Thymoquinone-entrapped chitosan-modified nanoparticles: formulation optimization to preclinical bioavailability assessments

The major limitation with the oral administration of most of the phytochemicals is their low aqueous solubility and bioavailability. Thymoquinone (THQ) is one of the most widely used phytochemicals used to treat a variety of diseases. However, strong lipophilic characteristics limit its clinical application. Therefore, this study was aimed to design novel chitosan (C) modified polycaprolactone (PL) nanoparticles (NPs) for improved oral bioavailability of THQ. THQ-CPLNPs was optimized 33-Box–Behnken design. After that, the optimized THQ-CPLNPs was characterized by different parameters. THQ-CPLNPs showed the size, PDI, and ZP of 182.32 ± 6.46 nm, 0.179 ± 0.012, and +21.36 ± 1.22 mV, respectively. The entrapment and loading capacity were found to be 79.86 ± 4.36%, and 13.45 ± 1.38%, respectively. THQ-CPLNPs exhibited burst release in initial 2 h followed by prolonged release up to 24 h in simulated intestinal fluids. THQ-CPLNPs showed excellent mucoadhesion properties which were further confirmed with the intestinal permeation study as well as confocal microscopy. The study revealed higher permeation of THQ-CPLNPs compared to neat THQ suspension (THQ-S). Moreover, in vivo gastric irritation study revealed good compatibility of THQ-CPLNPs with the gastric mucosa. Furthermore, pharmacokinetic results depicted ∼3.53-fold improved oral bioavailability of THQ from THQ-CPLNPs than THQ-S. Therefore, from the findings, it was concluded that the prepared polymeric NPs could be an effective delivery system for improved oral bioavailability of THQ.     

NMP与ROP相结合制备PCL-b-PSt共聚物及其性能研究

以4-羟基-2,2,6,6-四甲基哌啶氮氧自由基（HTEMPO）为引发剂,通过ε-己内酯（ε-CL）的开环聚合,合成末端基为氮氧自由基的聚己内酯 （PCL-T）。在其调控下,进行过氧化苯甲酰（BPO）引发苯乙烯（St）的自由基聚合,合成结构规整的聚己内酯-b-聚苯乙烯（PCL-b-PSt）共聚物。用氢核磁共振（1H-NMR）、电子自旋共振（ESR）、红外光谱（FT-IR）、凝胶渗透色谱（GPC） 和热重分析（TGA）等手段对聚合物的结构和性能进行了研究。结果表明：氮氧自由基的存在不影响ε-CL的开环聚合,异辛酸亚锡（Sn(Oct)2） 对ε-CL开环聚合的催化作用也对氮氧自由基无破坏性;在PCL-T的调控下,通过St的聚合可合成结构规整的PCL-b-PSt共聚物,且聚合过程具有“活性”聚合的特征;PCL-b-PSt共聚物的热稳定性高于PCL均聚物的热稳定性。     

可降解聚合物聚己内酯体内生物相容性的实验研究

目的 :评价可降解聚合物聚己内酯 (PCL )的体内生物相容性 ,为构建成骨细胞 - PCL材料复合的组织工程骨的可行性提供参考依据 ,并为临床修复骨缺损提供新的人工替代材料。 方法 :Wistar大鼠 30只 ,随机分为实验组与对照组 ,实验组大鼠两侧肌内各植入 2枚 PCL样品 ,对照组大鼠两侧肌内植入 2枚医用硅橡胶样品 ,进行大体标本、组织学及透射电镜观察。结果 :PCL 界面无明显的炎性反应 ,材料与组织界面接合紧密。结论 :PCL 是一种具有良好的生物相容性、缓慢降解、无毒性、无免疫原性的材料。     

Localized delivery of methylprednisolone sodium succinate with polymeric nanoparticles in experimental injured spinal cord model

