胶体粒子的机械性能调控及其在药物递送中的应用

胶体粒子是肿瘤治疗中最常用的载体, 尽管在过去的研究中不同的胶体粒子已经被广泛报道, 但如何进一步提高胶体粒子的药物递送效率仍然存在着一些挑战. 大量的研究表明胶体粒子的尺寸、形状、结构和表面化学等物理化学性质在药物递送过程中具有重要的作用, 但胶体粒子的机械性能对药物递送过程的影响研究和综述相对较少. 本综述从不同机械性能胶体粒子的制备与表征出发, 概述了胶体粒子的机械性能对血液循环、肿瘤富集、渗透以及细胞内化过程的影响, 并对该领域存在的问题以及发展的趋势进行了展望. 该综述有助于帮助科学工作者更好地理解胶体粒子的机械性能对药物递送的影响规律, 从而优化胶体粒子的设计并提高纳米药物的递送效率和生物利用率.     

Tunable self-assembled stereocomplexed-polylactic acid nanoparticles as a drug carrier

In this study, a model hydrophilic drug (porphyrin) was encapsulated within hydrophobic polylactic acid (PLA) nanoparticles (NPs) with different crystallinity and the relevant release behaviors were investigated. The crystalline modification was done using a modified nanoprecipitation method, where homo and stereocomplexed PLA NPs with different average diameters based on varying polymer concentrations and solvent/nonsolvent ratios (S/N) were prepared. Entrapment efficiency and drug release of sterocomplexed-PLA NPs were compared with neat poly(l -lactic acid) (PLLA) NPs. Furthermore, to get the more sustained release, porphyrin-loaded NPs were immobilized within electrospun poly(d ,l -lactide-co-glycolide (PLGA) nanofibers (NFs). Outcomes revealed that solution concentration and solvent/nonsolvent ratio play significant roles in the formation of homo and stereocomplexed NPs. On the other hand, it was found that the formation of stereocrystals did not significantly affect the size and morphology of NPs compared with neat NPs. With regard to the entrapment efficiency and drug content, stereocomplexd-PLA NPs behave relatively the same as neat PLLA NPs while the more sustained release was observed for stereocomplexed NPs. Also, it was observed that electrospinning of PLGA solution loaded by NPs led to the uniform distribution of NPs into PLGA fibers. Encapsulating the drug-loaded NPs into nanofibers decreased the rate of drug release by 50% after 24 h, compared with direct loading of drug into PLGA NFs. We conclude that it is possible to tune the entrapment efficiency and modify the release rate of the drug by giving small changes in the process parameters without altering the physical properties of the original drug substance and polymer.     

Self-assembly in magnetic supramolecular hydrogels

Most recent advances in the synthesis of supramolecular hydrogels based on low molecular weight gelators (LMWGs) have focused on the development of novel hybrid hydrogels, combining LMWGs and different additives. The dynamic nature of the noncovalent interactions of supramolecular hydrogels, together with the specific properties of the additives included in the formulation, allow these novel hybrid hydrogels to present interesting features, such as stimuli-responsiveness, gel-sol reversibility, self-healing and thixotropy, which make them very appealing for multiple biomedical and biotechnological applications. In particular, the inclusion of magnetic nanoparticles in the hydrogel matrix results in magnetic hydrogels, a particular type of stimuli-responsive materials that respond to applied magnetic fields. This review focuses on the recent advances in the development of magnetic supramolecular hydrogels, with special emphasis in the role of the magnetic nanoparticles in the self-assembly process, as well as in the exciting applications of these materials.     

In vivo Toxicity Evaluation of a Nano-drug Delivery System Using a Caenorhabditis elegansModel System

Drug carrier materials need to possess good biological safety. Presently, most biosafety evaluation studies use rodent animal models, including rats and rabbits. However, the cost of raising these animals is relatively high and the experimental period is long. Caenorhabditis elegans(C. elegans) presents an ideal toxicological evaluation model due to its simple structure, easy cultivation, short life cycle, and evolutionary conservation. In this paper, we used C. elegans to test the biological safety of our pH-responsive carrier system(FFPFF self-assembling into a nanosphere structure, FFPFF Nps), which was designed for anti-tumor drug delivery. Our results showed that exposure to high doses of FFPFF Nps did not have a significant impact on the survival rate, growth, development, movement, and reproduction of C. elegans. The preliminary evaluation of the overall biological model of C. elegans shows that FFPFF Nps has good biological safety and warrants further study.     

