Redox-responsive interleukin-2 nanogel specifically and safely promotes the proliferation and memory precursor differentiation of tumor-reactive T-cells
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Abstract:
Interleukin-2 (IL-2) is a potent T-cell mitogen that can adjuvant anti-cancer adoptive T-cell transfer (ACT) immunotherapy by promoting T-cell engraftment.Keywords:
Adoptive Cell Transfer
Nanogel
Cancer Immunotherapy
Precursor cell
The self-assembly and stimuli-responsive properties of nanogel poly(n-isopropylacrylamide) (p(NIPAm)) and zwitterion-modified nanogel poly(n-isopropylacrylamide-co-sulfobetainemethacrylate) (p(NIPAm-co-SBMA)) were explored by dissipative particle dynamics simulations. Simulation results reveal that for both types of nanogel, it is beneficial to form spherical nanogels at polymer concentrations of 5-10%. When the chain length (L) elongates from 10 to 40, the sizes of the nanogels enlarge. As for the p(NIPAm) nanogel, it shows thermoresponsiveness; when it switches to the hydrophilic state, the nanogel swells, and vice versa. The zwitterion-modified nanogel p(NIPAm-co-SBMA) possesses thermoresponsiveness and ionic strength responsiveness concurrently. At 293 K, both hydrophilic p(NIPAm) and superhydrophilic polysulfobetaine methacrylate (pSBMA) could appear on the outer surface of the nanogel; however, at 318 K, superhydrophilic pSBMA is on the outer surface to cover the hydrophobic p(NIPAm) core. As the temperature rises, the nanogel shrinks and remains antifouling all through. The salt-responsive property can be reflected by the nanogel size; the volumes of the nanogels in saline systems are larger than those in salt-free systems as the ionic condition inhibits the shrinkage of the zwitterionic pSBMA. This work exhibits the temperature-responsive and salt-responsive behavior of zwitterion-modified-pNIPAm nanogels at the molecular level and provides guidance in antifouling nanogel design.
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Dissipative particle dynamics
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Topical candidiasis is a known skin fungal infection which is usually treated by conventional dosage forms such as cream, gel, emulgel which are having numerous adverse effects on skin. To overcome such disadvantages, different novel drug delivery systems have been considered. Polymer based nano-particulate systems have shown good skin penetration after topical application. Therefore, in the present study the main focus was on the pathology, pathogenesis, and consequently topical treatment of candidiasis. Nanogel containing miconazole have been prepared from the natural polymers i.e. gelatin and chitosan. The nanogel of miconazole (100 mg) nitrate was formulated by modified emulsification-diffusion technique and characterized for different parameters. From all the seven nanogel formulations named as F1 to F7, F1 (Gelatin and Chitosan in the percentage of 82.85 and 17.15 respectively) have been selected as model formulations. The reason behind that was as per ICH stability guideline, the formulations F1 was found optimum and stable. Miconazole nanogel formulations F1 also showed the maximum release i.e. 78 % approximately. XRD showed the formulated nanogel was in crystalline shape. In summary, the miconazole nanogel drug delivery systems have two main advantages i.e. they are topical preparation as well as nano sized. It can be postulated that nanogel may be a best approach to treat the fungal skin diseases.
Nanogel
Miconazole Nitrate
Gelatin
Nanocapsules
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Self-assembled hyaluronic acid-based nanogels are versatile drug carriers due to their biodegradable nature and gentle preparation conditions, making them particularly interesting for delivery of peptide therapeutics. This study aims to elucidate the relation between peptide structure and encapsulation in a nanogel. Key peptide properties that affect encapsulation in octenyl succinic anhydride-modified hyaluronic acid nanogels were identified as we explored the effect on nanogel characteristics using 12 peptides with varying charge and hydrophobicity. The size and surface properties of the microfluidics-assembled peptide-loaded nanogels were evaluated using dynamic light scattering, laser Doppler electrophoresis, and small angle neutron scattering. Additionally, the change in peptide secondary structure upon encapsulation in nanogels, their release from the nanogels, and the in vitro antimicrobial activity were assessed. In conclusion, the more hydrophobic peptides showed stronger binding to the nanogel carrier and localized internally rather than on the surface of the nanogel, resulting in more spherical nanogels with smoother surfaces and slower release profiles. In contrast, cationic and hydrophilic peptides localized at the nanogel surface resulting in fluffier nanogel structures and quick and more complete release in biorelevant medium. These findings emphasize that the advantages of nanogel delivery systems for different applications depend on the therapeutic peptide properties.
