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Drug Content Determination of Low-Dosed Hot-Melt Extruded Filaments using Raman Spectroscopy 利用拉曼光谱测定低剂量热熔挤出长丝的药物含量
IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-26 DOI: 10.1080/10837450.2024.2323622
Rebecca Chamberlain, Jörg Breitkreutz, Björn Fischer
The aim of this study was to evaluate the suitability of a non-disruptive Raman spectroscopic method to quantify drug concentrations below 5 w% within a polymer matrix produced by hot-melt extrusio...
本研究的目的是评估一种非破坏性拉曼光谱方法是否适用于对热熔挤出法生产的聚合物基质中低于 5 w% 的药物浓度进行定量。
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引用次数: 0
Nanoparticles as carriers of photosensitizers to improve photodynamic therapy in cancer 纳米颗粒作为光敏剂载体,改善癌症的光动力疗法
IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-26 DOI: 10.1080/10837450.2024.2322570
Duy Hieu Truong, Phuong Thi Thu Tran, Tuan Hiep Tran
Photodynamic therapy (PDT) has emerged as a promising non-invasive therapeutic approach for cancer treatment, offering unique advantages over conventional treatments. The combination of light activ...
光动力疗法(PDT)是一种很有前途的非侵入性癌症治疗方法,与传统疗法相比具有独特的优势。与传统疗法相比,光动力疗法具有独特的优势。
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引用次数: 0
Fabrication of controlled-release polymeric microneedles containing progesterone-loaded self-microemulsions for transdermal delivery. 制造含有黄体酮自微乳剂的控释聚合物微针,用于透皮给药。
IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 Epub Date: 2024-02-03 DOI: 10.1080/10837450.2024.2307996
Phuvamin Suriyaamporn, Porawan Aumklad, Theerasak Rojanarata, Prasopchai Patrojanasophon, Tanasait Ngawhirunpat, Boonnada Pamornpathomkul, Praneet Opanasopit

Progesterone (PG) has been approved for hormone replacement therapy to mitigate the risk of endometrial carcinoma. However, there has been a lack of success in oral PG due to its rapid degradation. Transdermal PG has advantages but lacks efficacy due to its poor solubility (Log p = 3.9). Therefore, this study aimed to evaluate how combining self-microemulsifying drug delivery systems (SMEDDS) and polymeric microneedles (MNs) could improve the transdermal delivery of PG in a controlled-release manner. Among PG-SMEDDS, PG-SME5 was selected for its desirable properties and stability. The two-layer polymeric MNs formulation incorporating PG-SME5 (PG-SMEDDS-tMNs) was formulated from aqueous blends of polymers as a first layer and 20% PCL as a second layer. It successfully penetrated neonatal porcine skin with the dissolution of the first layer observed within 15 min after application. In vitro skin permeation revealed that the percentage of PG which permeated the skin over 82 h using PG-SMEDDS-tMNs was higher than a PG-suspension and PG-SMEDDS. The Higuchi kinetic showed controlled release over 15 days of PG from PG-SMEDDS-tMNs. These studies suggested that incorporating PG-SMEDDS into controlled-release two-layer polymeric MNs could be a promising approach for improving the transdermal delivery of PG.

孕酮(PG)已被批准用于激素替代疗法,以降低子宫内膜癌的风险。然而,由于黄体酮降解快,口服黄体酮的疗效不佳。透皮孕酮具有一定优势,但由于其溶解度较低(Log P = 3.9)而缺乏疗效。因此,本研究旨在评估自微乳化给药系统(SMEDDS)与聚合物微针(MNs)的结合如何以控释方式改善 PG 的透皮给药。在 PG-SMEDDS 中,PG-SME5 因其理想的特性和稳定性而被选中。包含 PG-SME5 的双层聚合物 MNs 制剂(PG-SMEDDS-tMNs)由聚合物水混合物作为第一层,20% PCL 作为第二层配制而成。它成功地渗透了新生猪皮肤,在使用后 15 分钟内观察到第一层溶解。体外皮肤渗透显示,使用 PG-SMEDDS-tMNs 82 小时内渗透皮肤的 PG 百分比高于 PG 悬浮液和 PG-SMEDDS。樋口动力学显示,PG-SMEDDS-tMNs 可在 15 天内控制 PG 的释放。这些研究表明,将 PG-SMEDDS 加入控释双层聚合物 MNs 中可能是改善 PG 透皮给药的一种很有前景的方法。
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引用次数: 0
Development and efficacy evaluation of a novel water-in-oil-in-water adjuvant for an inactivated foot-and-mouth disease vaccine. 用于口蹄疫灭活疫苗的新型水包油佐剂的开发与药效评估
IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 Epub Date: 2024-01-17 DOI: 10.1080/10837450.2024.2305107
Rong Zhang, Yanming Wei, Xuerong Liu, Yongshu Wu

