Traumatic brain injury (TBI) is known to activate poly (ADP-ribose) polymerase (PARP-1), which leads to pronounced negative effects on mitochondrial DNA (mt-DNA) repair and function. Notably, PARP inhibitors are reported to be beneficial in experimental models of TBI. A targeting strategy for the delivery of neuronal mitochondria-specific PARP inhibitors could result in a greater neuroprotective effect and be a safer approach for TBI treatment. In the present study, we developed the PARP inhibitor olaparib (Ola) as a model drug and devised red blood cell (RBC)-coated nanostructured lipid carriers (RBCNLCs) co modified with C3 and SS31 peptide (C3/SS31-RBCNLCs) for brain neuronal mitochondria-targeting. Our results indicated that biomimetic nanosystems have the physical and chemical properties of the NLCs, as well as the biological properties of RBC. A high concentration of Ola delivered into brain mitochondria by C3/SS31-RBCNLCs-Ola effectively improved mitochondrial function and prevented neuronal cell death caused by excessive activation of injury-induced mitochondrial PARP (mt-PARP) in vitro and in vivo. Taken together, the results of this study support the preclinical feasibility of developing highly effective nano-drugs as part of precision medicine for TBI. Statement of Significance TBI-induced neuronal mitochondria DNA damage activates Poly(ADP-ribose) Polymerase (PARP1) which leads to a pronounced negative effect on mitochondrial DNA repair and mitochondrial function. In recent years, PARP inhibitors showed strong benefits in experimental models of TBI, more importantly PARP inhibitors specially target neuronal mitochondria may play a greater neuroprotective role and may be a safer approach for TBI treatment. Herein, we designed red blood cell (RBC) membrane coated nanostructure lipid carriers dual-modified with C3 and SS31 (C3/SS31-RBCNLCs) to accomplish these objectives. After encapsulating Olaparib (Ola) as the model PARP inhibitor, the data demonstrated that C3/SS31-RBCNLCs, with brain neuronal mitochondria targeting, can reduce neuronal cell death and improve mitochondrial dysfunction triggered by mitochondrial PARP activation in vitro and in vivo . (c) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Recent studies have demonstrated that ivermectin (IVM) exhibits antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of coronavirus disease 2019 (COVID-19). However, the repurposing of IVM for the treatment of COVID-19 has presented challenges primarily due to the low IVM plasma concentration after oral administration, which was well below IC50. Here, a red blood cell (RBC)-hitchhiking strategy was used for the targeted delivery of IVM-loaded nanoparticles (NPs) to the lung. IVM-loaded poly (lactic-co-glycolic acid) (PLGA) NPs (IVM-PNPs) and chitosan-coating IVM-PNPs (IVM-CSPNPs) were prepared and adsorbed onto RBCs. Both RBC-hitchhiked IVM-PNPs and IVM-CSPNPs could significantly enhance IVM delivery to lungs, improve IVM accumulation in lung tissue, inhibit the inflammatory responses and finally significantly alleviate the progression of acute lung injury. Specifically, the redistribution and circulation effects were related to the properties of NPs. RBC-hitchhiked cationic IVM-CSPNPs showed a longer circulation time, slower accumulation and elimination rates, and higher anti-inflammatory activities than RBC-hitchhiked anionic IVM-PNPs. Therefore, RBC-hitchhiking provides an alternative strategy to improve IVM pharmacokinetics and bioavailability for repurposing of IVM to treat COVID-19. Furthermore, according to different redistribution effects of different NPs, RBC-hitchhiked NPs may achieve various accumulation rates and circulation times for different requirements of drug delivery.

目的:探讨自制秋水仙碱缓释微丸对痛风性关节炎急性发作模型大鼠的预防作用.方法:采用流化床包衣技术制备秋水仙碱缓释微丸.将24只SD大鼠随机分为正常组、模型组、片剂组和缓释微丸组,每组6只.片剂组将秋水仙碱片研磨成粉,水溶后灌胃给药,缓释微丸组通过特制的灌胃器给予秋水仙碱缓释微丸,正常组和模型组给予等量生理盐水.给药14d后,除正常组外,其他各组用尿酸钠诱导大鼠痛风性关节炎发作.比较各组大鼠踝关节肿胀度,酶联免疫吸附试验(ELISA)法检测大鼠血清中白细胞介素(IL)-1β和肿瘤坏死因子(TNF)-α水平,苏木精—伊红(HE)染色观察大鼠踝关节炎性病变.通过比较各组大鼠腹泻率、摄食量、体重变化及血清中谷丙转氨酶(ALT)、谷草转氨酶(AST)、肌酐(Cr)含量来评估药物的安全性.结果:体外溶出结果显示,缓释微丸中的秋水仙碱成分在6h内溶出80％以上,具有良好的缓释特性.与模型组比较,片剂组和缓释微丸组大鼠关节肿胀度及血清中IL-1β、TNF-α水平显著下降(P＜0.05),踝关节滑膜增生及炎性浸润细胞明显减少.与片剂组比较,缓释微丸组大鼠关节肿胀度及IL-1β和TNF-α水平明显降低,摄食量和体重增加(均P＜0.05),炎性细胞减少,两组肝、肾功能(AST、ALT、Cr含量)及腹泻率比较无明显差异(均P＞0.05).结论:相较于秋水仙碱市售普通片剂,所制缓释微丸对尿酸钠诱导的痛风性关节炎大鼠关节肿胀和炎症的抑制作用更显著,且安全性好.

