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1.
J Nanobiotechnology ; 22(1): 501, 2024 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-39169328

RESUMEN

Macrophages are multifunctional innate immune cells that play indispensable roles in homeostasis, tissue repair, and immune regulation. However, dysregulated activation of macrophages is implicated in the pathogenesis of various human disorders, making them a potential target for treatment. Through the expression of pattern recognition and scavenger receptors, macrophages exhibit selective uptake of pathogens and apoptotic cells. Consequently, the utilization of drug carriers that mimic pathogenic or apoptotic signals shows potential for targeted delivery to macrophages. In this study, a series of mannosylated or/and phosphatidylserine (PS) -presenting liposomes were developed to target macrophages via the design of experiment (DoE) strategy and the trial-and-error (TaE) approach. The optimal molar ratio for the liposome formulation was DOPC: DSPS: Chol: PEG-PE = 20:60:20:2 based on the results of cellular uptake and cytotoxicity evaluation on RAW 264.7 and THP-1 in vitro. Results from in vivo distribution showed that, in the DSS-induced colitis model and collagen II-induced rheumatoid arthritis model, PS-presenting liposomes (PS-Lipo) showed the highest accumulation in intestine and paws respectively, which holds promising potential for macrophage target therapy since macrophages are abundant at inflammatory sites and contribute to the progression of corresponding diseases. Organs such as the heart, liver, spleen, lung, and kidney did not exhibit histological alterations such as inflammation or necrosis when exposed to PC-presenting liposomes (PC-Lipo) or PS-Lipo. In addition, liposomes demonstrated hemobiocompatibility and no toxicity to liver or kidney for circulation and did not induce metabolic injury in the animals. Thus, the well-designed PS-Lipo demonstrated the most potential for macrophage target therapy.


Asunto(s)
Apoptosis , Liposomas , Macrófagos , Fosfatidilserinas , Liposomas/química , Animales , Ratones , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Humanos , Células RAW 264.7 , Fosfatidilserinas/metabolismo , Fosfatidilserinas/química , Células THP-1 , Masculino , Ratones Endogámicos C57BL , Sistemas de Liberación de Medicamentos/métodos , Distribución Tisular
2.
Int J Nanomedicine ; 18: 7209-7223, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38076729

RESUMEN

Purpose: The remarkable peroxidase-like activity of single-atom nanozymes (SAzymes) allows them to catalyze the conversion of H2O2 to •OH, rendering them highly promising for antibacterial applications. However, their practical in vivo application is hindered by the near-neutral pH and insufficient H2O2 levels present in physiological systems. This study was aimed at developing a SAzyme-based nanoreactor and investigating its in vivo antibacterial activity. Methods: We developed a hollow mesoporous molybdenum single-atom nanozyme (HMMo-SAzyme) using a controlled chemical etching approach and pyrolysis strategy. The HMMo-SAzyme not only exhibited excellent catalytic activity but also served as an effective nanocarrier. By loading glucose oxidase (GOx) with HMMo-SAzyme and encapsulating it with hyaluronic acid (HA), a nanoreactor (HMMo/GOx@HA) was constructed as glucose-triggered cascade catalyst for combating bacterial infection in vivo. Results: Hyaluronidase (HAase) at the site of infection degraded HA, allowing GOx to convert glucose into gluconic acid and H2O2. An acid environment significantly enhanced the catalytic activity of HMMo-SAzyme to promote the further catalytic conversion of H2O2 to •OH for bacterial elimination. In vitro and in vivo experiments demonstrated that the nanoreactor had excellent antibacterial activity and negligible biological toxicity. Conclusion: This study represents a significant advancement in developing a cascade catalytic system with high efficiency based on hollow mesoporous SAzyme, promising the advancement of biological applications of SAzyme.