To develop a novel water-in-oil-in-water (W/O/W) adjuvant and evaluate the effect on foot-and-mouth disease (FMD) inactivated vaccine, in this study, we prepared the novel nano-emulsion adjuvant based on QS-21 (BEA) which is composed of the mixture of mineral oil Marcol52, surfactant Tween80, oleate polyoxyethylene ether ester, polyoxyethylene palmitic acid ester and span80, cosurfactant polyethylene glycol and QS-21. The two-step emulsification method formed the W/O/W nano-emulsion with two films and three-phase structures. The effective particle diameter of the BEA was about 184 nm, and it has good thermal stability. Then, BEA was emulsified as an adjuvant to prepare for the inactivated FMDV vaccine, and BALB/c mice and pigs were immunized to evaluate its safety and immunization effect. The results showed that the inactivated BEA-FMDV vaccine significantly increased BALB/c mice and pigs' antibodies and cytokine IFN-γ in serum. Meanwhile, the pig-neutralizing antibodies were higher than control group. Safety tests found no symptoms of FMD or significant toxic reactions. After 28 days of immunization, the protection rate can reach 93.3%. The BEA vaccine had good stability at 4 °C, no stratification after 180 days, and the content of 146S in the vaccine did not decrease. In conclusion, the BEA prepared in this study is suitable for FMDV inactivated vaccine and is an effective adjuvant.

为了开发一种新型水包油(W/O/W)佐剂并评估其对口蹄疫(FMD)灭活疫苗的效果,本研究制备了基于 QS-21 的新型纳米乳液佐剂(BEA),该佐剂由矿物油 Marcol52、表面活性剂 Tween80、油酸聚氧乙烯醚酯、聚氧乙烯棕榈酸酯和 span80、共表面活性剂聚乙二醇和 QS-21 混合组成。两步乳化法形成了两膜三相结构的 W/O/W 纳米乳液。BEA 的有效粒径约为 184 nm,具有良好的热稳定性。然后,以BEA为佐剂乳化制备口蹄疫灭活疫苗,并对BALB/c小鼠和猪进行免疫接种,以评价其安全性和免疫效果。结果表明,BEA-FMDV 灭活疫苗能显著增加 BALB/c 小鼠和猪的抗体和血清中的细胞因子 IFN-γ。同时,猪中和抗体高于对照组。安全性试验未发现 FMD 症状或明显的毒性反应。免疫 28 天后,保护率可达 93.3%。BEA 疫苗在 4 °C 下稳定性良好,180 天后无分层现象,疫苗中 146S 的含量也没有降低。总之,本研究制备的 BEA 适用于口蹄疫病毒灭活疫苗,是一种有效的佐剂。
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引用次数: 0
Oridonin loaded peptide nanovesicles alleviate nonalcoholic fatty liver disease in mice. 装载奥利多宁的肽纳米粒子能缓解小鼠的非酒精性脂肪肝。
IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 Epub Date: 2024-02-19 DOI: 10.1080/10837450.2024.2315460
Lifen Zhang, Yao Yu, Qi Wang, Xi Huang, Zheng Feng, Zhi Li