Gout is a common metabolic disease caused by the chronic deposition of monosodium urate (MSU) crystals in joints and tissues. Low-dose of colchicine (COL) has become the first-line drug for clinical prevention of acute gout attacks. However, their high cytotoxicity leads to a narrow therapeutic index and frequent toxic reactions. This study developed colchicine sustained-release pellets (COL-SRPs) using fluidized-bed technology to overcome the shortcomings of fluctuation in blood concentration and other side effects of commercial rapid release COL preparations. The COL-SRPs showed a smooth surface and spherical shape under a scanning electron microscope (SEM). The in vitro release curves of the COL-SRPs under different pH dissolution medium were not significantly different (similarity factors 2 ˃ 50). The release of COL from pellets may be a diffuse action. Pharmacokinetic studies demonstrated that the mean residence time (MRT) and tmax of the COL-SRPs group were significantly higher than those in the commercial colchicine tablets (COL-Ts) group. Pharmacodynamic studies comprehensively evaluated serum inflammatory factor indicators (IL-1β and TNF-α), liver and kidney function indexes (ALT, AST and CRE), as well as ankle joint histopathology, further suggesting that the COL-SRPs exhibited a more optimal preventive potential against acute gout attack. The COL-SRPs prepared in this study provide a powerful alternative to commercial COL-Ts by overcoming their shortcomings and having great industrial production potential.

Acute lung injury (ALI) is a disease associated with suffering and high lethality, but to date without any effective pharmacological management in the clinic. In the pathological mechanisms of ALI, a strong inflammatory response plays an important role. Herein, based on macrophage 'homing' into inflammation sites and cell membrane coating nanotechnology, we developed a biomimetic anti-inflammation nanosystem (MM-CEP/NLCs) for the treatment of ALI. MM-CEP/NLCs were made with nanostructured lipid carriers (NLCs) coated with natural macrophage membranes (MMs) to achieve effective accumulation of cepharanthine (CEP) in lung inflammation to achieve the effect of treating ALI. With the advantage of suitable physicochemical properties of NLCs and unique biological functions of the macrophage membrane, MM-CEP/NLCs were stabilized and enabled sustained drug release, providing improved biocompatibility and long-term circulation. In vivo, the macrophage membranes enabled NLCs to be targeted and accumulated in the inflammation sites. Further, MM-CEP/NLCs significantly attenuated the severity of ALI, including lung water content, histopathology, bronchioalveolar lavage cellularity, protein concentration, and inflammation cytokines. Our results provide a bionic strategy via the biological properties of macrophages, which may have greater value and application prospects in the treatment of inflammation.

Nanocarriers have been extensively applied for intravascular drug delivery. However, rapid clearance from circulation by mononuclear phagocyte system has limited their applications. Erythrocytes carriers are potential solutions to overcome the limitations of nanocarriers and considered to be ideal natural carriers for drug delivery because of their unique properties. The purpose of this work is to combine nanocarriers with erythrocytes carriers for sustained release and prolonged circulation time of vitamin K-1. Chitosan nanoparticles loading VK1(VKCSNPs) were prepared using ionotropic gelation method, which was optimized using box-behnken design and response surface methodology. VK-CSNPs adsorbed onto red blood cells (RBC-VK-CSNPs) rapidly via electrostatic interactions. The exposure of phosphatidylserine, osmotic fragility and turbulence fragility of RBC loading nanoparticles were investigated to study the toxicity of nanoparticles to erythrocytes. In vivo pharmacokinetic study indicated that C-max, AUC and MRT of RBC-VK-CSNPs group were remarkably higher than that of VK-CSNPs group. Flow cytometry showed VK-CSNPs steadily retained on the surface of RBC for a long time without affecting the circulation profiles of RBC themselves. The nanoparticles carried on RBC released drug, desorbed and were eliminated in vivo. Therefore, the circulation time of RBC-hitchhiking chitosan nanoparticles was greatly prolonged compared with nanoparticles alone. RBC-hitchhiking could be a valuable hybrid strategy for prolonging the in vivo life of nanocarriers.

Hyper-inflammation associated with cytokine storm syndrome causes high mortality in patients with COVID-19. Glucocorticoids, such as methylprednisolone sodium succinate (MPSS), effectively inhibit this inflammatory response. However, frequent and chronic administration of glucocorticoids at high doses leads to hormone dependence and serious side effects. The aim of the present study was to combine nanoparticles with erythrocytes for the targeted delivery of MPSS to the lungs. Chitosan nanoparticles loading MPSS (MPSS-CSNPs) were prepared and adsorbed on the surface of red blood cells (RBC-MPSS-CSNPs) by non-covalent interaction. In vivo pharmacokinetic study indicated that RBC-hitchhiking could significantly reduce the plasma concentration of the drug and prolong the circulation time. The mean residence time (MRT) and area under the curve (AUC) of the RBC-MPSS-CSNPs group were significantly higher than those of the MPSS-CSNPs group and the MPSS injection group. Moreover, in vivo imaging and tissue distribution indicated that RBC-hitchhiking facilitated the accumulation of nanoparticles loading fluorescein in the lung, preventing uptake of these nanoparticles by the liver. Furthermore, compared with the MPSS-CSNPs and MPSS treatment groups, treatment with RBC-MPSS-CSNPs considerably inhibited the production of inflammatory cytokines such as TNF-α and IL-6, and consequently attenuated lung injury induced by lipopolysaccharide in rats. Therefore, RBC-hitchhiking is a potentially effective strategy for the delivery of nanoparticles to the lungs for the treatment of acute lung injury and acute respiratory distress syndrome.