With important social and economic consequences, spinal cord injuries (SCIs) still exist among major health problems. Although many therapeutic agents and methods investigated for the treatment of acute SCI, only high dose methylprednisolone (MP) is being used currently in practice. Due to the serious side effects, high dose systemic MP administration after SCI is a critical issue that is mostly considered controversial. In our study, it is aimed to develop a nanoparticle-gel combined drug delivery system for localization of MP on trauma site and eliminating dose-dependent side effects by lowering the administered dose. For this purpose, methyl prednisolone sodium succinate (MPSS) loaded polycaprolactone based nanoparticles were developed and embedded in an implantable fibrin gel. The effects of MPSS delivery system are evaluated on an acute SCI rat model, by quantification the levels of three inflammatory cytokines (interleukin-1β, interleukin-6 and caspase-3) and assessment of the damage on ultrastructural level by transmission electron microscopy. Developed NP-gel system showed very similar results with systemic high dose of MPSS. It is believed that developed system may be used as a tool for the safe and effective localized delivery of several other therapeutic molecules on injured spinal cord cases.     

Novel poly-DL-lactide-polycaprolactone copolymer based flexible drug delivery system for sustained release of ciprofloxacin

This research evaluated 7525DLPCL for soft flexible drug delivery systems. The effect of ciprofloxacin hydrochloride (CIP) loading at three levels (10, 20, and 30%), on thermo-mechanical properties was studied. CIP release was monitored for 12 weeks. Addition of CIP to 7525DLPCL caused an increase in compressive modulus of 7525DLPCL. CIP release was found to be sigmoidal with two phenomena (apart from a minor burst) contributing to release–diffusion and later diffusion plus erosion. An increased burst was observed with greater CIP loading and the majority of CIP (> 70%) was released as an effect of diffusion plus erosion. Additional factors, like the effect of CIP particle size, had no significant effect on drug release. Change in the implant shape from a cylinder (5?mm diameter; 3?mm thickness) to disc (6?mm diameter, 0.5?mm thickness) also failed to show a significant impact on drug release. Erosion of 7525DLPCL is a major contributing factor towards this release and other factors like shape of implants and particle size of drug have little effect on CIP release. Such flexible drug delivery systems offer new avenues for long-term skeletal drug delivery of antibiotics for conditions like osteomyelitis or periodontitis.     

Antibiotic-free nanotherapeutics: Hypericin nanoparticles thereof for improved in vitro and in vivo antimicrobial photodynamic therapy and wound healing

Hypericin (HY) is a naturally-occurring, potent photosensitizer. However, its lipophilicity limits its therapeutic applications. Our attempt is, thus, to develop a biodegradable nanocarrier for hypericin capable of preserving its antibacterial photoactivity. Amphiphilic block copolymers were synthesized to prepare hypericin-laden nanoparticles (HY-NPs). The antimicrobial photoactivity of HY-NPs was assessed; in vitro against biofilm and planktonic cells of methicillin resistant Staphylococcus aureus (MRSA) clinical isolates and in vivo on infected wounds in rats. Nanoparticles of 45 nm in diameter ensured higher amounts of reactive oxygen species upon irradiation. HY-NPs demonstrated superior inhibition of biofilm over planktonic cells. In vivo wound healing studies in rats revealed faster healing, better epithelialization, keratinization and development of collagen fibers when HY-NPs were applied. Determination of growth factors and inflammatory mediators in the wound area confirmed superior healing potential of nanoencapsulated hypericin suggesting that hypericin can join the era of antibiotic-free antimicrobial therapy.     

