cells and organisms as well. In the present study, we report our findings on the cellular uptake characteristics of nine structurally related polylysine-based polypeptides with cationic side chains composed of (i) single amino acid (poly[Lys(Xi)], XiK) or (ii) oligo[dl-alanine] (poly[Lys(dl-Alam)], AK) or (iii) oligo[dl-alanine] with an additional amino acid (X) at the terminal position (poly[Lys(Xi-dl-Alam)] (XAK)) or (iv) at the position next to the polylysine backbone (poly[Lys(dl-Alam-Xi)] (AXK)). In vitro cytotoxicity and cellular uptake were characterized on HT-29 human colon carcinoma and HepG2 human hepatocarcinoma cell lines. Data indicate that the polycationic polypeptides studied are essentially nontoxic in the concentration range studied, and their uptake is very much dependent on the side chain structure (length, identity of amino acid X, and distance between the terminal positive charges) and also on the cell lines. Our findings in uptake inhibition studies suggest that predominantly macropinocytosis and caveole/lipid raft mediated endocytosis are involved. The efficacy of their internalization is markedly influenced by the hydrophobicity and charge properties of the amino acid X. Interestingly, the uptake properties of the these polypeptides show certain similarities to the entry pathways of several cell penetrating peptides.


Asunto(s)
Péptidos/síntesis química , Péptidos/metabolismo , Polilisina/síntesis química , Polilisina/metabolismo , Cationes , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Endocitosis , Humanos , Péptidos/toxicidad , Polilisina/toxicidad , Conformación Proteica , Relación Estructura-Actividad
16.
Int J Nanomedicine ; 12: 2243-2254, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28356740

RESUMEN

Brain ischemia/reperfusion (I/R) injury (BI/RI) is a leading cause of death and disability worldwide. However, the outcome of pharmacotherapy for BI/RI remains unsatisfactory. Innovative approaches for enhancing drug sensitivity and recovering neuronal activity in BI/RI treatment are urgently needed. The purpose of this study was to evaluate the protective effects of tumor necrosis factor (TNF)-α-loaded poly(ethylene glycol)-b-(poly(ethylenediamine L-glutamate)-g-poly(L-lysine)) (TNF-α/PEG-b-(PELG-g-PLL)) nanoparticles on BI/RI. The particle size of PEG-b-(PELG-g-PLL) and the loading and release rates of TNF-α were determined. The nanoparticle cytotoxicity was evaluated in vitro using rat cortical neurons. Sprague Dawley rats were preconditioned with free TNF-α or TNF-α/PEG-b-(PELG-g-PLL) polyplexes and then subjected to 2 hours ischemia and 22 hours reperfusion. Brain edema was assessed using the brain edema ratio, and the antioxidative activity was assessed by measuring the superoxide dismutase (SOD) activity and the malondialdehyde (MDA) content in the brain tissue. We further estimated the inflammatory activity and apoptosis level by determining the levels of interleukin-4 (IL-4), IL-6, IL-8, IL-10, and nitric oxide (NO), as well as the expression of glial fibrillary acidic protein (GFAP), intercellular adhesion molecule-1 (ICAM-1), and cysteine aspartase-3 (caspase-3), in the brain tissue. We provide evidence that TNF-α preconditioning attenuated the oxidative stress injury, the inflammatory activity, and the apoptosis level in I/R-induced cerebral injury, while the application of block copolymer PEG-b-(PELG-g-PLL) as a potential TNF-α nanocarrier with sustained release significantly enhanced the bioavailability of TNF-α. We propose that the block copolymer PEG-b-(PELG-g-PLL) may function as a potent nanocarrier for augmenting BI/RI pharmacotherapy, with unprecedented clinical benefits. Further studies are needed to better clarify the underlying mechanisms.


Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Portadores de Fármacos/química , Nanopartículas/química , Polietilenglicoles/química , Polilisina/análogos & derivados , Daño por Reperfusión/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/uso terapéutico , Animales , Edema Encefálico/complicaciones , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/patología , Isquemia Encefálica/complicaciones , Isquemia Encefálica/patología , Caspasa 3/metabolismo , Supervivencia Celular/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Malondialdehído/metabolismo , Peso Molecular , Neuronas/efectos de los fármacos , Neuronas/patología , Tamaño de la Partícula , Polietilenglicoles/síntesis química , Polilisina/síntesis química , Polilisina/química , Ratas Sprague-Dawley , Daño por Reperfusión/complicaciones , Daño por Reperfusión/patología , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/farmacología
17.
Bioorg Med Chem Lett ; 27(5): 1252-1255, 2017 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-28153357

RESUMEN

A new dendrimer probe was designed for bone imaging. Bidentate iminodiacetate groups were introduced to the probe to obtain strong bind to bones. The assembled dendrimeric probe, with four iminodiacetate moieties and a fluorescent tag, displayed good selectivity to hydroxyapatite, calcium oxalate and calcium phosphate salts. In mice, the probe offered vivid skeletal details after intravenous delivery.


