Gold nanoparticles conjugating recombinant influenza hemagglutinin trimers and flagellin enhanced mucosal cellular immunity

The immunogenicity of subunit vaccines can be augmented by formulating them into nanoparticles. We conjugated recombinant trimetric influenza A/Aichi/2/68(H3N2) hemagglutinin (HA) onto functionalized gold nanoparticle (AuNP) surfaces in a repetitive, oriented configuration. To further improve the immunogenicity, we generated Toll-like receptor 5 (TLR5) agonist flagellin (FliC)-coupled AuNPs as particulate adjuvants. Intranasal immunizations with an AuNP-HA and AuNP-FliC particle mixture elicited strong mucosal and systemic immune responses that protected hosts against lethal influenza challenges. Compared with the AuNP-HA alone group, the addition of AuNP-FliC improved mucosal B cell responses as characterized by elevated influenza specific IgA and IgG levels in nasal, tracheal, and lung washes. AuNP-HA/AuNP-FliC also stimulated antigen-specific interferon-γ (IFN-γ)-secreting CD4⁺ cell proliferation and induced strong effector CD8⁺ T cell activation. Our results indicate that intranasal co-delivery of antigen and adjuvant-displaying AuNPs enhanced vaccine efficacy by inducing potent cellular immune responses.     

共载同源成分葛根素与大豆苷元的聚合物混合胶束的制备及表征

目的 鉴于葛根黄酮类成分间溶解性与渗透性的自调节作用,以泊洛沙姆407(Pluronic F127,F127)和15-羟基硬脂酸聚乙二醇脂(Solutol HS15)为载体材料制备共载葛根素与大豆苷元的聚合物混合胶束(puerarin and daidzein co-delivery polymer mixed mic...     

Ceramide lipid-based nanosuspension for enhanced delivery of docetaxel with synergistic antitumor efficiency

Ceramide (CE), a bioactive lipid with tumor suppression, has been widely used as a drug carrier and enhancer for cancer therapy. CE-based combination therapy was prone to be attractive in cancer therapy. In our previous study, the combination of CE and docetaxel (DTX) was proved to be an effective strategy for cancer therapy. To further improve the antitumor efficiency of DTX, the CE lipid-based nanosuspensions (LNS) was prepared for the delivery of DTX to exhibit synergistic therapeutic effect. The enhanced delivery and synergistic therapeutic effect of DTX-loaded CE-LNS (CE?+?DTX-LNS) were evaluated. CE?+?DTX-LNS exhibited spherical or ellipsoidal shape, uniform particle size distribution (108.1?±?3.8?nm), sustained release characteristics and good stability in vitro. Notably, CE?+?DTX-LNS could effectively co-localize CE and DTX into same tumor cell and subsequently play synergistic cell damage effect compared with CE-LNS?+?DTX-LNS (p?in vivo fluorescence imaging results showed that CE?+?DTX-LNS could effectively prolong the in vivo circulation time and enhance the accumulation in tumor sites. Moreover, the antitumor efficacy of CE?+?DTX-LNS observed in B16 murine melanoma model was 93.94?±?2.77%, significantly higher than that of CE-LNS, DTX-LNS, Duopafei® (p?p?co-delivery of CE and DTX into same tumor cell was the basis for enhanced synergistic therapeutic effect. Furthermore, histological examination of Blank-LNS showed no visible tissue toxicity compared to normal saline. Consequently, CE-LNS could effectively delivery DTX and CE?+?DTX-LNS exhibit synergistic inhibition of tumor growth due to the co-localization of CE and DTX. CE-LNS hold great potential to be an appropriate carrier for CE-based combination chemotherapy.     

药物共递送系统在肿瘤治疗中的应用

化疗仍然是肿瘤治疗的主要手段,但化疗药物水溶性极低及毒副作用严重已成为其临床应用的一大障碍。同时,随着药物的广泛应用及肿瘤细胞多药耐药性的提高,单一的药物治疗已远远不能满足临床需要。联合用药,即同时给≥2种药物以加强对肿瘤细胞的杀伤抑制作用,已成为肿瘤治疗的首要选择。不仅可产生协同作用,也可通过抑制肿瘤细胞的多药耐药性加强化疗药物的抗肿瘤活性。药物共递送系统,依靠药物载体将两种药物同时递送到肿瘤组织或细胞中,不仅可克服药物水溶性低的缺点、大大提高药物的细胞摄取,且抗肿瘤效果较单一药物递送系统用药为优。同时,随着基因治疗的快速发展,药物与基因的共递送系统也成为当代药学及材料学的研究热点。本文将就药物与药物、药物与基因共递送系统的制备方法、性质及其抗肿瘤活性进行讨论。     

阴离子脂质体介导的腺病毒/卡莫司汀共转运系统载药量测定

目的建立一套有效可靠的检测方法,以测定阴离子脂质体介导的腺病毒和化疗药卡莫司汀共转运载体系统中腺病毒和卡莫司汀的含量。方法以钙离子融合法制备共转运载体复合物;根据腺病毒(Ad5)的hexon基因序列设计用于Taqman探针荧光定量聚合酶链式反应(PCR)的引物和探针序列,优化反应体系,从而准确测定腺病毒含量;优化色谱条件,建立针对共转运载体复合物检测卡莫司汀含量的高效液相色谱法。结果以荧光定量聚合酶链式反应法测得共转运载体复合物中腺病毒载药量为(23.2±1.8)%;高效液相色谱法测得卡莫司汀在共转运载体复合物中的载药量为(55±2.8)%。结论本实验成功建立了分别用于测定共转运载体系统中腺病毒和卡莫司汀含量的荧光定量聚合酶链式反应和高效液相色谱法;这两种检测方法操作简便、准确可靠,具有一定的普遍适用性。     