聚己内酯半月板支架应力-应变特性的有限元分析

目的：分析聚己内酯（PCL）半月板支架在膝关节中的应力-应变特性,评估其作为植入材料的可行性。方法：通过磁共振成像（MRI）扫描志愿者膝关节获取平面图像数据,建立包括股骨、胫骨、腓骨、股骨髁及胫骨平台关节软骨、内和外侧半月板及韧带在内的完整膝关节三维有限元模型,通过计算胫骨平台的接触面积与既往文献对比验证模型的有效性;分别建立内侧半月板切除术后的膝关节三维有限元模型及PCL半月板支架替代后的膝关节模型;对比分析在1400N股骨轴向垂直压力下3种膝关节模型的半月板位移和接触压力变化以及股骨髁关节软骨和胫骨平台关节软骨的压缩应力变化。结果：在1400N股骨轴向压缩载荷下健康膝关节模型内、外侧半月板位移分别为0.83和1.76mm,PCL模型内、外侧半月板位移分别为1.15和2.20mm。在同等载荷下,健康膝关节在胫骨平台关节软骨内、外侧最大压缩应力分别为2.5和1.7MPa,在内、外侧股骨髁关节软骨最大压缩应力分别为2.7和2.1MPa。在内侧半月板完整切除模型,内、外侧胫骨平台关节软骨最大压缩应力较健康模型分别增加260.0%和311.7%;内、外侧股骨髁关节软骨最大压缩应力较健康模型分别增长214.8%和271.4%。而在将内侧半月板替换为PCL支架的模型中,内、外胫骨平台关节软骨最大压缩应力较健康模型分别增加8.0%和5.9%;内、外侧股骨髁关节软骨最大压缩应力较健康模型分别增加11.1%和4.8%。结论：PCL支架在膝关节三维有限元模型中具有较好的生物力学特性,能够降低半月板切除后股骨髁及胫骨平台关节软骨的应力,达到保护关节软骨的目的。     

还原响应型透明质酸/聚己内酯纳米粒子的制备及其体外抗肺癌效应研究

目的： 构建一种具有良好生物安全性、肿瘤主动靶向性及能实现药物快速释放的药物纳米载体。方法： 通过点击化学反应制备由二硫键连接的两亲性透明质酸/聚己内酯接枝聚合物;采用动态光散射、透射电镜对聚合物的自组装行为进行研究;通过体外药物释放实验探究药物载体还原响应控制释放特性;通过流式细胞术、激光共聚焦显微镜等技术对A549细胞内吞噬载药纳米粒子的机制进行研究;结果： 所制备的含二硫键的接枝聚合物可自组装形成粒径大约为75 nm的球形纳米粒子;该纳米粒子在质量浓度为200 μg·mL^-1时仍具有较好的生物安全性;当纳米粒子包载阿霉素后其粒径增大至128 nm,且药物在还原性条件下可实现快速释放;载药后的纳米粒子经透明质酸/CD44受体间的相互作用快速进入肿瘤细胞内,并能显著抑制肿瘤细胞生长。结论： 本研究合成的含二硫键的透明质酸/聚己内酯接枝聚合物具有良好生物相容性、肿瘤靶向性及药物控制释放特性,作为抗肿瘤药物载体具有一定优势。     

Endogenously triggered electrospun fibres for tailored and controlled antibiotic release

The study was aimed at assessing the potential of enzyme-embedded antibiotic-releasing polycaprolactone (PCL)-based electrospun fibres for tunable drug delivery. This was attempted by incorporation of gentamicin sulphate (GS) in the biocompatible polymer (PCL) matrix, with the degradation of the matrix being ensured by co-impregnating a polymer-degrading enzyme (lipase). Single phase solutions were obtained by hydrophobic ion pairing of GS and surfactant coating of lipase with an anionic surfactant, docusate sodium salt Aerosol OT (AOT). By electrospinning the solution, we could produce PCL fibres containing 11% (w/w) GS–AOT and 28?U (w/w) lipase–AOT. However, sustained release of GS was not obtained. FESEM analysis showed that the fibres did not undergo the expected degradation. Subsequent experiments with unmodified lipase gave satisfactory results; the polymer underwent degradation displaying characteristic perforations in the fibres, suggestive of ‘endo-attack’. By modulating the concentrations of lipase (1 to 28?U, w/w), we could obtain GS release rates that varied from 0.53 to 32?mg/ml/d. Accordingly, the lifetime of the fibres could be tuned (10?h to 25?days). The fibres showed excellent antibacterial activity against Staphylococcus aureus throughout their lifetime.