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Hu Q.,Fudan University | Gu G.,Fudan University | Liu Z.,Fudan University | Jiang M.,Shandong University of Traditional Chinese Medicine | And 12 more authors.
Biomaterials | Year: 2013

The development of a drug delivery strategy which can mediate efficient tumor targeting together with high cellular internalization and extensive vascular extravasation is essential and important for glioma treatment. To achieve this goal, F3 peptide that specifically bind to nucleolin, which is highly expressed on the surface of both glioma cells and endothelial cells of glioma angiogenic blood vessels, is utilized to decorate a nanoparticulate drug delivery system to realize glioma cell and neovasculature dual-targeting and efficient cellular internalization. Tumor homing and penetrating peptide, tLyp-1 peptide, which contains the motif of (R/K)XX(R/K) and specially binds to neuropilin is co-administrated to improve the penetration of the nanoparticles across angiogenic vasculature into glioma parenchyma. The F3 conjugation via a maleimide-thiol coupling reaction was confirmed by XPS analysis with 1.03% nitrogen detected on the surface of the functionalized nanoparticles. Enhanced cellular interaction with C6 cells, improved penetration in 3D multicell tumor spheroids, and increased cytotoxicity of the loaded paclitaxel were achieved by the F3-functionalized nanoparticles (F3-NP). Following co-administration with tLyp-1 peptide, F3-NP displayed enhanced accumulation at the tumor site and deep penetration into the glioma parenchyma and achieved the longest survival in mice bearing intracranial C6 glioma. The findings here clearly indicated that the strategy by co-administrating a tumor homing and penetrating peptide with functionalized nanoparticles dual-targeting both glioma cells and neovasculature could significantly improve the anti-glioma drug delivery, which also hold a great promise for chemotherapy of other hard-to-cure cancers. © 2012 Elsevier Ltd.

Gu G.,Fudan University | Xia H.,Fudan University | Xia H.,Shanghai Institute for Food and Drug Control SIFDC | Hu Q.,Fudan University | And 11 more authors.
Biomaterials | Year: 2013

By taking advantage of the dramatically upregulated expression of matrix metalloproteinases MMP-2 and MMP-9 in glioblastomas and the powerful transport ability of low molecular weight protamine (LMWP), we constructed an activatable low molecular weight protamine (ALMWP) and conjugated it to PEG-PCL nanoparticles (NP) to develop a 'smart' drug delivery system for enhanced targeted glioblastoma therapy. Important parameters such as particle size distribution, zeta potential and surface content were determined, which confirmed the conjugation of ALMWP to the surface of nanoparticle. ALMWP-NP loaded with paclitaxel (PTX) exhibited a desirable pharmacokinetic and biodistribution profiles for anti-glioblastoma drug delivery. Cellular experiments showed that ALMWP-NP exhibited significantly elevated MMP-dependent cellular accumulation in C6 cells via lipid raft-mediated endocytosis and energy-dependent macropinocytosis, and improved the cytotoxicity of PTX. In vitro C6 tumor spheroid uptake confirmed the tumor penetrating ability of ALMWP-NP, in vivo imaging and glioma distribution justified its specific accumulation in the glioma. The improved glioma-targeting and tumor penetration led to an anticipated enhanced in vivo anti-glioblastoma effect: animals (nude mice bearing intracranial C6 glioma) treated with ALMWP-NP-PTX survive significantly longer than those treated with saline, Taxol® NP-PTX and LMWP-NP-PTX. The findings here offered strong evidence for the glioblastoma-targeting therapy of ALMWP-NP-PTX, and could also lead to a significant advancement in the application of CPPs for targeted therapy of glioma. © 2012 Elsevier Ltd.

Gu G.,Fudan University | Gu G.,Shanghai Institute for Food and Drug Control SIFDC | Hu Q.,Fudan University | Feng X.,Fudan University | And 7 more authors.
Biomaterials | Year: 2014

