Intramuscular injection of palmitic acid-conjugated Exendin-4 loaded multivesicular liposomes for long-acting and improving in-situ stability.

BACKGROUND: Exendin-4 (Ex4) is a promising drug for diabetes mellitus with a half-life of 2.4 h in human bodies. Besides, the Ex4 formulations currently employed in the clinic or under development have problems pertaining to stability. In this study, palmitic acid-modified Ex4 (Pal-Ex4) was prepared and purified to extend the half-life of Ex4. In addition, Pal-Ex4-MVLs were further designed and optimized as a long-acting delivery system for intramuscular injection. METHODS: Pal-Ex4 was encapsulated within multivesicular liposomes (MVLs) via a two-step double emulsification process. The formulated products were then assessed for their vesicle size, encapsulation efficiency, and in vitro and in vivo. RESULTS: Pal-Ex4-MVLs with a notable encapsulation efficiency of 99.18% were successfully prepared. Pal-Ex4-MVLs, administered via a single intramuscular injection in Sprague-Dawley rats, sustained stable plasma concentrations for 168 h, presenting extended half-life (77.28 ± 12.919 h) and enhanced relative bioavailability (664.18%). MVLs protected Ex4 through providing stable retention and slow release. This approach considerably improved the in-situ stability of the drug for intramuscular administration. CONCLUSIONS: The combination of palmitic acid modification process with MVLs provides dual protection for Ex4 and can be a promising strategy for other hydrophilic protein/polypeptide-loaded sustained-release delivery systems with high drug bioactivity.

Human Serum Albumin Nanoparticles as a Carrier of 20(S)-Protopanaxadiol via Intramuscular Injection to Alleviate Cyclophosphamide-Induced Myelosuppression.

Myelosuppression is a prevalent and potentially life-threatening side effect during chemotherapy. As the main active component of ginseng, 20(S)-protopanaxadiol (PPD) is capable of relieving myelosuppression by restoring hematopoiesis and immunity. In this study, PPD was encapsulated in human albumin nanoparticles (PPD-HSA NPs) by nanoparticle albumin-bound (Nab) technology for intramuscular injection to optimize its pharmacokinetic properties and promote recovery of myelosuppression. The prepared PPD-HSA NPs had a particle size of about 280 nm with a narrow size distribution. PPD dispersed as an amorphous state within the PPD-HSA NPs, and the NPs exhibited in vitro sustained release behavior. PPD-HSA NPs showed a favorable pharmacokinetic profile with high absolute bioavailability, probably due to the fact that NPs entered into the blood circulation via lymphatic circulation and were eliminated slowly. In vivo distribution experiments demonstrated that PPD-HSA NPs were mainly distributed in the liver and spleen, but a strong fluorescence signal was also found in the inguinal lymph node, indicating drug absorption via a lymph route. The myelosuppressive model was established using cyclophosphamide as the inducer. Pharmacodynamic studies confirmed that PPD-HSA NPs were effective in promoting the level of white blood cells. Moreover, the neutrophil and lymphocyte counts were significantly higher in the PPD-HSA NPs group compared with the control group. This preliminary investigation revealed that PPD-HSA NPs via intramuscular administration may be an effective intervention strategy to alleviate myelosuppression.

Tauroursodeoxycholic acid attenuates neuronal apoptosis via the TGR5/ SIRT3 pathway after subarachnoid hemorrhage in rats.

BACKGROUND: Neuronal apoptosis plays a critical event in the pathogenesis of early brain injury after subarachnoid hemorrhage (SAH). This study investigated the roles of Tauroursodeoxycholic acid (TUDCA) in attenuate neuronal apoptosis and underlying mechanisms after SAH. METHODS: Sprague-Dawley rats were subjected to model of SAH and TUDCA was administered via the internal carotid injection. Small interfering RNA (siRNA) for TGR5 were administered through intracerebroventricular injection 48 h before SAH. Neurological scores, brain water content, Western blot, TUNEL staining and immunofluorescence staining were evaluated. RESULTS: TUDCA alleviated brain water content and improved neurological scores at 24 h and 72 h after SAH. TUDCA administration prevented the reduction of SIRT3 and BCL-2 expressions, as well as the increase of BAX and cleaved caspase-3.Endogenous TGR5 expression were upregulated after SAH and treatment with TGR5 siRNA exacerbated neurological outcomes after SAH and the protective effects of TUDCA at 24 h after SAH were also abolished by TGR5 siRNA. CONCLUSIONS: Our findings demonstrate that TUDCA could attenuated neuronal apoptosis and improve neurological functions through TGR5/ SIRT3 signaling pathway after SAH. TUDCA may be an attractive candidate for anti-apoptosis treatment in SAH.

Tauroursodeoxycholic acid attenuates neuronal apoptosis via the TGR5/ SIRT3 pathway after subarachnoid hemorrhage in rats

BACKGROUND: Neuronal apoptosis plays a critical event in the pathogenesis of early brain injury after subarachnoid hemorrhage (SAH). This study investigated the roles of Tauroursodeoxycholic acid (TUDCA) in attenuate neuronal apoptosis and underlying mechanisms after SAH. METHODS: Sprague-Dawley rats were subjected to model of SAH and TUDCA was administered via the internal carotid injection. Small interfering RNA (siRNA) for TGR5 were administered through intracerebroventricular injection 48 h before SAH. Neurological scores, brain water content, Western blot, TUNEL staining and immunofluorescence staining were evaluated. RESULTS: TUDCA alleviated brain water content and improved neurological scores at 24 h and 72 h after SAH. TUDCA administration prevented the reduction of SIRT3 and BCL-2 expressions, as well as the increase of BAX and cleaved caspase-3.Endogenous TGR5 expression were upregulated after SAH and treatment with TGR5 siRNA exacerbated neurological outcomes after SAH and the protective effects of TUDCA at 24 h after SAH were also abolished by TGR5 siRNA. CONCLUSIONS: Our findings demonstrate that TUDCA could attenuated neuronal apoptosis and improve neurological functions through TGR5/ SIRT3 signaling pathway after SAH. TUDCA may be an attractive candidate for anti-apoptosis treatment in SAH.