Enhancing cancer chemo-immunotherapy by biomimetic nanogel with tumor targeting capacity and rapid drug-releasing in tumor microenvironment

In the development of chemo-immunotherapy, many efforts have been focusing on designing suitable carriers to realize the co-delivery of chemotherapeutic and immunotherapeutic with different physicochemical properties and mechanisms of action. Besides, rapid drug release at the tumor site with minimal drug degradation is also essential to facilitate the antitumor effect in a short time. Here, we reported a cancer cell membrane-coated pH-responsive nanogel (NG@M) to co-deliver chemotherapeutic paclitaxel (PTX) and immunotherapeutic agent interleukin-2 (IL-2) under mild conditions for combinational treatment of triple-negative breast cancer. In the designed nanogels, the synthetic copolymer PDEA-co-HP-β-cyclodextrin-co-Pluronic F127 and charge reversible polymer dimethylmaleic anhydride-modified polyethyleneimine endowed nanogels with excellent drug-loading capacity and rapid responsive drug-releasing behavior under acidic tumor microenvironment. Benefited from tumor homologous targeting capacity, NG@M exhibited 4.59-fold higher accumulation at the homologous tumor site than heterologous cancer cell membrane-coated NG. Rapidly released PTX and IL-2 enhanced the maturation of dendritic cells and quickly activated the antitumor immune response in situ, followed by prompted infiltration of immune effector cells. By the combined chemo-immunotherapy, enhanced antitumor effect and efficient pulmonary metastasis inhibition were achieved with a prolonged median survival rate (39 days).

Enzyme-instructed hybrid nanogel/nanofiber oligopeptide hydrogel for localized protein delivery

Enzyme-catalysis self-assembled oligopeptide hydrogel holds great interest in drug delivery, which has merits of biocompatibility, biodegradability and mild gelation conditions. However, its application for protein delivery is greatly limited by inevitable degradation of enzyme on the encapsulated proteins leading to loss of protein activity. Moreover, for the intracellularly acted proteins, cell membrane as a primary barrier hinders the transmembrane delivery of proteins. The internalized proteins also suffer from acidic and enzymatic degradation in endosomes and lysosomes. We herein develop a protease-manipulated hybrid nanogel/nanofiber hydrogel for localized delivery of intracellularly acted proteins. The embedded polymeric nanogels (CytoC/aNGs) preserve activity of cytochrome

Hypoxia-degradable and long-circulating zwitterionic phosphorylcholine-based nanogel for enhanced tumor drug delivery

Tumor microenvironment has been widely utilized for advanced drug delivery in recent years, among which hypoxia-responsive drug delivery systems have become the research hotspot. Although hypoxia-responsive micelles or polymersomes have been successfully developed, a type of hypoxia-degradable nanogel has rarely been reported and the advantages of hypoxia-degradable nanogel over other kinds of degradable nanogels in tumor drug delivery remain unclear. Herein, we reported the synthesis of a novel hypoxia-responsive crosslinker and the fabrication of a hypoxia-degradable zwitterionic poly(phosphorylcholine)-based (

Nanogels as prospective Biomaterial: Radio-induced Synthesis, Characterization, and Biological Assays / Los nanogeles como biomateriales prospectivos: síntesis radioinducida, caracterización y ensayos biológicos

Nowadays, there is a growing interest in biodegradable polymers-based materials due to their diverse application in the biomedical field. Most studied systems involve biocompatible micro and nanodevices, such as liposomes, dendrimer, micelles or polymeric nanogels. The use of Radiation Technology, specifically gamma radiation, to produce micro and nanogels raises the possibility to obtain higher purity products, an important feature for biomedical and pharmaceutical applications. The radio-induced synthesis, characterization, cytotoxicity evaluation, and immunological response of nanogels are described in this study. Nanogel synthesis was performed in the absence of oxygen using aqueous polyvinylpyrrolidone solutions. Crosslinking reactions were carried out at 25 °C in a gamma irradiation chamber with a 60Co source. Nanogels properties were analysed by Scanning Electron Microscopy, Attenuated Total Reflection-Fourier Transform Spectroscopy, Dynamic Light Scattering, and Viscosimetry. The cytotoxicity and immunological response were evaluated by MTT test and analysis of the neutrophil respiratory burst. The results showed that nanogels formation strongly depends on the total absorbed dose. The nanogels have an elliptical shape and their chemical structure is similar to the initial polymer. The nanogels are biocompatible and promote a low-intensity neutrophil activation, similar to the well-characterized biomaterial TiO2, suggesting their potential biomedical uses(AU)