Asunto(s)
Peróxido de Hidrógeno , Molibdeno , Antibacterianos/farmacología , Catálisis , Glucosa , Glucosa Oxidasa , Ácido Hialurónico
3.
Molecules ; 26(23)2021 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-34885750

RESUMEN

Poly(benzyl malate) (PBM), together with its derivatives, have been studied as nanocarriers for biomedical applications due to their superior biocompatibility and biodegradability. The acquisition of PBM is primarily from chemical routes, which could offer polymer-controlled molecular weight and a unique controllable morphology. Nowadays, the frequently used synthesis from L-aspartic acid gives an overall yield of 4.5%. In this work, a novel synthesis route with malic acid as the initiator was successfully designed and optimized, increasing the reaction yield up to 31.2%. Furthermore, a crystalline form of PBM (PBM-2) that polymerized from high optical purity benzyl-ß-malolactonate (MLABn) was discovered during the optimization process. X-ray diffraction (XRD) patterns revealed that the crystalline PBM-2 had obvious diffraction peaks, demonstrating that its internal atoms were arranged in a more orderly manner and were different from the amorphous PBM-1 prepared from the racemic MLABn. The differential scanning calorimetry (DSC) curves and thermogravimetric curves elucidated the diverse thermal behaviors between PBM-1 and PBM-2. The degradation curves and scanning electron microscopy (SEM) images further demonstrated the biodegradability of PBM, which have different crystal structures. The hardness of PBM-2 implied the potential application in bone regeneration, while it resulted in the reduction of solubility when compared with PBM-1, which made it difficult to be dissolved and hydrogenated. The solution was therefore heated up to 75 °C to achieve benzyl deprotection, and a series of partially hydrogenated PBM was sequent prepared. Their optimal hydrogenation rates were screened to determine the optimal conditions for the formation of micelles suitable for drug-carrier applications. In summary, the synthesis route from malic acid facilitated the production of PBM for a shorter time and with a higher yield. The biodegradability, biosafety, mechanical properties, and adjustable hydrogenation widen the application of PBM with tunable properties as drug carriers.


Asunto(s)
Plásticos Biodegradables/síntesis química , Portadores de Fármacos/síntesis química , Malatos/química , Polímeros/síntesis química , Plásticos Biodegradables/química , Portadores de Fármacos/química , Humanos , Hidrógeno/química , Hidrogenación/efectos de los fármacos , Micelas , Microscopía Electrónica de Rastreo , Polimerizacion , Polímeros/química , Solubilidad , Difracción de Rayos X
5.
Int J Biol Macromol ; 186: 839-848, 2021 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-34280447

RESUMEN

Antibacterial photodynamic therapy (PDT) has attracted extremely attention due to not inducing bacteria to generate resistance. However, the poor utilization and low reactive oxygen species (ROS) field of photosensitizers hinder their further application for antibacterial. Here, we designed ultra-thin hollow silica nanoparticles (UHSN), followed by pore-engineering including covalent anchoring of chitosan (UHSN@CS) for enhanced loading and photodynamic property of photosensitizer. The UHSN@CS exhibit high loading efficiency (80.6%, pH = 6.0) and controllable pH-responsive release for Ce6. Additionally, UHSN@CS can enhance the ROS yield of photosensitizers and effectively adhere to S. aureus, thus enormously enhancing antibacterial performance toward bacteria. Moreover, UHSN@CS-Ce6 can obliterate mature S. aureus biofilm and cause an 81% decrease in the biomass, showing a better therapeutic effect than Ce6 (59.2%) under laser irradiation. In vivo results confirm that UHSN@CS-Ce6 is effective to promote infectious wound regeneration. As photodynamic-based nanoplatforms, UHSN@CS-Ce6 are potential antibacterial agents for skin infection therapy.


