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1.
《Molecular therapy》2022,30(6):2186-2198
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2.
The nonsteroidal anti-inflammatory drugs elevate cardiovascular risk, perhaps, due to their accumulation in the heart and kidneys. We designed nanodelivery systems for cardiotoxic diclofenac to reduce its presence in these organs. Diclofenac ethyl ester (DFEE) was encapsulated in traceable micelles based on poly(ethylene oxide)-b-poly(ε-caprolactone) (DFEE-PCL-TM) or poly(ethylene oxide)-b-poly(α-benzyl carboxylate-ε-caprolactone) (DFEE-PBCL-TM). Diclofenac pharmacokinetics and tissue distribution were studied after intravenous (iv) and intraperitoneal administration of the nanoformulations and compared with those after iv doses of free diclofenac (n = 3-6/group). The average diameters for DFEE-PBCL-TM and DFEE-PCL-TM were 37.2 ± 0.06 and 45.1 ± 0.06 nm, respectively. Drug concentration dropped below the assay sensitivity after free drug administration in 6 h, but persisted for 24 h following DFEE-PBCL-TM (2.3 ± 1.4 μg/mL) and DFEE-PCL-TM (1.9 ± 0.6 μg/mL) iv administration. The diclofenac heart:blood and kidney:blood ratios were 5- to 12-fold lower with the nanoformulations than with free diclofenac. Near-infrared fluorescence measurements in tissues suggested exposure patterns to nanocarriers parallel with those achieved for delivered diclofenac by nanoformulations. Administration of DFEE-PCL-TM by iv or intraperitoneal injection, resulted in comparable pharmacokinetics and 6 h postdose near-infrared fluorescence in the heart, kidneys, liver, and spleen. When compared to each other, DFEE-PBCL-TM showed significantly lower diclofenac levels in the heart compared to DFEE-PCL-TM (0.3 ± 0.03 vs. 0.5 ± 0.1 μg/g). Developed nanoformulations of diclofenac prolonged diclofenac circulation and reduced its presence in the heart and kidneys, strongly suggesting cardiac-safe delivery vehicles for diclofenac.  相似文献   
3.
Prion accumulation in the brain and lymphoreticular system causes fatal neurodegenerative diseases. Our previous study revealed that cellulose ethers (CE) have anti-prion activities in vivo and in prion-infected cells when administered at high doses. This study aims to improve the bioavailability of a representative CE using a liposomal formulation and characterized CE-loaded liposomes in cultured cells. The liposomal formulation reduced the EC50 dose of CE by <1/200-fold in prion-infected cells. Compared to empty liposomes, CE-loaded liposomes were taken up much more highly by prion-infected cells and less by macrophage-like cells. Phosphatidylserine modification reduced the uptake of CE-loaded liposomes in prion-infected cells and did not change the anti-prion activity, whereas increased the uptake in macrophage-like cells. Polyethylene glycol modification reduced the uptake of CE-loaded liposomes in both types of cells and reduced the anti-prion activity in prion-infected cells. These results suggest that a liposomal formulation of CE is more practical than unformulated CE and showed that the CE-loaded liposome uptake levels in prion-infected cells were not associated with anti-prion activity. Although further improvement of the stealth function against phagocytic cells is needed, the liposomal formulation is useful to improve CE efficacy and elucidate the mechanism of CE action.  相似文献   
4.
目的制备载紫杉醇的D-α-生育酚聚乙二醇1000琥珀酸酯(D-α-tocopheryl polyethylene glycol 1000 succinate,TPGS)修饰的羧甲基壳聚糖-大黄酸偶联物(PTX/TPGS-CR)纳米胶束,并对其进行初步评价。方法采用透析法,以载药量、包封率及粒径为指标,通过单因素考察优化PTX/TPGS-CR纳米胶束的制备工艺并进行验证。以溶血实验及血管刺激性实验初步考察PTX/TPGS-CR纳米胶束的安全性。四甲基偶氮唑盐微量酶反应比色法(MTT)法考察PTX/TPGS-CR纳米胶束对Hela细胞的毒性。通过激光扫描共聚焦显微镜定性和流式细胞仪定量考察Hela细胞对PTX/TPGS-CR纳米胶束的摄取情况。结果制备工艺优化后制得的PTX/TPGS-CR纳米胶束粒径为(197.3±4.4)nm,PDI为(0.131±0.021),电位为(-31.8±0.5)mV,载药量为(48.20±3.03)%,包封率为(87.26±4.91)%。溶血实验结果表明,其溶血率低于1.71%;血管静脉注射无明显刺激性。其对Hela细胞的杀伤作用具有浓度和时间依赖性,能被Hela细胞高效摄取。结论PTX/TPGS-CR纳米胶束载药量和包封率高,安全性好,其体外抗肿瘤活性稍优于Taxol?。  相似文献   
5.