En la actualidad existe un interés creciente en los materiales biodegradables basados en polímeros, debido a sus diversas aplicaciones en la esfera de la biomedicina. En la mayoría de los sistemas estudiados participan micro- y nanodispositivos biocompatibles, tales como liposomas, dendrímeros, micelas o nanogeles poliméricos. El uso de la tecnología de radiaciones, en particular de radiaciones gamma, para producir micro- y nanogeles, eleva la posibilidad de obtener productos de mayor pureza, un rasgo importante con vistas a su aplicación biomédica y farmacéutica. El estudio describe la síntesis radioinducida, caracterización, evaluación de la citotoxicidad y respuesta inmunológica de los nanogeles. La síntesis de los nanogeles se realizó en ausencia de oxígeno, usando soluciones acuosas de polivinilpirrolidona. Las reacciones de entrecruzamiento se realizaron a 25 ºC en cámara de irradiación gamma con una fuente de 60Co. Las propiedades de los nanogeles se analizaron mediante microscopía electrónica de barrido, espectroscopia por transformada de Fourier total atenuada, dispersión dinámica de luz y viscosimetría. La citotoxicidad y la respuesta inmunológica se evaluaron mediante prueba MTT y análisis del estallido respiratorio de neutrófilos. Los resultados muestran que la formación de nanogeles depende en gran medida de la dosis total absorbida. Los nanogeles tienen forma elíptica y su estructura química es similar a la del polímero inicial. Los nanogeles son biocompatibles y promueven una activación de neutrófilos de baja intensidad similar al bien caracterizado material TiO2, lo que sugiere usos biomédicos potenciales(AU)

A hyaluronic acid nanogel for melanoma targeted drug delivery / 药学学报

Melanoma is a malignant tumor with a high degree of malignancy. The incidence of melanoma keeps increasing annually. In this study, a melanoma targeted hyaluronic acid (HA) nanogel was synthesized via crosslinking of thiolated HA with terminally functionalized F127-TPGS mixed micelles. Its stability in vitro was evaluated by the average particle size, and the cytotoxicity of the nanogel was investigated by in vitro cell based assays. Next, cell uptake studies were performed to quantitatively and qualitatively investigate the uptake of the nanogels in B16F10 cells. A small sized nanogel with a diameter of 30 nm was synthesized, which was proven to be minimally cytotoxic against both 3T3 or B16F10 cells. Compared with 3T3 cells with low levels of CD44, B16F10 cells with high levels of CD44 showed significantly higher cell uptake efficiency (P<0.05).

Development and optimization of erythromycin-loaded lipid-based gel by Taguchi design: In vitro characterization and antimicrobial evaluation

The foremost aim of the current research was to prolong and sustain the release of erythromycin (ERY) by preparing a solid lipid nanoparticles (SLNs)-based gel formulation for the safe and effective treatment of acne. ERY-loaded SLNs were developed, and various process variables were optimized with respect to particle size, zeta potential, and entrapment efficiency using the Taguchi model. The average particle size, PDI, zeta potential, drug entrapment efficiency, and drug loading of optimized SLN (F4) were found to be 176.2±1.82 nm, 0.275±0.011, -34.0±0.84, 73.56%, and 69.74% respectively. The optimized SLN (F4) was successfully incorporated into the carbopol-based hydrogel. The in vitro release of ERY from the SLN gel and plain gel were compared and found to be 90.94% and 87.94% respectively. In vitro study of ERY-loaded SLN gel showed sustained delivery of drug from formulation thus enhancing the antimicrobial activity after 30 hours when compared to ERY plain gel.