Asunto(s)
Antibacterianos/farmacología , Quitosano/química , Clorofilidas/farmacología , Portadores de Fármacos , Nanopartículas , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Infecciones Cutáneas Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Infección de Heridas/tratamiento farmacológico , Animales , Antibacterianos/química , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Clorofilidas/química , Cricetinae , Preparaciones de Acción Retardada , Composición de Medicamentos , Concentración de Iones de Hidrógeno , Modelos Animales , Nanotecnología , Fármacos Fotosensibilizantes/química , Especies Reactivas de Oxígeno/metabolismo , Infecciones Cutáneas Estafilocócicas/microbiología , Infecciones Cutáneas Estafilocócicas/patología , Staphylococcus aureus/crecimiento & desarrollo , Staphylococcus aureus/metabolismo , Cicatrización de Heridas/efectos de los fármacos , Infección de Heridas/microbiología , Infección de Heridas/patología
6.
ACS Appl Mater Interfaces ; 13(1): 1277-1287, 2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33393300

RESUMEN

Selective discrimination and lasting tracking of live bacteria are primary steps for microbiology research and treatment of bacterial infection. However, conventional detection methods, such as the gold standard of Gram staining, are being challenged under actual test conditions. Herein, we provided a novel method, namely, three excitation peaks and single-color emission carbon quantum dots (T-SCQDs) for the rapid (5 min) peptidoglycan-targeting discrimination of Gram-positive bacteria and lasting tracking (24 h) through one-step staining. Bacterial viability testing indicates that T-SCQDs can achieve nondestructive identification of Gram-positive bacteria within 50-500 µg mL-1. Interestingly, the fluorescence imaging system suggests that T-SCQDs can also selectively distinguish the type of colonies based on fluorescence intensity. Furthermore, T-SCQDs were successfully used to visually distinguish Gram-positive bacteria from the microbial environment of A549 cells by confocal fluorescence microscopy. These properties endow T-SCQDs with excellent functions for the diagnosis of infection and other biological applications.


Asunto(s)
Colorantes Fluorescentes/química , Peptidoglicano/metabolismo , Puntos Cuánticos/química , Staphylococcus aureus/aislamiento & purificación , Células A549 , Carbono/química , Carbono/metabolismo , Carbono/toxicidad , Colorantes Fluorescentes/metabolismo , Colorantes Fluorescentes/toxicidad , Humanos , Microscopía Confocal , Microscopía Fluorescente , Puntos Cuánticos/metabolismo , Puntos Cuánticos/toxicidad
7.
J Mater Chem B ; 8(37): 8527-8535, 2020 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-32869819

RESUMEN

Poly(ß-l-malic acid) (PMLA) together with its derivatives is an aliphatic polyester with superior bio-properties for anti-tumor drugs. In order to surmount the obstacles of low drug loading and rapid premature release during the circulation of polyester-based micelles, micelles based on poly(ß-benzyl malate)-b-polyethylene glycol (PBM-PEG) were developed in this study. The micelles had high drug loading capacity (>20 wt%) and held robust stability, owing to the π-π stacking interactions between polymer chains, and between the polymer and drug. Computer simulation also confirmed that there was the strongest binding free energy between PBMs, and PBM and doxorubicin (DOX), compared with other polyesters. A cell-penetrating moiety (TAT) was employed, and furthermore, a protective outer shell (PEG5k) was also introduced via a matrix metalloproteinase-2 (MMP-2) cleavable peptide. Before reaching the tumor site, the TAT peptide was shielded by long chain PEG, and the micelles showed low bioactivity. While at the tumor tissues where MMP-2 was highly expressed, the cleavage of the linker leads to the exposure of TAT, thus enhancing the cellular internalization. The desired therapeutic consequent was also observed, with no accompanying systemic toxicity detected. Our findings indicated that this MMP-2 sensitive PBM polymeric micelle would be a promising antitumor drug carrier with enhanced therapeutic effects.