DCE-MRI参数联合IFIT1基因对腰椎间盘突出患者椎间盘退变程度的评估价值

探讨DCE-MRI参数及IFIT1基因对腰椎间盘突出症(LDH)患者椎间盘退变(IDD)程度的评估价值。随机选取确诊的66例LDH患者作为研究对象,根据改良Pfirrmann分级法将患者分为2组:轻中度IDD(Ⅰ~Ⅲ级)组(46例)和重度IDD(Ⅳ~Ⅴ级)组20例。通过DCE-MRI检查考察患者的K-trans值,采用日本骨科学会评分(JOA)评估腰椎功能,采用视觉模拟评分法(VAS)评估腰部疼痛,采用RT-PCR检测外周血单个核细胞(PBMC)中IFIT1的mRNA表达。轻中度IDD组的K-trans值显著低于重度IDD组。轻中度IDD组患者PBMC中的IFIT1 mRNA相对表达量显著低于重度IDD组。K-trans值与PBMC中的IFIT1 mRNA水平和VAS评分正相关,与JOA评分负相关(P<0.05)。PBMC中的IFIT1 mRNA水平与VAS评分正相关,与JOA评分负相关(P<0.05)。K-trans值和PBMC中的IFIT1 mRNA水平联合诊断重度IDD的AUC值、敏感性和特异性分别为0.991、91.3%和100.0%,AUC值和特异性均高于单独诊断。DCE-MRI检查中的K-trans值联合PBMC中的IFIT1 mRNA水平可用于LDH患者IDD程度的诊断。     

Effect of thermal annealing on a bilayer polyvinyl alcohol/polyacrylic acid electrospun hydrogel nanofibres loaded with doxorubicin and clarithromycin for a synergism effect against osteosarcoma cells

Polyvinyl alcohol/polyacrylic acid (PVA/PAA) bilayer hydrogel nanofibres were successfully fabricated by electrospinning and physically crosslinked via heat treatment. The effects of the thermal annealing process on the structure, morphology, swelling, thermal properties and hydrophilicity of electrospun nanofibres were investigated. In addition, these membranes were also used to incorporate doxorubicin and clarithromycin for osteosarcoma treatment, one in each layer. These drugs were used because it is hypothesized in this work that a synergism occurs between both drugs. So, these membranes were analyzed towards their dual-drug release and potential cytotoxicity towards the U2OS human osteosarcoma cell line. Moreover, the water contact angle, disintegration, swelling and weight loss studies confirmed the rapid swelling and improved water stability of the annealed PVA/PAA bilayer nanofibres. The annealed bilayer nanofibres exhibited an increase in the average diameter and degree of crystallinity. In addition, the results revealed that a variation occurred in the degree of hydrophilicity of annealed PVA/PAA bilayer nanofibres. The PAA nanofibres surface exhibited higher hydrophilicity than the PVA nanofibres surface. Drug delivery presented to be as fast rate release for clarithromycin and slow-rate release for doxorubicin, which may be advantageous because both drugs exhibited to be synergetic for certain dosages presenting the combination of the drugs higher than 50% of cell inhibition, while these membranes had higher inhibition values (up to 90%), which was attributed to the PAA but also the drugs. These unique properties are of potential interest in drug delivery applications for dual drug delivery where the tunability of surfaces is desirable.     

Ultrasound Microbubbles Enhance the Efficacy of Insulin-Like Growth Factor-1 Therapy for the Treatment of Noise-Induced Hearing Loss

The application of insulin-like growth factor 1 (IGF-1) to the round window membrane (RWM) is an emerging treatment for inner ear diseases. RWM permeability is the key factor for efficient IGF-1 delivery. Ultrasound microbubbles (USMBs) can increase drug permeation through the RWM. In the present study, the enhancing effect of USMBs on the efficacy of IGF-1 application and the treatment effect of USMB-mediated IGF-1 delivery for noise-induced hearing loss (NIHL) were investigated. Forty-seven guinea pigs were assigned to three groups: the USM group, which received local application of recombinant human IGF-1 (rhIGF-1, 10 µg/µL) following application of USMBs to the RWM; the RWS group, which received IGF-1 application alone; and the saline-treated group. The perilymphatic concentration of rhIGF-1 in the USM group was 1.95- and 1.67- fold of that in the RWS group, 2 and 24 h after treatment, respectively. After 5 h of 118 dB SPL noise exposure, the USM group had the lowest threshold shift in auditory brainstem response, least loss of cochlear outer hair cells, and least reduction in the number of synaptic ribbons on postexposure day 28 among the three groups. The combination of USMB and IGF-1 led to a better therapeutic response to NIHL. Two hours after treatment, the USM group had significantly higher levels of Akt1 and Mapk3 gene expression than the other two groups. The most intense immunostaining for phosphor-AKT and phospho-ERK1/2 was detected in the cochlea in the USM group. These results suggested that USMB can be applied to enhance the efficacy of IGF-1 therapy in the treatment of inner ear diseases.     