In this study, we attempted to identify unknown autoantigen for intraepidermal neutrophilic IgA dermatosis‐type IgA pemphigus by novel IgA‐specific immunoprecipitation. Mass‐spectrometry study identified polymeric immunoglobulin receptor (PIGR) as the candidate protein, and we confirmed that PIGR expressed in both epidermis and cultured keratinocytes. Eukaryotic recombinant protein of PIGR expressed in COS7 cells was reacted with both patient and normal sera, indicating that PIGR binds physiologically to IgA. To detect antigen‐specific binding by IgA autoantibodies, we performed several experiments using deglycosylated PIGR and F(ab)2 fragments from patient sera. However, these analyses suggested that patient IgA bound physiologically, but not immunologically, to PIGR. Nevertheless, our study provided two important insights. Newly developed IgA‐immunoprecipitation system should be a useful tool in the future study of identification of antigens for IgA autoantibodies. Detection of epidermal PIGR in this study confirmed previous results and indicated possible immunological role of PIGR in epidermis.  相似文献   
6.
Background: The aim was to investigate cutaneous delivery and biodistribution of the hedgehog pathway inhibitor, vismodegib (VSD), indicated for basal cell carcinoma (BCC), from polymeric micelle formulations under infinite/finite dose conditions.

Methods: VSD-loaded micelles were characterized for drug content, particle size, and shape; a micelle gel was characterized for its rheological behavior. Cutaneous deposition and biodistribution of VSD were determined using porcine and human skin in vitro with quantification by UHPLC-MS/MS.

Results: The optimal micelle solution (Zav 20–30 nm) increased the aqueous solubility of VSD by >8000-fold; drug content was stable after 4 weeks at 4°C. Application of micelle solution and micelle gel (0.086% w/v) to human skin for 12 h under infinite dose conditions resulted in statistically equivalent VSD deposition (0.62 ± 0.11 and 0.67 ± 0.14 μg/cm2, respectively). Cutaneous biodistribution in human skin under infinite (micelle solution and gel) and finite (micelle gel) dose conditions showed that the VSD concentrations obtained in the basal epidermis, at depths of 120–200 μm, were ?3800- and ?2300-fold greater than the IC50 reported for hedgehog signaling pathway inhibition in vitro.

Conclusion: Cutaneous delivery of VSD from micelle-based formulations might enable targeted, topical treatment of superficial BCC with minimal risk of systemic exposure.  相似文献   
7.
Levodopa (l-DOPA) is the most effective pharmacologic agent in Parkinson’s disease and remains the “gold standard”. Nevertheless, in long-term treatments, dyskinesias and motor complications can emerge. In this work, the combined use of l-DOPA methylester hydrochloride prodrug (LDME) with transbuccal drug delivery was supposed as a good alternative method to optimize the bioavailability of l-DOPA, to maintain constant plasma levels and to decrease the drug unwanted effects. The effects of environmental pH on buccal delivery of LDME were evaluated ex vivo. The increase of pH value from 5.8 to 6.2 implies an improvement of drug permeation. Since the pH increase causes the raising of hydrolytic conversion of LDME to l-DOPA, the pH value 6.2 was considered as a good compromise between drug stability and permeation rate. It was found that during the passage through the biological tissue, LDME undergoes a primary conversion to l-DOPA catalyzed by membrane’s enzymes. Supplementation of delivery with Tween 80® produces substantial enhancement of LDME passage through the membrane. The drug could be loaded in the IntelliDrug mechatronic device, released close to the buccal mucosa, so achieving and maintaining constant therapeutic blood levels for extensive time.  相似文献   
8.
Poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NP) of Val-Val dipeptide monoester prodrugs of ganciclovir (GCV) including L-Val-L-Val-GCV (LLGCV), L-Val-D-Val-GCV (LDGCV) and D-Val-L-Val-GCV (DLGCV) were formulated and dispersed in thermosensitive PLGA-PEG-PLGA polymer gel for the treatment of herpes simplex virus type 1 (HSV-1)-induced viral corneal keratitis. Nanoparticles containing prodrugs of GCV were prepared by a double-emulsion solvent evaporation technique using various PLGA polymers with different drug/polymer ratios. Nanoparticles were characterized with respect to particle size, entrapment efficiency, polydispersity, drug loading, surface morphology, zeta potential and crystallinity. Prodrugs-loaded NP were incorporated into in situ gelling system. These formulations were examined for in vitro release and cytotoxicity. The results of optimized entrapment efficiencies of LLGCV-, LDGCV- and DLGCV-loaded NP are of 38.7?±?2.0%, 41.8?±?1.9%, and 45.3?±?2.2%; drug loadings 3.87?±?0.20%, 2.79?±?0.13% and 3.02?±?0.15%; yield 85.2?±?3.0%, 86.9?±?4.6% and 76.9?±?2.1%; particle sizes 116.6?±?4.5, 143.0?±?3.8 and 134.1?±?5.2?nm; and zeta potential ?15.0?±?4.96, ?13.8?±?5.26 and ?13.9?±?5.14?mV, respectively. Cytotoxicity studies suggested that all the formulations are non-toxic. In vitro release of prodrugs from NP showed a biphasic release pattern with an initial burst phase followed by a sustained phase. Such burst effect was completely eliminated when NP were suspended in thermosensitive gels with near zero-order release kinetics. Prodrugs-loaded PLGA NP dispersed in thermosensitive gels can thus serve as a promising drug delivery system for the treatment of anterior eye diseases.  相似文献   
9.
New medical devices with anti-inflammatory properties are critical to prevent inflammatory processes and infections in medical/surgical procedures. In this work, we present a novel functionalization of silicone for medical use with a polymeric prodrug and a thermosensitive polymer, by graft polymerization (gamma rays), for the localized release of salicylic acid, an analgesic, and anti-inflammatory drug. Silicone rubber (SR) films were functionalized in two stages using graft polymerization from ionizing radiation (60Co). The first stage was grafting poly(N-vinylcaprolactam) (PNVCL), a thermo-sensitive polymer, onto SR to obtain SR-g-PNVCL. In the second stage, poly(2-methacryloyloxy-benzoic acid) (P2MBA), a polymeric prodrug, was grafted to obtain (SR-g-PNVCL)-g-P2MBA. The degree of functionalization depended on the concentrations of monomers and the irradiation dose. The films were characterized by attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy/energy-dispersive X-ray spectrometry (SEM–EDX), thermogravimetric analysis (TGA), and contact angle. An upper critical solution temperature (UCST) of the films was demonstrated by the swelling degree as a temperature function. (SR-g-PNVCL)-g-P2MBA films demonstrated hydrolysis-mediated drug release from the polymeric prodrug, pH, and temperature sensitivity. GC–MS confirmed the presence of the drug (salicylic acid), after polymer hydrolysis. The concentration of the drug in the release media was quantified by HPLC. Cytocompatibility and thermo-/pH sensitivity of functionalized medical silicone were demonstrated in cancer and non-cancer cells.  相似文献   
10.
修饰已上市药物以改善药物存在的缺陷,是目前全球药物研发的一个重要方向。以高分子前药为基础的给药系统具有前药修饰和微纳米载药的双重优势,可以增强药物在体内、体外的稳定性,增加药物的靶向性,提高药物的生物利用度、降低药物不良反应和提高治疗效果。本文根据高分子前药的研发机制,从被动靶向、主动靶向、触发释药和协同给药进行综述,探讨该类药物的研发现状及所面临的问题,并对此给出适当可行的解决方案。  相似文献   
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