Asunto(s)
Antineoplásicos/uso terapéutico , Portadores de Fármacos/química , Micelas , Neoplasias/tratamiento farmacológico , Poliésteres/química , Polietilenglicoles/química , Animales , Antineoplásicos/química , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/uso terapéutico , Portadores de Fármacos/síntesis química , Liberación de Fármacos , Femenino , Humanos , Ratones Endogámicos BALB C , Neoplasias/patología , Oligopéptidos/química , Poliésteres/síntesis química , Polietilenglicoles/síntesis química , Electricidad Estática , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Theranostics ; 10(11): 4795-4808, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32308750

RESUMEN

Background: Biofilm infection caused by multidrug-resistant bacteria is difficult to eradicate by conventional therapies. Photodynamic therapy (PDT) is an effective antibacterial method for fighting against biofilm infection. However, the blocked photosensitizers outside of biofilm greatly limit the efficacy of PDT. Methods: Herein, a novel acid-responsive superporogen and photosensitizer (SiO2-PCe6-IL) was developed. Because of the protonation of the photosensitizer and the high binding energy of the polyionic liquid, SiO2-PCe6-IL changed to positive SiO2-PIL+ in an acidic microenvironment of biofilm infection. SiO2-PIL+ could combine with negatively charged extracellular polymeric substances (EPS) and create holes to remove the biofilm barrier. To strengthen the interaction between SiO2-PIL+ and EPS, SiO2-PIL+ of high charge density was prepared by grafting the high-density initiation site of ATRP onto the surface of the SiO2 base. Results: Due to the rapid protonation rate of COO- and the strong binding energy of SiO2-PIL+ with EPS, SiO2-PCe6-IL could release 90% of Ce6 in 10 s. With the stronger electrostatic and hydrophobic interaction of SiO2-PIL+ with EPS, the surface potential, hydrophobicity, adhesion and mechanical strength of biofilm were changed, and holes in the biofilm were created in 10 min. Combining with the release of photosensitizers and the porous structure of the biofilm, Ce6 was efficiently concentrated in the biofilm. The in vitro and in vivo antibacterial experiments proved that SiO2-PCe6-IL dramatically improved the PDT efficacy against MRSA biofilm infection. Conclusion: These findings suggest that SiO2-PCe6-IL could rapidly increase the concentration of photosensitizer in biofilm and it is an effective therapy for combating biofilm infection.


Asunto(s)
Biopelículas/efectos de los fármacos , Líquidos Iónicos/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Fotoquimioterapia/métodos , Dióxido de Silicio/química , Infecciones Estafilocócicas/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Concentración de Iones de Hidrógeno , Fármacos Fotosensibilizantes/química , Porosidad , Porfirinas/química , Conejos , Infecciones Estafilocócicas/microbiología
9.
Chem Commun (Camb) ; 56(35): 4785-4788, 2020 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-32227029

RESUMEN

To utilize the advantages of drug carriers of different sizes, a size switchable "ball-and-rod" drug delivery system was constructed, which could switch its size in response to enzymes in tumors. It would be a promising system with long circulation and deep penetration properties, which enable its application in tumor treatment.

12.
Int J Mol Med ; 44(4): 1595, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31432105

RESUMEN

Following the publication of the above article, the authors have realized that the chemical structure presented for the intermediate product in Fig 3 was drawn incorrectly; specfically, the 'N's had been omitted from the structure. The structure as it should have appeared is shown in the revised version of Fig. 3 opposite. All the authors agree to the contents of this Corrigendum, and apologize to the Editor of International Journal of Molecular Medicine and to the readership for any inconvenience caused. [the original article was published in International Journal of Molecular Medicine 42: 3495­3502, 2018; DOI: 10.3892/ijmm.2018.3893].