This study was to construct a nanovesicle delivery system to improve the loading efficiency and stability of ORI for the treatment of nonalcoholic fatty liver disease (NAFLD). This nanovesicles (NVs) exerted a narrow size distribution (195.6 ± 11.49 nm) and high entrapment efficiency (84.46 ± 1.34%). In vitro cell studies demonstrated that the NVs treatment enhanced the cellular uptake of ORI and reduced lipid over-accumulation and total cholesterol levels in NAFLD cell model. At the same time, in vivo study proved that, compared with the normal group, the model group mice showed a decrease in body weight, a significant increase in liver index (6.71 ± 0.62, p < 0.01), and symptoms of liver lipid accumulation, lipid vesicles, and liver tissue fibrosis. Compared with the model group, after high-dose ORI NVs intervention, mice gained weight, decreased liver index (4.69 ± 0.55, p < 0.01), reduced hepatic lipid droplet vacuoles, reduced lipid accumulation (reduced oil red area, p < 0.001), and alleviated the degree of liver fibrosis (reduced blue collagen area, p < 0.001). In conclusion, ORI/HP-β-CD/H9-HePC NVs showed specific liver accumulation and improved therapeutic effects, the nano drug loading system provides a promising strategy for the encapsulation of ORI to effectively alleviate the process of NAFLD.

本研究旨在构建一种纳米颗粒给药系统,以提高ORI的负载效率和稳定性,用于治疗非酒精性脂肪肝(NAFLD)。该纳米颗粒粒径分布窄(195.6 ± 11.49 nm),包载效率高(84.46 ± 1.34%)。体外细胞研究表明,在非酒精性脂肪肝细胞模型中,NVs 处理增强了细胞对 ORI 的吸收,降低了脂质过度积累和总胆固醇水平。同时,体内研究证明,与正常组相比,模型组小鼠体重下降,肝脏指数显著增加(6.71 ± 0.62,p<0.05)。
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引用次数: 0
Solid self-microemulsifying drug delivery system (S-SMEDDS) prepared by spray drying to improve the oral bioavailability of cinnamaldehyde (CA). 通过喷雾干燥法制备固体自微乳化给药系统(S-SMEDDS),以提高肉桂醛(CA)的口服生物利用度。
IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 Epub Date: 2024-02-09 DOI: 10.1080/10837450.2024.2312851
Yun Meng, Ye Cai, Mengyao Cui, Yuhang Xu, Long Wu, Xiang Li, Xiaoqin Chu

The aim of this study was to prepare a solid self-microemulsifying drug delivery system (S-SMEDDS) of cinnamaldehyde (CA) by spray drying technique to improve the oral bioavailability of CA. The preparation of CA S-SMEDDS with maltodextrin as the solid carrier, a core-wall material mass ratio of 1:1, a solid content of 20% (w/v), an inlet air temperature of 150 °C, an injection speed of 5.2 mL/min, and an atomization pressure of 0.1 MPa was determined by using the encapsulation rate as the index of investigation. Differential scanning calorimetry (DSC) revealed the possibility of CA being encapsulated in S-SMEDDS in an amorphous form. The in-vitro release showed that the total amount of CA released by S-SMEDDS was approximately 1.3 times higher than that of the CA suspension. Pharmacokinetic results showed that the relative oral bioavailability of CA S-SMEDDS was also increased to 1.6-fold compared to CA suspension. Additionally, we explored the mechanism of CA uptake and transport of lipid-soluble drugs CA by S-SMEDDS in a Caco-2/HT29 cell co-culture system for the first time. The results showed that CA S-SMEDDS uptake on the co-culture model was mainly an energy-dependent endocytosis mechanism, including lattice protein-mediated endocytosis and vesicle-mediated endocytosis. Transport experiments showed that CA S-SMEDDS significantly increased the permeability of CA in this model. These findings suggested that CA S-SMEDDS is an effective oral solid dosage form for increasing the oral bioavailability of lipid-soluble drug CA.