Preparation of nanogels with different gelation speeds as embolization and drug delivery materials and evaluation of their capacity / 中国药学杂志

OBJECTIVE: To design nanogels with different phase transition speeds and screen embolization and drug delivery materials that can be used for transcatheter arterial chemoembolization (TACE). METHODS: Random copolymer PNA nanogels and interpenetrating polymer PNA-IPN nanogels, in which the ratio of co-monomers between N-isopropylacrylamide (NIPAM) and acrylic acid (AA) were 3∶1, 2∶1 and 1∶1, respectively, were prepared by emulsion polymerization. The embolization and drug-loaded capacities of nanogels were evaluated by characterization of their particle morphology, temperature sensitivity, solution phase transition behavior and rheological properties. RESULTS: Nanogel particles were relatively uniform spheres. The particle size of PNA was 386-795 nm, and the particle size of PNA-IPN was 367-750 nm. The increase of temperature led to the decrease of particle size, while the increase of the ratio of the co-monomer AA caused the decrease of temperature sensitivity and gel strength of nanogels, and the increase of the phase transition temperature and the gelation speed. Compared with PNA, PNA-IPN-2 had slightly smaller particle size, lower gelation temperature, faster gelation speed and significantly increased gel strength. The PNA-IPN-2 could load doxorubicin by charge action with 10.3% of loading efficiency. CONCLUSION: The 140 mg•mL-1 PNA-IPN-2 solution has suitable gelation temperature, gelation speed and gel strength. The shearthinning nature and drug release feature are very favorable for TACE, so the PNA-IPN-2 solution is promising for the applications in TACE as nanogels embolization and drug delivery materials.

In vitro anti-tumor effect of RRM2-siRNA based on active and passive dual targeted nanogel / 第二军医大学学报

Objective To prepare antibody-targeting temperature-sensitive polylated N-isopropylacrylamide/ polyethyleneimine (PNIPAM/PEI) nanogel for delivering siRNA against ribonucleotide reductase (RR) subunit M2 (RRM2, RRM2-siRNA) and to establish a new targeted nano-gel delivery system for anti tumor therapy by studying its anti-tumor ability in vitro. Methods We synthesized the core-shell temperature-sensitive PNIPAM/PEI nanogel by radical graft copolymerization and evaluated its chemo-physical properties (such as, size and zeta potential) using transmission electron microscopy (TEM). According to the principle of charge interaction, the PNIPAM/PEI siRNA nanogel encapsulated RRM2-siRNA was prepared by conjugating anti human epidermal growth factor receptor 2 (Her2) antibody. The effect of PNIPAM/PEI-siRNA nanogel complex encapsulated siRNA was determined by agarose gel electrophoresis. The in vitro uptake of NCI-N87 cells by nanogel complex was quantitatively observed by fluorescence microscopy and flow cytometry (FCM). The expression of RRM2 after RRM2 interference using nanogel-siRNA complex in NCI-N87 cells was tested by realtime PCR The tumor migration suppressing effect of the nanogel complex on Her2-positive tumor cells was determined by Transwell assay. Results The core-shell temperature-responsive PNIPAM/PEI nanogel was synthesized by radical graft copolymerization, with homogeneous size of 359. 8 nm, and zeta potential of 21. 4 mV. Furthermore, the nanogel complexes encapsulated RRM2-siRNA with different ratios of N/P (N/P ratio: the molar ratio of nitrogen-from-polyethylenimine to phosphate-from-RNA) were prepared and the electrophoresis results showed that the optimal N/P ratio was 60. The cellular uptake experiment showed that the nanogel had good temperature sensitivity and tumor targeting ability at different temperatures (37ºC, 42ºC); and the nanogel complex down-regulated the expression of RRM2 and inhibited the migration of NCI-N87 cells. Conclusion The antibody-targeting temperature-sensitive PNIPAM/PEI nanogel is successfully prepared, and it can bind and deliver siRNA into target cells and can be used as a new drug delivery system for anti-tumor therapy.

Research progress in nanogel carrier systems / 中国药学杂志

Nanogels combine the advantages of hydrogels and nanoparticles, such as small particle size, prolonged blood circulation time, biocompatibility, biodegradation and high drug loading. Common carrier materials is used for the preparation of nanogels include polyacrylic acid, polyacrylamide, pluronic, polysaccharide and their derivates. They can be cross-linked based on amine reaction, "click" chemistry, photo-induced cross-linking, physical cross-linking or heterogeneous polymerization of monomers to form nanogel carrier systems. Nanogels, as ideal and novel drug delivery systems, have great promise in the delivery of chemotherapeutic drugs, proteins and genes. The carrier materials, preparation methods and applications of nanogels were reviewed based on relevant articles published in recent years.