Co-delivery of gambogic acid and TRAIL plasmid by hyaluronic acid grafted PEI-PLGA nanoparticles for the treatment of triple negative breast cancer

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based combination therapy and gene therapy are new strategies to potentially overcome the limitations of TRAIL, however, the lack of efficient and low toxic vectors remains the major obstacle. In this study, we developed a hyaluronic acid (HA)-decorated polyethylenimine-poly(d,l-lactide-co-glycolide) (PEI-PLGA) nanoparticle (NP) system for targeted co-delivery of TRAIL plasmid (pTRAIL) and gambogic acid (GA) in triple-negative breast cancer (TNBC) therapy. GA was encapsulated into the core of the PEI-PLGA NPs while pTRAIL was adsorbed onto the positive NP surface via charge adsorption. The coating of HA on PEI-PLGA NPs functions as a targeting ligand by binding to CD44 receptor of TNBC cells and a shell to neutralize the excess positive charge of inner NPs. The resultant pTRAIL and GA co-loaded HA-coated PEI-PLGA NPs exhibited spherical shape (121.5?nm) and could promote the internalization of loaded cargoes into TNBC cells through the CD44-dependent endocytic pathway. The dual drug-loaded NPs significantly augmented apoptotic cell death in vitro and inhibited TNBC tumor growth in vivo. This multifunctional NP system efficiently co-delivered GA and pTRAIL, thus representing a promising strategy to treat TNBC and bringing forth a platform strategy for co-delivery of therapeutic DNA and chemotherapeutic agents in combinatorial TNBC therapy.     

Enhancement of cytotoxicity of artemisinin toward cancer cells by transferrin-mediated carbon nanotubes nanoparticles

Artemisinin (ART) is a kind of drug with an endoperoxide bridge which tends to react with Fe²⁺ to generate radicals for killing cancer cells. However, simultaneous delivery of hydrophobic ART and Fe²⁺ ions into cancer cells remains a major challenge. In this study, a multi-functional tumor-targeting drug delivery system employing hyaluronic acid-derivatized multi-walled carbon nanotubes (HA-MWCNTs) as drug carriers, transferrin (Tf) as targeting ligand and ART as a model drug for cancer treatment was constructed. This delivery system (HA-MWCNTs/Tf@ART) not only retained optical property of MWCNTs and cytotoxicity of ART but also demonstrated synergistic anti-tumor effect using ART and Tf. Compared with free ART, remarkably enhanced anti-tumor efficacy of this drug vehicle was realized both in cultured MCF-7 cells in vitro and in a tumor-bearing murine model in vivo, due to increased intracellular accumulation of ART and co-delivery of Tf and ART analogs. HA-MWCNTs/Tf@ART with laser irradiation demonstrated the highest inhibition effect compared to the other groups. This result may provide a new way of using promising natural drugs for cancer therapy.     

Co-delivery of doxorubicin and paclitaxel by PEG-polypeptide nanovehicle for the treatment of non-small cell lung cancer

Despite progress, combination therapy of different functional drugs to increase the efficiency of anticancer treatment still remains challenges. An amphiphilic methoxy poly(ethylene glycol)-b-poly(l-glutamic acid)-b-poly(l-lysine) triblock copolymer decorated with deoxycholate (mPEsG-b-PLG-b-PLL/DOCA) was synthesized and developed as a nanovehicle for the co-delivery of anticancer drugs: doxorubicin (DOX) and paclitaxel (PTX). The amphiphilic copolymer spontaneously self-assembled into micellar-type nanoparticles in aqueous solutions and the blank nanoparticles possessed excellent stability. Three different domains of the copolymer performed distinct functions: PEG outer corona provided prolonged circulation, middle biodegradable and hydrophilic PLG shell was designed for DOX loading through electrostatic interactions, and hydrophobic deoxycholate modified PLL served as the container for PTX. In vitro cytotoxicity assays against A549 human lung adenocarcinoma cell line demonstrated that the DOX + PTX co-delivered nanoparticles (Co-NPs) exhibited synergistic effect in inducing cancer cell apoptosis. Ex vivo DOX fluorescence imaging revealed that Co-NPs had highly efficient targeting and accumulation at the implanted site of A549 xenograft tumor in vivo. Co-NPs exhibited significantly higher antitumor efficiency in reducing tumor size compared to free drug combination or single drug-loaded nanoparticles, while no obvious side effects were observed during the treatment, indicating this co-delivery system with different functional antitumor drugs provides the clinical potential in cancer therapy.     

Preparation and characterization of 2-hydroxyethyl starch microparticles for co-delivery of multiple bioactive agents

The present study reports the generation of 2-hydroxyethyl starch microparticles for co-delivery and controlled release of multiple agents. The obtained microparticles are characterized by using Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction analysis, energy-dispersive X-ray spectroscopy, and scanning electron microscopy. By using ofloxacin and ketoprofen as drug models, the release sustainability of the microparticles is examined at pH 1.2, 5.4, and 6.8 at 37 °C, with Fickian diffusion being found to be the major mechanism controlling the kinetics of drug release. Upon being loaded with the drug models, the microparticles show high efficiency in acting against Escherichia coli and Bacillus cereus. The results suggest that our reported microparticles warrant further development for applications in which co-administration of multiple bioactive agents is required.