本研究旨在通过喷雾干燥技术制备肉桂醛固体自微乳化给药系统(S-SMEDDS),以提高肉桂醛的口服生物利用度。以麦芽糊精为固体载体,芯壁材料质量比为1:1,固体含量为20%(w/v),进气温度为150 °C,注射速度为5.2 mL/min,雾化压力为0.1 MPa,以包封率为考察指标,确定了CA S-SMEDDS的制备方法。差示扫描量热法(DSC)显示,CA 有可能以无定形形式被包裹在 S-SMEDDS 中。体外释放表明,S-SMEDDS 释放的 CA 总量约为 CA 悬浮液的 1.3 倍。药代动力学结果表明,CA S-SMEDDS的相对口服生物利用度也比CA悬浮剂提高了1.6倍。此外,我们还首次在Caco-2/HT29细胞共培养系统中探讨了S-SMEDDS对脂溶性药物CA的吸收和转运机制。结果表明,共培养模型对CA S-SMEDDS的摄取主要是一种能量依赖性内吞机制,包括晶格蛋白介导的内吞和囊泡介导的内吞。转运实验表明,CA S-SMEDDS能显著提高该模型中CA的通透性。这些研究结果表明,CA S-SMEDDS是一种有效的口服固体制剂,可提高脂溶性药物CA的口服生物利用度。
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引用次数: 0
Preparation and evaluation of vaginal suppo-sponges loaded with benzydamine, in-vitro/in-vivo study. 制备和评估装有苄达明的阴道海绵,体外/体内研究
IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1080/10837450.2024.2306803
Noha S El-Salamouni, Marwa A Yakout, Gihan S Labib, Ragwa M Farid

This study aimed to design a new Benzydamine HCl (BNZ) suppo-sponge for controlled, mucoadhesive dosage form for vaginal candidiasis treatment, offering advantages over traditional creams, ointments, or gels. BNZ-loaded suppo-sponges were fabricated by simple casting / freeze-drying technique utilizing the cross-linking of chitosan (Cs) with vanillin (V). Vaginal suppo-sponges were prepared based on different vanillin cross-linking ratios (V).n), from 0 to 2%w/w. To best of our knowledge, this is the first study that uses Schiff's base between chitosan and vanillin as a drug delivery system to treat fungal vaginal infections. Schiff's base formation was confirmed by FT-IR. In-vitro appraisal showed acceptable physical and mechanical characteristics. Formulations based on cross-linking of Cs with V showed a more pronounced in-vitro antifungal activity. In-vitro drug release revealed a prolonged release pattern, becoming more noticeable with the higher cross-linked suppo-sponges (22.34% after 8 h). In-vivo testing of CsV2 suppo-sponge indicated a more pronounced reduction in fungal count than both CsV0 and Tantum® Rosa in the first week, with a peak reduction on day 7 and the 10th and 11th days of the second week. Conclusively, Chitosan/vanillin suppo-sponges represent a promising delivery system for drugs intended for local treatment of vaginal candidiasis. than both CsV0 and Tantum® Rosa in the first week, with a peak reduction on day 7 and the 10th and 11th days of the second week. Conclusively, Chitosan/vanillin suppo-sponges represent a promising delivery system for drugs intended for local treatment of vaginal candidiasis.

与传统的药膏、软膏或凝胶相比,以可控方式释放局部给药的粘液黏附剂型在治疗念珠菌性阴道炎方面具有明显优势。这项研究旨在设计一种新型盐酸苄达明(BNZ)辅助海绵,用于治疗念珠菌性阴道炎。利用壳聚糖(Cs)与香兰素(V)的交联,通过简单的浇铸/冷冻干燥技术制成了含有 BNZ 的辅助海绵。根据不同的香兰素交联比例(Vn)(0-2%w/w)制备了阴道用海绵。据我们所知,这是首次使用壳聚糖和香兰素之间的希夫碱作为药物输送系统来治疗真菌阴道感染的研究。傅立叶变换红外光谱(FTIR)证实了希夫碱的成功形成。体外鉴定显示,其物理和机械特性均可接受。基于 Cs 与 V 交联的制剂显示出更明显的体外抗真菌活性。体外药物释放显示出延长的释放模式,交联度越高的支持海绵释放得越明显(8 小时后释放 22.34%)。CsV2 支持海绵的体内测试表明,与 CsV0 和 Tantum® Rosa 相比,CsV2 支持海绵在第一周能更明显地减少真菌数量,在第 7 天、第二周的第 10 天和第 11 天达到峰值。总之,壳聚糖/香兰素辅助海绵是一种用于局部治疗阴道念珠菌病的药物输送系统,具有广阔的前景。
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引用次数: 0
An innovative carrier for the formulation of amorphous solid dispersion by hot-melt extrusion with no further downstream processes: a case study with indomethacin. 通过热熔挤出法配制无定形固体分散体的创新载体,无需进一步的下游工艺:吲哚美辛案例研究。
IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 Epub Date: 2024-01-25 DOI: 10.1080/10837450.2024.2306802
S P Lacerda, S Del Confetto, L Haurie, M Bernard, S Faget, M I Ré