Novel Amphiphilic Block Copolymers for the Formation of Stimuli-Responsive Non-Lamellar Lipid Nanoparticles

Non-lamellar lyotropic liquid crystalline (LLC) lipid nanoparticles contain internal multidimensional nanostructures such as the inverse bicontinuous cubic and the inverse hexagonal mesophases, which can respond to external stimuli and have the potential of controlling drug release. To date, the internal LLC mesophase responsiveness of these lipid nanoparticles is largely achieved by adding ionizable small molecules to the parent lipid such as monoolein (MO), the mixture of which is then dispersed into nanoparticle suspensions by commercially available poly(ethylene oxide)–poly(propylene oxide) block copolymers. In this study, the Reversible Addition-Fragmentation chain Transfer (RAFT) technique was used to synthesize a series of novel amphiphilic block copolymers (ABCs) containing a hydrophilic poly(ethylene glycol) (PEG) block, a hydrophobic block and one or two responsive blocks, i.e., poly(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate) (PTBA) and/or poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA). High throughput small angle X-ray scattering studies demonstrated that the synthesized ABCs could simultaneously stabilize a range of LLC MO nanoparticles (vesicles, cubosomes, hexosomes, inverse micelles) and provide internal particle nanostructure responsiveness to changes of hydrogen peroxide (H₂O₂) concentrations, pH and temperature. It was found that the novel functional ABCs can substitute for the commercial polymer stabilizer and the ionizable additive in the formation of next generation non-lamellar lipid nanoparticles. These novel formulations have the potential to control drug release in the tumor microenvironment with endogenous H₂O₂ and acidic pH conditions.     

Theranostic Approach for the Protein Corona of Polysaccharide Nanoparticles

Polysaccharide nanoparticles are promising materials in the wide range of disciplines such as medicine, nutrition, food production, agriculture, material science and others. They excel not only in their non‐toxicity and biodegradability but also in their easy preparation. As well as inorganic particles, a protein corona (PC) around polysaccharide nanoparticles is formed in biofluids. Moreover, it has been considered that the overall response of the organism to nanoparticles presence depends on the PC. This review summarises scientific publications about the structural chemistry of polysaccharide nanoparticles and their impact on theranostic applications. Three strategies of implementation of the PC in theranostics have been discussed: I) Utilisation of the PC in therapy; II) How the composition of the PC is analysed for specific disease markers; III) How the formed PC can interact with the immune system and enhances the immunomodulation or immunoelimination. Thus, the findings from this review can contribute to improve the design of drug delivery systems. However, it is still necessary to elucidate the mechanisms of nano‐bio interactions and discover new connections in nanoscale research.     

Effect of Penetration Enhancers on Toenail Delivery of Efinaconazole from Hydroalcoholic Preparations

The incorporation of permeation enhancers in topical preparations has been recognized as a simple and valuable approach to improve the penetration of antifungal agents into toenails. In this study, to improve the toenail delivery of efinaconazole (EFN), a triazole derivative for onychomycosis treatment, topical solutions containing different penetration enhancers were designed, and the permeation profiles were evaluated using bovine hoof models. In an in vitro permeation study in a Franz diffusion cell, hydroalcoholic solutions (HSs) containing lipophilic enhancers, particularly prepared with propylene glycol dicaprylocaprate (Labrafac PG), had 41% higher penetration than the HS base. Moreover, the combination of hydroxypropyl-β-cyclodextrin with Labrafac PG further facilitated the penetration of EFN across the hoof membrane. In addition, this novel topical solution prepared with both lipophilic and hydrophilic enhancers was physicochemically stable, with no drug degradation under ambient conditions (25 °C, for 10 months). Therefore, this HS system can be a promising tool for enhancing the toenail permeability and therapeutic efficacy of EFN.