13.
Biomacromolecules ; 20(4): 1765-1776, 2019 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-30844253

RESUMEN

In this study, a tissue-engineered trachea, consisting of multilevel structural electrospun polylactide (PLA) membranes enveloping 3D-printed thermoplastic polyurethane (TPU) skeletons, was developed to create a mechanically robust, antibacterial and bioresorbable graft for the tracheal reconstruction. The study design incorporated two distinct uses of stereocomplex PLA: patterned electrospun fibers to enhance tissue integration compared to the random layered fibers, meanwhile possessing good antibacterial property; and 3D-printed TPU scaffold with elasticity to provide external support and protection. Herein, ionic liquid (IL)-functioned graphene oxide (GO) was synthesized and presented enhanced mechanical and hydrophilicity properties. More interesting, antibacterial activity of the GO- g-IL modified PLA membranes were proved by Escherichia coli and Staphylococcus aureus, showing superior antibacterial effect compared to single GO or IL. The synergistic antibacterial effect could be related to that GO break cytomembrane of bacteria by its extremely sharp edges, while IL works by electrostatic interaction between its cationic structures and electronegative phosphate groups of bacteria membranes, leading to the loss of cell electrolyte and cell death. Hence, after L929 fibroblast cells were seeded on patterned fibrous membranes with phenotypic shape, further effective cell infiltration, cell proliferation and attachment were observed. In addition, the tissue-engineered trachea scaffolds were implanted into rabbit models. The in vivo result confirmed that the scaffolds with patterned membranes manifested favorable biocompatibility and promoted tissue regeneration.


Asunto(s)
Escherichia coli/crecimiento & desarrollo , Grafito , Ensayo de Materiales , Poliésteres , Impresión Tridimensional , Staphylococcus aureus/crecimiento & desarrollo , Andamios del Tejido/química , Tráquea/metabolismo , Animales , Línea Celular , Elasticidad , Fibroblastos/metabolismo , Grafito/química , Grafito/farmacología , Ratones , Poliésteres/química , Poliésteres/farmacología , Conejos , Tráquea/patología , Tráquea/cirugía
14.
Biomater Sci ; 7(4): 1399-1410, 2019 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-30768109

RESUMEN

With the increase in antibiotic resistance, the development of new antibacterial agents is urgent. Photosensitizers with no detectable resistance are promising antibacterial agents. However, most photosensitizers are insoluble, structurally unstable and ineffective against Gram-negative bacteria due to their negatively charged cell wall that hinder their use. In this study, a novel bacteria-activated photosensitizer ionic liquid was designed and assembled to improve the solubility, stability and antibacterial ability of photodynamic therapy. The cation 1-vinyl-3-dodecyl imidazole has been designed, which has strong binding energy with the major constituent of the cell wall. The anion selected was chlorin e6 (Ce6) since it could respond to the acidic microenvironment of bacterial infection. The Ce6 ionic liquid (Ce6-IL) composed of 1-vinyl-3-dodecyl imidazole and Ce6 not only exhibited bacteria-activated ability because its cation could firmly bond with peptidoglycan in the cell wall, but also had excellent acid responsive ability due to the protonation reaction of COO- in its anion. The binding energy of the cation with peptidoglycan was calculated via molecular dynamics simulation, and the pH-responsive behavior of Ce6-IL was verified via HR-MS. The surface potential, mechanical property, morphology and uptake rate results indicated that the cation could destroy the cell wall and promote the anion Ce6 to enter the bacteria. Due to the dual-mode antibacterial action of its cation and anion, Ce6-IL was more effective against Gram-negative and Gram-positive bacteria than Ce6 alone and had wide-spectrum antibacterial ability. The in vitro studies showed that the IC50 of Ce6-IL against E. coli and S. aureus was reduced by 100 and 10 times, respectively. Furthermore, the in vivo studies indicated that Ce6-IL was more effective for eliminating bacterial infection and could accelerate wound healing. The compatibility test showed that Ce6-IL had low toxicity and exhibited excellent biocompatibility.