The aim of this work was to study the possibility to use SepitrapTM as a carrier for the formulation of amorphous solid dispersions by HME (hot melt extrusion) processing aiming solubility enhancement of poorly water-soluble drugs. SepitrapTM is a microencapsulated powder solubilizer designed to simplify the manufacture of drugs in oral solid forms, not yet tested for this purpose. The performance of SepitrapTM was evaluated in HME processing for amorphous solid dispersions of poorly-water soluble drugs with indomethacin as a model drug. The study was conducted using a twin-screw extruder, two compositions of SepitrapTM and different loads of indomethacin, demonstrating that SepitrapTM could represent a new range of carriers for amorphous solid dispersions for HME processing, reducing necessary downstream steps such as grinding.

这项工作的目的是研究是否有可能使用 SepitrapTM 作为载体,通过 HME(热熔挤出)工艺配制无定形固体分散体,以提高水溶性差的药物的溶解度。SepitrapTM 是一种微胶囊粉末增溶剂,旨在简化口服固体药物的生产,但尚未进行过相关测试。以吲哚美辛为模型药物,对 SepitrapTM 的性能进行了评估。研究使用双螺杆挤出机、两种 SepitrapTM 成分和不同的吲哚美辛用量进行,结果表明,SepitrapTM 可以作为一种新的载体,用于非晶固体分散体的 HME 加工,减少了研磨等必要的下游步骤。
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引用次数: 0
Novel bioequivalent oral disintegrating tablet of aripiprazole prepared by direct compression technique with shortened disintegration time. 采用直接压片技术制备的新型生物等效阿立哌唑口腔崩解片,缩短了崩解时间。
IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 Epub Date: 2024-01-12 DOI: 10.1080/10837450.2024.2301780
Do Hwan Kim, Jun Soo Park, Min Young Jeong, In Gyu Yang, Wookyung Kim, Seung Bo Shim, Hye Seon Kim, Hyun Yang Park, Myoung Jin Ho, Myung Joo Kang

Herein, we aimed to formulate a novel oral disintegrating tablet (ODT) of aripiprazole (ARP) capable of rapid disintegration using a direct compression technique. Different ODTs were fabricated with directly compressible excipients, and their disintegration time, wettability (water absorption ratio and wetting time), and mechanical properties (hardness and friability) were evaluated. The optimized ODT comprised F-Melt® type C, Prosolv® SMCC HD90, and Na croscarmellose (10 mg of ARP in a 130 mg tablet). The ODT with 3.1-5.2 kp hardness exhibited rapid disintegration (14.1-17.2 sec), along with appropriate mechanical strength (friability < 0.24%). In a bioequivalent study in Korean healthy subjects (randomized, single-dose, two-period crossover design, n = 37), the novel ODT offered the equivalent pharmacokinetic profile to that of a conventional immediate release tablet (Otsuka, Abilify®, Japan), despite different disintegration and dissolution profiles. The 90% confidence intervals of the geometric mean test to reference ratios considering the area-under-the-curve and maximum plasma drug concentrations were 1.0306-11051 and 0.9448-1.1063, respectively, satisfying FDA regulatory criteria for bioequivalence. The novel ART ODT was physicochemically stable under the accelerated storage condition (40 °C, RH75%) for 24 weeks. Therefore, the novel ARP-loaded ODT is expected to be an alternative to oral ARP therapy, providing improved patient adherence.

