Mannose-conjugated chitosan nanoparticles for delivery of Rifampicin to Osteoarticular tuberculosis
Mannose-conjugated chitosan nanoparticles for delivery of Rifampicin to Osteoarticular tuberculosis
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DOI：
10.1007/s13346-021-01003-7
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发表时间：
2021-05-21
影响因子：
5.4
通讯作者：
Sawarkar, Sujata P.
中科院分区：
文献类型：
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作者：
Prabhu, Pratiksha;Fernandes, Trinette;Sawarkar, Sujata P.
结核病 (TB) 是一种潜在致命的传染病，是世界上第二大传染病死亡原因。骨关节结核采用第一线和第二线抗结核药物 (ATD) 的标准治疗方案进行为期 8-20 个月的长期治疗。由于这些药物的生物利用度较低，因此通常通过口服途径或静脉注射途径以高剂量给药。传统治疗的常见缺点是治疗周期长、剂量频繁、剂量大以及毒性导致患者依从性差。这方面标志着需要配方来消除这些缺点。 MTB是单核吞噬细胞的细胞内病原体。由于巨噬细胞捕获纳米形式，这一属性使纳米疗法成为 MTB 治疗的理想方法。聚合物纳米颗粒通过调理作用和吞噬作用从体内清除，这形成了靶向含有分枝杆菌的巨噬细胞的理想策略。为了进一步提高靶向性，纳米颗粒与配体缀合，配体作为巨噬细胞表面受体的简单底物。目前工作的目的是开发含有聚合物纳米粒子的关节内可注射原位凝胶系统，该系统比传统的治疗方法具有有希望的优势。配制原位凝胶系统中的纳米颗粒的基本原理是确保制剂在关节腔内的定位，以及纳米颗粒与甘露糖作为配体的持续释放和缀合，以改善巨噬细胞的摄取。将利福平标准ATD配制成壳聚糖纳米粒。采用脱乙酰度85%的壳聚糖(DDA)和三聚磷酸钠(TPP)作为交联剂制备纳米粒子。发现截留百分比约为71%。制备的纳米颗粒与甘露糖缀合。通过进行傅立叶变换红外光谱法来确定配体的缀合。发现颗粒尺寸在 130-140 nm 范围内，zeta 电位为 38.5 mV。此外，我们还进行了扫描电子显微镜来表征配体共轭纳米颗粒的表面形态。将缀合的壳聚糖纳米颗粒掺入包含泊洛沙姆 407 和 HPMC K4M 的原位胶凝系统中。评估胶凝系统的粘度、胶凝特性和可注射性。发现在模拟滑液中，按照零级释放动力学，40 小时结束时，掺入原位凝胶中的共轭纳米颗粒的药物释放约为 70.3%。基于最初获得的令人鼓舞的结果，纳米颗粒正被设想用于使用结核感染的巨噬细胞进行离体细胞摄取研究
Tuberculosis (TB) is a potentially fatal contagious disease and is a second leading infectious cause of death in the world. Osteoarticular TB is treated using standard regimen of 1st and 2nd line anti-tubercular drugs (ATDs) for extensive period of 8-20 months. These drugs are commonly administered in high doses by oral route or by intravenous route, because of their compromised bioavailability. The common drawbacks associated with conventional therapy are poor patient compliance due to long treatment period, frequent and high dosing, and toxicity. This aspect marks for the need of formulations to eliminate these drawbacks. MTB is an intracellular pathogen of mononuclear phagocyte. This attribute makes nanotherapeutics an ideal approach for MTB treatment as macrophages capture nano forms. Polymeric nanoparticles are removed from the body by opsonization and phagocytosis, which forms an ideal strategy to target macrophage containing mycobacteria. To further improve targetability, the nanoparticles are conjugated with ligand, which serves as an easy substrate for the receptors present on the macrophage surface. The purpose of present work was to develop intra-articular injectable in situ gelling system containing polymeric nanoparticles, which would have promising advantages over conventional method of treatment. The rationale behind formulating nanoparticle incorporated in situ gel-based system was to ensure localization of the formulation in intra-articular cavity along with sustained release and conjugation of nanoparticles with mannose as ligand to improve uptake by macrophages. Rifampicin standard ATD was formulated into chitosan nanoparticles. Chitosan with 85% degree of deacetylation (DDA) and sodium tripolyphosphate (TPP) as the crosslinking agent was used for preparing nanoparticles. The percent entrapment was found to be about 71%. The prepared nanoparticles were conjugated with mannose. Conjugation of ligand was ascertained by performing Fourier transformed infrared spectroscopy. The particle size was found to be in the range of 130-140 nm and zeta potential of 38.5 mV. Additionally, we performed scanning electron microscopy to characterize the surface morphology of ligand-conjugated nanoparticles. The conjugated chitosan nanoparticles were incorporated into in situ gelling system comprising Poloxamer 407 and HPMC K4M. The gelling system was evaluated for viscosity, gelling characteristics, and syringeability. The drug release from conjugated nanoparticles incorporated in in situ gel was found to be about 70.3% at the end of 40 h in simulated synovial fluid following zero-order release kinetics. Based on the initial encouraging results obtained, the nanoparticles are being envisaged for ex vivo cellular uptake study using TB-infected macrophages