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Nanogels (NGs) have attracted great attention because of their outstanding biocompatibility, biodegradability, very low toxicity, flexibility, and softness. NGs are characterized with a low and nonspecific interaction with blood proteins, meaning that they do not induce any immunological responses in the body. Due to these properties, NGs are considered promising candidates for pharmaceutical and biomedical application. In this work, we introduce the development of novel functional nanogel obtained from two naturally based products-citric acid (CA) and pentane-1,2,5-triol (PT). The nanogel was synthesized by precipitation esterification reaction of CA and PT in tetrahydrofuran using N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide (EDC) and 4-(dimethylamino)pyridine (DMAP) catalyst system. Dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM) and atomic force microscopy (AFM) analyses revealed formation of spherical nanogel particles with a negative surface charge. Next, the nanogel was loaded with doxorubicin hydrochloride (DOX) by electrostatic interactions between carboxylic groups present in the nanogel and amino groups of DOX. The drug-loaded nanogel exhibited high encapsulation efficiency (EE~95%), and a bi-phasic release behavior. Embedding DOX into nanogel also stabilized the drug against photodegradation. The degradability of nanogel under acidic and neutral conditions with time was investigated as well.
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Abstract New hybrid poly(ethylene glycol) (PEG) hydrogels crosslinked with both nanogels and nanogel‐coated liposome complexes are obtained by Michael addition of the acryloyl group of a cholesterol‐bearing pullulan (CHP) nanogel to the thiol group of pentaerythritol tetra(mercaptoethyl) polyoxyethylene. The nanogel‐coated liposome complex is stably retained after gelation and the complexes are well dispersed in the hybrid gel. Microrheological measurements show that the strength and gelation time of the hybrid hydrogel can be controlled by changing the liposome:nanogel ratio. The hydrogel is gradually degraded by hydrolysis under physiological conditions. In this process, the nanogel is released first, followed by the nanogel‐coated liposomes. Hybrid hydrogels that can incorporate various molecules into the nanogel and liposomes, and release them in a two‐step controllable manner, represent a new functional scaffold capable of delivering multiple drugs, proteins or DNA.
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Pentaerythritol
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Nanogel
Doxorubicin Hydrochloride
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We describe a quantitative intrathymic (i.t.) adoptive transfer system for detecting thymocyte precursor cells in rats and mice. In this system, the generation of donor-origin thymocytes is analyzed on the FACS after the injection of test cells directly into the thymus of sublethally irradiated, histocompatible, RT-7 (rat) or Ly-1 (mouse) alloantigen-disparate recipients. Like the standard i.v. adoptive transfer assays for prothymocytes, the i.t. transfer assay is time, dose, and irradiation dependent. However, unlike the i.v. assays, the i.t. assay is highly sensitive, independent of cell migration, and specific for T-lineage precursor cells. Thus, the i.t. system requires between 25- and 50-fold fewer precursor cells than do the i.v. systems to generate a given number of donor-origin thymocytes; it detects nonmigratory as well as migratory subsets of precursor cells; it detects prethymic and intrathymic precursor cells with equal facility; and it produces a discrete, self-limited wave of donor-origin thymocytes and peripheral T cells. Moreover, neither hemopoietic nor lymphopoietic stem cell chimerism occurs at extrathymic sites. Comparison of the kinetics of thymocytopoiesis in the i.t. and i.v. transfer systems suggest that the seeding efficiency of prothymocytes in the i.v. assay approximates 0.04; the lag phase of the time-response curve is not due to a delay in the entry of prothymocytes into the thymus; and the relative amount of thymocyte precursor activity in various lymphohemopoietic tissues is highest in bone marrow, lowest (or absent) in lymph node, and intermediate in spleen, blood, and thymus. Moreover, the occurrence of saturation kinetics in the dose-response curve of the i.t. system supports the hypothesis that a finite number of microenvironmental niches for prothymocytes may exist in the thymus. These initial observations will require confirmation and extension in future studies. However, based on the present findings and related observations, we anticipate that the i.t. adoptive transfer system will contribute importantly to the definitive analysis of both normal and abnormal thymocytopoiesis.