Tumor neovasculature and tumor cells dual-targeting chemotherapy can not only destroy the tumor neovasculature, cut off the supply of nutrition and starve the tumor cells, but also directly kill tumor cells, holding great potential in overcoming the drawbacks of anti-angiogenic therapy only and improving the anti-glioma efficacy. In the present study, by taking advantage of the specific expression of fibronectin extra domain B (EDB) on both glioma neovasculature endothelial cells and glioma cells, we constructed EDB-targeted peptide APTEDB-modified PEG-PLA nanoparticles (APT-NP) for paclitaxel (PTX) loading to enable tumor neovasculature and tumor cells dual-targeting chemotherapy. PTX-loaded APT-NP showed satisfactory encapsulated efficiency, loading capacity and size distribution. In human umbilical vein endothelial cells, APT-NP exhibited significantly elevated cellular accumulation via energy-dependent, caveolae and lipid raft-involved endocytosis, and improved PTX-induced apoptosis therein. Both in vitro tube formation assay and in vivo matrigel angiogenesis analysis confirmed that APT-NP significantly improved the antiangiogenic ability of PTX. In U87MG cells, APT-NP showed elevated cellular internalization and also enhanced the cytotoxicity of the loaded PTX. Following intravenous administration, as shown by both in vivo live animal imaging and tissue distribution analysis, APT-NP achieved a much higher and specific accumulation within the glioma. As a result, APT-NP-PTX exhibited improved anti-glioma efficacy over unmodified nanoparticles and Taxol® in both subcutaneous and intracranial U87MG xenograft models. These findings collectively indicated that APTEDB-modified nanoparticles might serve as a promising nanocarrier for tumor cells and neovasculature dual-targeting chemotherapy and hold great potential in improving the efficacy anti-glioma therapy. © 2014 Elsevier Ltd.

Xia H.,Fudan University | Xia H.,Shanghai Institute for Food and Drug Control SIFDC | Gu G.,Fudan University | Hu Q.,Fudan University | And 10 more authors.
Bioconjugate Chemistry | Year: 2013

Based on the powerful cell-penetrating ability of low molecular weight protamine (LMWP) and the overexpression of matrix metalloproteinases in the tumor sites, we constructed an activatable low molecular weight protamine (ALMWP) and modified it onto the surface of poly(ethylene glycol)-poly(lactic acid) nanoparticles to develop a "smart" drug delivery system with enhanced permeability for facilitating site-specific targeting delivery of anticancer drug. The obtained ALMWP-functionalized nanoparticles (ALMWP-NP) with a particle size of 134.0 ± 4.59 nm and a zeta potential of -34.4 ± 2.7 mV, exhibited an enhanced MMP-dependent accumulation in HT-1080 cells via both energy-independent direct translocation and clathrin-mediated, cytoskeleton-dependent endocytosis. Pharmacokinetic and biodistribution study in HT-1080 tumor-bearing mice showed that ALMWP-NP significantly increased the accumulation of paclitaxel (PTX) in the tumor site but not the nontarget tissues. In addition, intratumor distribution analysis demonstrated that more ALMWP-NP penetrated deeply into the tumor parenchyma. As a result, PTX loaded by ALMWP-NP exhibited improved antitumor efficacy over that by unmodified nanoparticles and LMWP-functionalized nanoparticles. The findings suggested that ALMWP-NP could be used as a safe and effective tumor-targeting drug delivery system and opened a new gateway to the application of cell-penetrating peptides for targeted antitumor therapy. © 2013 American Chemical Society.

Zhao Y.,National Institutes of Food and Drug Control NIFDC | Ji N.,Sichuan Vspec Technologies Co. Beijing Office | Li X.,National Institutes of Food and Drug Control NIFDC | Hou J.,National Institutes of Food and Drug Control NIFDC | And 6 more authors.
Journal of Innovative Optical Health Sciences | Year: 2016

Human serum albumin (HSA) injectable product is a severely afflicted area on drug safety due to its high price and restricted supply. Raman spectroscopy performances high specificity on HSA detection and it is even possible to determine HSA injectable products noninvasively. In this study, we developed a noninvasive rapid screening method for of HSA injectable products by using portable Raman spectrometer. Qualitative models were established by using principal component analysis combined with classical least squares (PCA-CLS) algorithm, while quantitative model was established by using partial least squares (PLS) algorithm. Model transfer in different instruments of both the same and different apparatus modules was further discussed in this paper. A total of 34 HSA injectable samples collected from markets were used for verification. The identification results showed 100% accuracy and the predicted concentrations of those identified as true HSA were consistent with their labeled concentrations. The quantitative results also indicated that model transfer was excellent in the same apparatus modules of Raman spectrometer at all concentration levels, and still good enough in the different apparatus modules although the relative standard deviation (RSD) value showed a little increasing trend at low HSA concentration level. In conclusion, the method was proved to be feasible and efficient for screening HSA injections, especially on its screening speed and the consideration of glass containers. Moreover, with inspiring results on the model transfer, the method could be used as a universal screening mean to different Raman instruments. © 2016 © The Author(s)

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