Asunto(s)
Antibacterianos/farmacología , Escherichia coli/efectos de los fármacos , Líquidos Iónicos/farmacología , Fotoquimioterapia , Porfirinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Animales , Aniones/síntesis química , Aniones/química , Aniones/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Cationes/síntesis química , Cationes/química , Cationes/farmacología , Clorofilidas , Simulación por Computador , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Líquidos Iónicos/síntesis química , Líquidos Iónicos/química , Pruebas de Sensibilidad Microbiana , Porfirinas/síntesis química , Porfirinas/química , Conejos , Relación Estructura-Actividad , Cicatrización de Heridas/efectos de los fármacos
15.
J Biomed Nanotechnol ; 15(1): 28-41, 2019 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-30480513

RESUMEN

Poly(ß-benzyl malate) (PBM), a derivative of poly(ß-malic acid) (PMLA), is a potential antitumor drug carrier due to its desirable biocompatibility and nontoxicity. In this study, micelles based on PBM-PEG polymers were prepared, which possessed several key features, including (i) micelle formation via self-assembly with a size of approximately 100 nm, (ii) π-π stacking interactions between the polymer chains and between the polymer and the drug, improving the stability of micelles and drug loading capacity (drug loading rate increased to 20 wt%), (iii) the cell penetrating peptide (TAT) was shielded by a long PEG chain before reaching the tumor site and exposed to tumor tissue, and (iv) high efficiency tumor uptake via exposure to TAT. At the site of a tumor, the extracellular pH level caused cleavage of the hydrazine bond, which led to the exposure of TAT on the polymeric micelles, thus enhancing cellular internalization. Then, the polymeric micelles disintegrated and DOX was released in response to the acidic pH in the lysosomal and endosomal compartments within the tumor cells. Both in vitro and in vivo efficacy studies indicated that this pH-sensitive PBM polymeric micelle is a promising antitumor drug carrier.


Asunto(s)
Sistemas de Liberación de Medicamentos , Micelas , Antineoplásicos , Línea Celular Tumoral , Doxorrubicina , Portadores de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Malatos , Polietilenglicoles , Polímeros
16.
Int J Mol Med ; 42(6): 3495-3502, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30272259

RESUMEN

Poly (ß­malic acid), referred to as PMLA, has been synthesized and introduced as a polymeric drug carrier due to its desirable biological properties. In the present study, a novel pH­sensitive polymer­drug conjugate based on PMLA, PMLA­Hz­doxorubicin (DOX), was prepared, and another conjugate, PMLA­ami­DOX, was synthesized as a comparison. The structures, conjugation efficiency, and drug release properties of the prodrugs were determined. The cytotoxicity and cell uptake were assessed using the HT1080 human fibrosarcoma cell line as an in vitro cell model. The release of DOX in the two conjugates were pH­dependent in PBS buffer at a pH of 5.6, 6.0, 6.8 and 7.4. The quantity of drug released increased with the decrease in pH, and PMLA­ami­DOX released twice as much as PMLA­Hz­DOX (12 h). The cytotoxicity of PMLA­Hz­DOX at pH 7.4 was lower than that of free DOX and increased with the decrease in pH, indicating that the cytotoxicity of PMLA­Hz­DOX was pH­sensitive. Flow cytometry and confocal experiments confirmed the efficiency of the PMLA­Hz­DOX conjugate. Therefore, bonding DOX to PMLA via an acid­sensitive hydrazone bond may be used to reduce its toxic side effects on normal tissues while responding to tumor pH and releasing the drug.


Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Sistemas de Liberación de Medicamentos , Malatos/química , Polímeros/química , Antineoplásicos/química , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Doxorrubicina/farmacología , Liberación de Fármacos , Endocitosis , Humanos , Concentración de Iones de Hidrógeno , Malatos/síntesis química , Nanoconjugados/química , Polímeros/síntesis química , Espectroscopía de Protones por Resonancia Magnética , Electricidad Estática
17.
J Biomed Nanotechnol ; 14(6): 1039-1051, 2018 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-29843869

