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Purpose: In this study, cationic mannosylated nanostructured lipid carriers (Man-NLCs) were developed for the targeted delivery of rifampicin to alveolar macrophages. Methods: Rifampicin loaded Man-NLCs (RFP-Man-NLCs) and rifampicin loaded unmodified nanostructured lipid carriers (REP-NLCs) were prepared using thin film homogenization method and characterized by particle size, polydispersity index, zeta potential, transmission electron microscopy, encapsulation efficiency, pharmacokinetics, biodistribution, cell specific targeting, cytotoxicity and inflammatory response. Results: RFP-Man-NLCs and REP-NLCs obtained displayed a size distribution around 160 nm (PDI <0.30) with positive charges of approximately 30 mV. The encapsulation efficiency of RFP was above 90%. In the biodistribution study, both RFP-Man-NLCs and RFP-NLCs, compared with the commercially available rifampicin solution, displayed superior lung-targeting ability. Compared to REP-NLCs, RFP-Man-NLCs exhibited significantly higher uptake efficiency in NR8383 cells and alveolar macrophages, which achieved cell-specific targeting. In addition, RFP-Man-NLCs were demonstrated to be a safe formulation with minimum toxicity and no inflammatory response. Conclusions: RFP-Man-NLCs provided an alternative strategy for selectively delivering rifampicin to alveolar macrophages. [ABSTRACT FROM AUTHOR]

Purpose: To develop a tumor-targeted drug delivery system based on solid lipid nanoparticles (SLNs) conjugated with the enzymatically cleavable polyethylene glycol (PEG). Methods: SLNs loaded with paclitaxel (PTX) were prepared using the film ultrasonication method, followed by conjugation with a PEGylated peptide (Pp) that can specifically interact with matrix metalloproteinases (MMPs) that is over-expressed by tumor cells. The physicochemical characteristics of the Pp-PTX-SLNs were studied and the in vitro drug release, cytotoxicity and cell uptake of the formulations were investigated. Furthermore, using an animal model, the pharmacokinetic properties, biodistribution and anti-tumor activity of this system were evaluated. Results: The resulting Pp-PTX-SLNs penetrated through tumor cells via facilitated uptake mediated by MMPs. The uncleavable Pp'-PTX-SLNs showed a lower cell uptake efficiency, compared with the Pp-PTX-SLNs. In a tumor-bearing mice model, Pp-PTX-SLNs accumulated to a greater extent at the tumor location, persisted longer in blood circulation, and showed lower toxicity than did PTX-SLNs or Taxol®. Most importantly, the mice treated with Pp-PTX-SLNs survived longer than the groups treated with Pp'-PTX-SLNs, PTX-SLNs or Taxol®. Conclusions: These results suggest that Pp-PTX-SLNs hold promise as a new strategy for paclitaxel chemotherapy, and that Pp-SLNs can be a useful nanocarrier for other chemotherapeutic drugs. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

The present study aimed at developing a drug delivery system targeting the densest site of tuberculosis infection, the alveolar macrophages (AMs). Rifampicin (RFP)-loaded solid lipid nanoparticles (RFP-SLNs) with an average size of 829.6 ± 16.1 nm were prepared by a modified lipid film hydration method. The cytotoxicity of RFP-SLNs to AMs and alveolar epithelial type II cells (AECs) was examined using MTT assays. The viability of AMs and AECs was above 80 % after treatment with RFP-SLNs, which showed low toxicity to both AMs and AECs. Confocal Laser Scanning Microscopy was employed to observe the interaction between RFP-SLNs and both AMs and AECs. After incubating the cells with RFP-SLNs for 2 h, the fluorescent intensity in AMs was more and remained longer (from 0.5 to 12 h) when compared with that in AECs (from 0.5 to 8 h). In vitro uptake characteristics of RFP-SLNs in AMs and AECs were also investigated by detection of intracellular RFP by High performance liquid chromatography. Results showed that RFP-SLNs delivered markedly higher RFP into AMs (691.7 ng/mg in cultured AMs, 662.6 ng/mg in primary AMs) than that into AECs (319.2 ng/mg in cultured AECs, 287.2 ng/mg in primary AECs). Subsequently, in vivo delivery efficiency and the selectivity of RFP-SLNs were further verified in Sprague-Dawley rats. Under pulmonary administration of RFP-SLNs, the amount of RFP in AMs was significantly higher than that in AECs at each time point. Our results demonstrated that solid lipid nanoparticles are a promising strategy for the delivery of rifampicin to alveolar macrophages selectively. [ABSTRACT FROM AUTHOR]

Purpose: PHBHHx (poly(3-hydroxybutyrate-co-3-hydroxyhexanoate)) is an excellent biomaterial for tissue repair. Here, we aim to develop a PHBHHx-based three-dimensional (3D) scaffold system for sustained delivery of proteins (insulin serves as a model protein). Methods: The insulin-phospholipid complex (INS-PLC) was prepared to enhance the insulin lipophilicity. INS-PLC loaded PHBHHx 3D scaffolds (INS-PLC-SCAs) containing PEG-2000 were fabricated by lyophilization. In vitro release was performed in the medium with or without lipase. The bioactivity of INS-PLC-SCAs was measured in diabetic rats. Results: In vitro release shows that the release rate of INS-PLC-SCAs was very slow (~6% of total insulin was released within 120 days), and PEG-2000 or lipase had no effect on its release pattern. The bioactivity test shows that the hypoglycaemic effect of insulin was maintained after formulated into scaffolds. After subcutaneous (s.c.) implantation, its therapeutic effect lasted for over 130 h, and its bioavailability was enhanced by 4-fold. Conclusions: PHBHHx based 3D scaffold has a great potential for sustained delivery of proteins, especially growth factors. When growth factors are incorporated, it can serve as a bifunctional system that provides a porous skeleton for cells attachment and proliferation, as well as a matrix for long term release of the loaded growth factors. [ABSTRACT FROM AUTHOR]

Purpose: To improve gene transducibility mediated by adenovirus (Ad) in cancer cells and further enhance anti-tumor effects by co-delivery. Methods: Calcium-induced phase change method was used to prepare the complex of anionic liposomes and adenovirus (AL/Ad5). Gene expression was qualitatively detected by X-gal staining and quantitatively detected by ELISA. Taking adenovirus-mediated stromal cell-derived factor-1α (Ad5-SDF1α) as therapeutic gene and carmustine (BCNU) as chemotherapeutic agent, a co-delivering system of AL/Ad5-SDF1α/BCNU was prepared and administered to tumor-bearing mice by intratumor injection. Results: Enhanced LacZ gene transduction was obtained in B16 and Lewis lung carcinoma cells in vitro and in vivo. Complexes of AL/Ad5-SDF1α improved SDF1α gene expression and led to accumulation of dendritic cells among the murine B16 melanoma cells in vivo. This co-delivery system of AL/Ad5-SDF1α/BCNU could significantly suppress tumor growth and prolong survival of tumor-bearing mice. Conclusions: Through the co-delivering system, AL/Ad5-SDF1α could synergize with BCNU to improve the antitumor effect. It may be a promising strategy for solid tumor therapy. [ABSTRACT FROM AUTHOR]