在此,我们旨在利用直接压缩技术配制一种能够快速崩解的新型阿立哌唑(ARP)口腔崩解片(ODT)。我们使用可直接压缩的辅料制备了不同的口腔崩解片,并对其崩解时间、润湿性(吸水率和润湿时间)以及机械性能(硬度和易碎性)进行了评估。优化后的 ODT 包括 F-Melt® C 型、Prosolv® SMCC HD90 和 Na croscarmellose(130 毫克片剂中含 10 毫克 ARP)。硬度为 3.1-5.2 kp 的 ODT 具有快速崩解(14.1-17.2 秒)和适当的机械强度(易碎性 < 0.24%)。在对韩国健康受试者进行的生物等效性研究(随机、单剂量、两阶段交叉设计,n = 37)中,尽管崩解和溶出情况不同,但新型口崩片剂与传统速释片剂(日本大冢制药,Abilify®)具有相同的药代动力学特征。考虑到曲线下面积和最大血浆药物浓度,试验与参比的几何平均比值的90%置信区间分别为1.0306-11051和0.9448-1.1063,符合FDA的生物等效性监管标准。新型 ART ODT 在加速储存条件(40 °C,相对湿度 75%)下 24 周内理化性质稳定。因此,这种新型 ARP 负载 ODT有望成为口服 ARP 治疗的替代品,提高患者的依从性。
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引用次数: 0
Efficient treatment of colon cancer with codelivery of TRAIL and imatinib by liposomes. 用脂质体联合递送 TRAIL 和伊马替尼有效治疗结肠癌。
IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 Epub Date: 2024-01-30 DOI: 10.1080/10837450.2024.2301763
Rongrong Fu, Rui Chang, Andong Peng, Changshun Feng, Weifan Zhu, Yi Chen, Xue Tian, Rui Wang, Hui Yan, Dianlong Jia, Jun Li

To solve the problem of resistance of tumor cells to TRAIL and the inevitable side effects of imatinib during treatment, we successfully prepared a kind of multifunctional liposome that encapsulated imatinib in its internal water phase and inserted TRAIL on its membrane in this study, which named ITLPs. The liposomes appeared uniform spherical and the particle size was approximately 150 nm. ITLPs showed high accumulation in TRAIL-resistance cells and HT-29 tumor-bearing mice model. In vitro cytotoxicity assay results showed that the killing activity of HT-29 cells treated with ITLPs increased by 50% and confirmed that this killing activity was mediated by the apoptosis pathway. Through mechanism studies, it was found that ITLPs arrested up to 32.3% of cells in phase M to exert anti-tumor effects. In vivo anti-tumor study showed that ITLPs achieved 61.8% tumor suppression and little toxicity in the HT-29 tumor-bearing mice model. Overall results demonstrated that codelivery of imatinib and TRAIL via liposomes may be a prospective method in the treatment of the TRAIL-resistance tumor.

摘要:肿瘤坏死因子相关凋亡诱导配体(TRAIL)可通过与死亡受体相互作用诱导细胞凋亡。然而,TRAIL的半衰期较短,且肿瘤细胞对TRAIL具有抗药性,这限制了其治疗效果。研究表明,伊马替尼对结肠癌细胞株有效,并能增强TRAIL诱导的细胞凋亡。然而,其副作用在治疗过程中不可避免。为了解决这些问题,本研究成功制备了一种多功能脂质体,将伊马替尼包裹在其内部水相中,并在其膜上插入TRAIL,命名为ITLPs。脂质体呈均匀球形,粒径约为150 nm。ITLPs在TRAIL耐药细胞和HT-29肿瘤小鼠模型中表现出较高的蓄积性。体外细胞毒性实验结果表明,用ITLPs处理的HT-29细胞的杀伤活性提高了50%,并证实这种杀伤活性是由细胞凋亡途径介导的。通过机理研究发现,高达 32.3% 的细胞被 ITLPs 停滞在 M 期,从而发挥抗肿瘤作用。体内抗肿瘤研究表明,ITLPs在HT-29肿瘤小鼠模型中的抑瘤率为61.8%,毒性很小。总体结果表明,通过脂质体联合递送伊马替尼和TRAIL可能是治疗TRAIL耐药肿瘤的一种前瞻性方法。
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引用次数: 0
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