RESUMEN

To overcome the strong negative charge and improve the endocytosis of poly-ß-malic acid (PMLA) as a drug carrier, a pH-sensitive nanoconjugate of PMLA/hyd-PEG5000/PEG2000-TAT/DOX (PHPTD) was developed. The trans activator of transcription (TAT) modified with polyethylene glycol2000(PEG2000) was conjugated with the PMLA backbone which improved the endocytosis of PMLA. PEG5000 was utilized to shield TAT by a pH-sensitive hydrazone (Hyd) bond. In order to decrease the potential risk of accelerated blood clearance (ABC) phenomenon by anti-PEG IgM, the minimal content of TAT for penetrating tumor cells and the optimal protecting layer density of PEG5000 were screened. The result showed that 0.3 mol% TAT was enough to efficiently improve cellular uptake of PMLA (30 kda). The cytotoxicity and the 1H-NMR results indicated that 3.6 mol% PEG5000-modified nanoconjugates could shield 0.3 mol% TAT. The antitumor effect in breast cancer cells (MDA-MB-231) in tumor-bearing BALB/C mice demonstrated that this nanoconjugates exhibits high therapeutic efficiency in artificial solid tumors and low toxicity to normal tissues. It is indicated that TAT could be hidden in the long chain of PEG5000 at a neutral pH, when arrival to the tumor extracellular microenvironment, PEG5000 was cleaved from the nanoconjugates through the hydrazone bond due to the acidic tumor environment. Then, TAT was exposed, allowing the nanoconjugates to be transported into tumor cells. Our findings provide important and detailed information regarding the optimal content of TAT and the shielded density of PEG5000 and reveal their abilities of tumor penetration and potential for the efficient drug carrier.


Asunto(s)
Sistemas de Liberación de Medicamentos , Nanoconjugados , Animales , Antineoplásicos , Línea Celular Tumoral , Doxorrubicina , Endocitosis , Concentración de Iones de Hidrógeno , Malatos , Ratones , Ratones Endogámicos BALB C , Polietilenglicoles , Polímeros
18.
Theranostics ; 7(7): 1806-1819, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28638469

RESUMEN

Poly(ß-L-malic acid) (PMLA), a natural aliphatic polyester, has been proven to be a promising carrier for anti-cancer drugs. In spite of excellent bio-compatibility, the application of PMLA as the drug carrier for cancer therapy is limited by its low cellular uptake efficiency. The strong negative charge of PMLA impedes its uptake by cancer cells because of the electrostatic repulsion. In this study, a dual pH-sensitive charge-reversal PMLA-based nanocomplex (PMLA-PEI-DOX-TAT@PEG-DMMA) was developed for effective tumor-targeted drug delivery, enhanced cellular uptake, and intracellular drug release. The prepared nanocomplex showed a negative surface charge at the physiological pH, which could protect the nanocomplex from the attack of plasma proteins and recognition by the reticuloendothelial system, so as to prolong its circulation time. While at the tumor extracellular pH 6.8, the DMMA was hydrolyzed, leading to the charge reversal and exposure of the TAT on the polymeric micelles, thus enhancing the cellular internalization. Then, the polymeric micelles underwent dissociation and drug release in response to the acidic pH in the lyso/endosomal compartments of the tumor cell. Both in vitro and in vivo efficacy studies indicated that the nanocomplex significantly inhibited the tumor growth while the treatment showed negligible systemic toxicity, suggesting that the developed dual pH-sensitive PMLA-based nanocomplex would be a promising drug delivery system for tumor-targeted drug delivery with enhanced anticancer activity.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Portadores de Fármacos/farmacocinética , Sustancias Macromoleculares/farmacocinética , Malatos/farmacocinética , Terapia Molecular Dirigida/métodos , Polímeros/farmacocinética , Animales , Línea Celular Tumoral , Fenómenos Químicos , Modelos Animales de Enfermedad , Portadores de Fármacos/administración & dosificación , Endocitosis , Xenoinjertos , Humanos , Concentración de Iones de Hidrógeno , Sustancias Macromoleculares/administración & dosificación , Malatos/administración & dosificación , Ratones , Nanoestructuras/administración & dosificación , Polímeros/administración & dosificación , Resultado del Tratamiento
19.
PLoS One ; 11(9): e0162607, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27649562