Thymocyte
Adoptive Cell Transfer
Precursor cell
Splenocyte
Lymphopoiesis
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Nanogel: Types, Methods of Preparation, Limitation, Evaluation and Application – A Systematic Review
Nanogels combine the characteristics of nanomaterials with hydrogels. To meet the expanding demands from various areas, a sizable number of nanogels have been designed and manufactured using the emulsion solvent diffusion nano precipitated method, emulsion evaporation of the solvent method, reverse micellar method and modified diffusion emulsification method. Thermosensitive nanogel, pH-sensitive nanogel, ultrasound-sensitive magnetic response, response to multiple stimuli, chain transfer polymerization, photo-induced crosslinking polymerization and modifications for active targeting are the types of nanogels based on response towards stimuli and polysaccharide, chitosan, pullulan, hyaluronic acid, alginate, cyclodextrin, gum acacia, protein are used to prepare nanogel. Nanogels have considerable potential and novelty within the biomedical sector due to their uniformity, adjustable dimensions, little toxicity, resilience in the presence of serum, and capacity for responsive behavior with a comparatively high drug encapsulation capacity. Nanogels have considerable potential in bioactive substance delivery, organ targeting, and chemotherapy. The article highlighted the preparation, types, evaluation and applicability of nanogel as a targeted delivery system.
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Pullulan
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Abstract In this study, prostate cancer-targeted, drug-loaded PEtOx nanogel was prepared by the combination of living/cationic ring-opening polymerization and alkyne-azide cycloaddition “click” chemistry. A fluorescence probe was also conjugated with nanogel to track drug delivery. Nanogel formation was confirmed by 1H-NMR and FT-IR spectroscopies while SEM and DLS analyses showed uniform spherical nanogels and the particle size of nanogels could be controlled at 100-250 nm with relatively narrow size distributions. The physical stability of nanogels has been examined at pH 7.4 and %1-5 fetal bovine serum and intravenously administered nanogel formulations could remain in the bloodstream without much physical change until they reach the target site. The biocompatibility of the nanogels was evaluated using MTT cytotoxicity assays. The results showed that cytotoxicity was dose-dependent and drug-loaded nanogels against cancer cells in vitro were much higher than that of the drug-free nanogel. The targeting efficiency was examined with peptide conjugated and peptide-free nanogel. Intracellular uptake of peptide 563 conjugated nanogel by tumor cells was 60-fold higher than that of nanogel without peptide. Our findings suggest that prepared nanogel exhibits great potential to be used in a variety of drug delivery applications due to non-toxic, and enhanced intracellular uptake into the tumor region.
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Biocompatibility
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Reduction-sensitive nanogel was developed by including dithiodipropionic acid (DTPA) in tripolyphosphoric acid (TPPA) cross-linked poly(ethylenimine) (PEI) nanogel. According to the light scattering measurement, DTPA (a disulfide compound) seemed to cross-link PEI chains in a cooperative manner with TPPA (a multi-valent anion). Nanogels composed of TPPA, PEI, and DTPA exhibited negative zeta potential and the absolute value increased with the amount of TPPA and DTPA. TPPA and DTPA were found to be contained in the nanogel, evidenced by Fourier transform (FT)-IR spectroscopy and Raman spectroscopy, respectively. 1H-NMR spectroscopy also revealed DTPA was contained in the nanogel. The DTPA content in the nanogel was determined colorimetrically to be 7.14 and 9.4%, depending on the DTPA content in the raw mixture for the preparation of nanogel. On the transmission electron microscopy (TEM) micrographs of the negatively stained nanogel, the diameter was about 20–30 nm. The specific loading of carboxylic fluorescein (CF) in the nanogel was around 1.8%, determined by fluorometric analysis, and it was not affected by the DTPA content. The maximum release degree of CF loaded in nanogel containing no DTPA was less than 10% and it was almost the same regardless of dithiothreitol (DTT) concentration. Whereas, the release of the dye loaded in nanogel containing DTPA was markedly promoted by DTT, possibly because the disulfide bond can be broken by DTT and the diffusivity of the dye through the nanogel matrix can increase.
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Dithiothreitol
Zeta potential
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