Immunotherapeutic efficacy of tumors based on immune checkpoint blockade (ICB) therapy is frequently limited by an immunosuppressive tumor microenvironment and cross-reactivity with normal tissues. Herein, we develop reactive oxygen species (ROS)-responsive nanocomplexes with the function of ROS production for delivery and triggered release of anti-mouse programmed death ligand 1 antibody (αPDL1) and glucose oxidase (GOx). GOx and αPDL1 were complexed with oligomerized (−)-epigallocatechin-3-O-gallate (OEGCG), which was followed by chelation with Fe 3+ and coverage of the ROS-responsive block copolymer, POEGMA-b-PTKDOPA, consisting of poly(oligo(ethylene glycol)methacrylate) (POEGMA) and the block with thioketal bond-linked dopamine moieties (PTKDOPA) as the side chains. After intravenous injection, the nanocomplexes show prolonged circulation in the bloodstream with a half-life of 8.72 h and efficient tumor accumulation. At the tumor sites, GOx inside the nanocomplexes can produce H 2 O 2 via oxidation of glucose for Fenton reaction to generate hydroxyl radicals (•OH) which further trigger the release of the protein cargos through ROSresponsive cleavage of thioketal bonds. The released GOx improves the production efficiency of •OH to kill cancer cells for release of tumor-associated antigens via chemodynamic therapy (CDT). The enhanced immunogenic cell death (ICD) can activate the immunosuppressive tumor microenvironment and improve the immunotherapy effect of the released αPDL1, which significantly suppresses primary and metastatic tumors. Thus, the nanocomplexes with Fenton reaction-triggered protein release show great potentials to improve the immunotherapeutic efficacy of ICB via combination with CDT.
The physicochemical properties of different grades of Malaysian crude palm oil (high free fatty acid crude palm oil (HFFA-CPO) and low free fatty acid crude palm oil (LFFA-CPO)) were analyzed in this study to determine their applicability as edible oils. The percentages of free fatty acids (FFAs%), iodine value, hydroxyl value, unsaponifiable value, moisture content for HFFA-CPO and LFFA-CPO were 8.7 ± 0.3 and 3.8 ± 0.1%; 53.1 ± 0.4 and 56 ± 0.3 g I 2 /100 g; 32.5 ± 0.6 and 18.5 ± 0.9 mg KOH/g oil; 0.31 ± 0.01 and 0.46 ± 0.02%; 0.31 ± 0.01 and 0.33 ± 0.01%, respectively. The fatty acid compositions were determined using a gas chromatography-flame ionization detector (GC-FID). The results showed that the dominant fatty acids are palmitic acid (43.2%-44.4%) and oleic acid (39.8%-41.4%). The major triacylglycerols (TAGs) of HFFA-CPO and LFFA-CPO estimated using high-performance liquid chromatography (HPLC), were POP (30.8%-33.6%) and POO (24.9%-29.7%). In general, the physicochemical properties of HFFA-CPO and LFFA-CPO are consistent with the standard Malaysian crude palm oil, with the exception of FFAs%, hydroxyl value, moisture contents. Keywords: physicochemical characteristic / hydroxyl value / high free fatty acid crude palm oil / triacylglycerol profile / fatty acid composition Résumé-Caractéristiques physico-chimiques de l'huile de palme brute à haute teneur en acides gras libres. Les propriétés physico-chimiques des différentes nuances de l'huile de palme brute malaisienne (huile de palme brute à haute teneur en acides gras libres (HFFA-CPO) et huile de palme brute à faible teneur en acides gras libres (LFFA-CPO)) ont été analysées dans cette étude pour déterminer leur applicabilité sous forme d'huiles comestibles. Les pourcentages d'acides gras libres (FFAs %), de valeur d'iode, de valeur d'hydroxyle, de valeur insaponifiable, de teneur en humidité pour HFFA-CPO et LFFA-CPO étaient de 8,
A remarkable hallmark of cancer cells is the heterogeneous coexistence of overproduced intracellular glutathione (GSH) and a high level of reactive oxygen species (ROS) compared with those in normal cells, which have been frequently used as the stimuli to trigger drug release from the nanocarriers. Most of the stimuli-responsive delivery vehicles have been designed to respond to only one redox stimulus (e.g., GSH or ROS). Herein, we develop a GSH and ROS dual-responsive amphiphilic diblock copolymer prodrug (BCP) (GR-BCP) consisting of poly(ethylene glycol) (PEG)- and camptothecin (CPT)-conjugated poly(methacrylate) in the side chains via thioether bonds. In comparison, GSH or ROS single-responsive BCPs (G-BCPs or R-BCPs) were prepared, where CPT drugs were linked by disulfide or thioketal bonds, respectively. The three BCPs can form well-defined spherical micellar nanoparticles in an aqueous solution with a diameter of ∼50 nm. Compared with G-BCP and R-BCP, GR-BCP realized the highest cytotoxicity against HeLa cells with the half-inhibitory concentration (IC50) of 6.3 μM, which is much lower than 17.8 μM for G-BCP and 28.9 μM for R-BCP. Moreover, for in vivo antitumor performance, G-BCP, R-BCP, and GR-BCP showed similar efficiencies in blood circulation and tumor accumulation after intravenous injection. However, GR-BCP realized the most efficient tumor suppression with few side effects. Our findings demonstrate that intracellular GSH and ROS dual-responsive BCPs show a more efficient responsive drug release inside tumor cells for boosting the antitumor efficacy as compared with GSH or ROS single-responsive BCPs, which provides novel strategies for designing redox-responsive BCPs.
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