RESUMEN

Polymeric micelles represent an effective delivery system for poorly water-soluble anticancer drugs. In this work, two types of CPT-conjugated polymers were synthesized based on poly(ß-L-malic acid) (PMLA) derivatives. Folic acid (FA) was introduced into the polymers as tumor targeting group. The micellization behaviors of these polymers and antitumor activity of different self-assembled micelles were investigated. Results indicate that poly(ethylene glycol)-poly(ß-L-malic acid)-campotothecin-I (PEG-PMLA-CPT-I, P1) is a grafted copolymer, and could form star micelles in aqueous solution with a diameter of about 97 nm, also that PEG-PMLA-CPT-II (P2) is an amphiphilic block copolymer, and could form crew cut micelles with a diameter of about 76 nm. Both P1 and P2 micelles could improve the cellular uptake of CPT, especially the FA-modified micelles, while P2 micelles showed higher stability, higher drug loading efficiency, smaller size, and slower drug release rate than that of P1 micelles. These results suggested that the P2 (crew cut) micelles possess better stability than that of the P1 (star) micelles and might be a potential drug delivery system for cancer therapy.


Asunto(s)
Antineoplásicos/administración & dosificación , Composición de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/métodos , Malatos/química , Micelas , Polímeros/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Camptotecina/administración & dosificación , Camptotecina/farmacocinética , Camptotecina/farmacología , Supervivencia Celular/efectos de los fármacos , Liberación de Fármacos , Ácido Fólico/química , Células HeLa , Humanos , Microscopía Confocal , Microscopía Electrónica de Transmisión , Polietilenglicoles/química
20.
Mol Neurobiol ; 53(6): 3842-3853, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-26162321

RESUMEN

Acetyl-11-keto-ß-boswellic acid (AKBA), a main active constituent from Boswellia serrata resin, is a novel candidate for therapy of cerebral ischemia-reperfusion (I/R) injury. Nevertheless, its poor solubility in aqueous solvent, bioavailability, and rapid clearance limit its curative efficacy. To enhance its potency, in our study, AKBA-loaded o-carboxymethyl chitosan nanoparticle (AKBA-NP) delivery system was synthesized. The transmission electron microscopy and transmission electron microscope images of AKBA-NPs suggested that particle size was 132 ± 18 nm, and particles were spherical in shape with smooth morphology. In pharmacokinetics study, AKBA-NPs apparently increases the area under the curve of plasma concentration-time and prolonged half-life compared with AKBA. The tissue distribution study confirmed that AKBA-NPs had a better brain delivery efficacy in comparison with AKBA. The results from our pharmacodynamic studies showed that AKBA-NPs possess better neuroprotection compared with AKBA in primary neurons with oxygen-glucose deprivation (OGD) model and in animals with middle cerebral artery occlusion (MCAO) model. Additionally, AKBA-NPs modulate antioxidant and anti-inflammatory pathways more effectively than AKBA by increasing nuclear erythroid 2-related factor 2 and heme oxygenase-1 expression, and by decreasing nuclear factor-kappa B and 5-lipoxygenase expression. Collectively, our results suggest that AKBA-NPs serve as a potent delivery vehicle for AKBA in cerebral ischemic therapy.


Asunto(s)
Antiinflamatorios/metabolismo , Antioxidantes/metabolismo , Quitosano/análogos & derivados , Nanopartículas/química , Neuroprotección/efectos de los fármacos , Triterpenos/farmacología , Administración Intravenosa , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Quitosano/química , Modelos Animales de Enfermedad , Glucosa/deficiencia , Glutatión Peroxidasa/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Interleucina-1beta/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Nanopartículas/ultraestructura , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Oxígeno , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo , Distribución Tisular/efectos de los fármacos , Triterpenos/farmacocinética , Factor de Necrosis Tumoral alfa/metabolismo
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