Asunto(s)
Huesos , Dendrímeros/química , Diagnóstico por Imagen , Colorantes Fluorescentes/química , Iminoácidos/química , Polilisina/síntesis química , Administración Intravenosa , Animales , Huesos/diagnóstico por imagen , Ratones , Estructura Molecular , Polilisina/química , Polilisina/farmacología
18.
Acta Biomater ; 40: 235-242, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27134016

RESUMEN

UNLABELLED: Vascular endothelial growth factor (VEGF) is the growth factor responsible for the triggering of angiogenesis, the process of blood vessel formation supporting the long-term viability of any repaired or regenerated tissue. As the growth factor is effective only when concentration gradients are generated, new shuttles need to be developed that ensure both the control of gradients at the site of tissue repair and the release of VEGF at physiological levels. Magnetic hyperthermia is the production of heat induced by magnetic materials through their exposure to an external oscillating magnetic field. In this paper, magnetic nanoparticles capable of generating controllable hyperthermia were functionalised with hyperbranched poly(epsilon-lysine) peptides integrating in their core parallel thermoresponsive elastin-like peptide sequences and presenting an uppermost branching generation tethered by the zwitterionic amino acid carboxybetaine. The results show that these functionalised magnetic nanoparticles avidly bind VEGF and release it only upon generation of mild-hyperthermic pulses generated by oscillating magnetic filed. The VEGF release occurred in a temperature range at which the elastin-like peptides collapse. It is proposed that, through the application of an external magnetic field, these magnetic carriers could generated gradients of VEGF in vivo and allow its tuned delivery in a number of clinical applications. STATEMENT OF SIGNIFICANCE: The present paper for the first time reveals the possibility to control the delivery of VEGF through mild hyperthermia stimuli generated by a oscillating magnetic field. To this purpose, magnetic nanoparticles of high size homogeneity and coated with a thin coating of poly(acrylic acid) were functionalised with a novel class of poly(epsilon lysine) dendrimers integrating in their structure a thermoresponsive amino acid sequence mimicking elastin and exposing at high density a zwitterionic modified amino acid, the carboxybetaine, known to be able to bind macromolecules. Physicochemical and biochemical characterisation elegantly show the link between the thermal properties of the nanoparticles and of the dendrimer change of conformation and how this enable the release of VEGF at temperature values compatible with the growth factor stability.


Asunto(s)
Antracenos/química , Sistemas de Liberación de Medicamentos/métodos , Hipertermia Inducida/métodos , Campos Magnéticos , Nanopartículas de Magnetita/química , Polilisina/química , Factor A de Crecimiento Endotelial Vascular , Antracenos/síntesis química , Antracenos/farmacocinética , Betaína/síntesis química , Betaína/química , Betaína/farmacocinética , Humanos , Polilisina/síntesis química , Polilisina/farmacocinética , Factor A de Crecimiento Endotelial Vascular/química , Factor A de Crecimiento Endotelial Vascular/farmacocinética
19.
Int J Nanomedicine ; 11: 1717-30, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27175073

RESUMEN

The aim of this study was to observe the therapeutic effect of insulin-loaded linear poly(ethylene glycol)-brush-like poly(l-lysine) block copolymer poly(ethylene glycol)-b-(poly(ethylenediamine l-glutamate)-g-poly(l-lysine)) (PEG-b-(PELG-g-PLL) on renal ischemia/reperfusion-induced lung injury through downregulating hypoxia-inducible factor (HIF) as compared to free insulin. Sprague Dawley rats were pretreated with 30 U/kg insulin or insulin/PEG-b-(PELG-g-PLL) complex, and then subjected to 45 minutes of ischemia and 24 hours of reperfusion. The blood and lungs were collected, the level of serum creatinine and blood urea nitrogen were measured, and the dry/wet lung ratios, the activity of superoxide dismutase and myeloperoxidase, the content of methane dicarboxylic aldehyde and tumor necrosis factor-α, and the expression of HIF-1α and vascular endothelial growth factor (VEGF) were measured in pulmonary tissues. Both insulin and insulin/PEG-b-(PELG-g-PLL) preconditioning improved the recovery of renal function, reduced pulmonary oxidative stress injury, restrained inflammatory damage, and downregulated the expression of HIF-1α and VEGF as compared to ischemia/reperfusion group, while insulin/PEG-b-(PELG-g-PLL) significantly improved this effect.


Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Insulina/farmacología , Insulina/uso terapéutico , Isquemia/patología , Riñón/irrigación sanguínea , Lesión Pulmonar/tratamiento farmacológico , Polietilenglicoles/química , Polilisina/análogos & derivados , Daño por Reperfusión/tratamiento farmacológico , Animales , Nitrógeno de la Urea Sanguínea , Supervivencia Celular/efectos de los fármacos , Creatinina/sangre , Isquemia/sangre , Pulmón/metabolismo , Pulmón/patología , Lesión Pulmonar/sangre , Lesión Pulmonar/etiología , Masculino , Malondialdehído/metabolismo , Peso Molecular , Tamaño de los Órganos/efectos de los fármacos , Tamaño de la Partícula , Peroxidasa/metabolismo , Polietilenglicoles/síntesis química , Polilisina/síntesis química , Polilisina/química , Espectroscopía de Protones por Resonancia Magnética , Ratas Sprague-Dawley , Daño por Reperfusión/sangre , Daño por Reperfusión/complicaciones , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
20.
Angew Chem Int Ed Engl ; 55(17): 5124-34, 2016 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-26990715

RESUMEN

Peptide-decorated dendrimers (PDDs) are a class of spherical, regular, branched polymers that are modified by peptides covalently attached to their surface. PDDs have been used as protein mimetics, novel biomaterials, and in a wide range of biomedical applications. Since their design and development in the late eighties, poly-l-lysine has been a preferred core structure for PDDs. However, numerous recent innovations in polymer synthesis and ligation chemistry have re-energized the field and led to the emergence of well-defined peptide dendrimers with more diverse core structures and functions. This Minireview highlights the development of PDDs driven by significantly improved ligation chemistry incorporating structurally well-defined peptides and the emerging use of PDDs in imaging and drug development.


Asunto(s)
Dendrímeros/química , Péptidos/química , Animales , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/química , Técnicas de Química Sintética/métodos , Dendrímeros/síntesis química , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Técnicas de Transferencia de Gen , Humanos , Modelos Moleculares , Imagen Óptica/métodos , Péptidos/síntesis química , Polilisina/síntesis química , Polilisina/química , Cintigrafía/métodos
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