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Bioconjug Chem. 2017 Nov 15;28(11):2823-2831. doi: 10.1021/acs.bioconjchem.7b00519. Epub 2017 Oct 10.

Self-Assembled Tumor-Penetrating Peptide-Modified Poly(l-γ-glutamylglutamine)-Paclitaxel Nanoparticles Based on Hydrophobic Interaction for the Treatment of Glioblastoma.

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Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University , Shanghai 200062, P.R. China.
Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Fudan University, Ministry of Education , Shanghai 201203, P.R. China.
Department of Pharmacy, Shaoxing People's Hospital, Shaoxing Hospital of ZheJiang University , Shaoxing 312000, P.R. China.


To enhance the tumor-penetrating ability and targeting therapeutic effect of polymer-drug conjugates (PDCs), tumor-penetrating peptide RGERPPR (RGE) modified and PEGylated poly(l-γ-glutamylglutamine)-paclitaxel (PGG-PTX) nanoparticles (RGE-PEG/PGG-PTX NPs) were prepared by using a so-called "modular" design strategy. In brief, a RGERPPR-conjugated targeting material, DSPE-PEG-RGERPPR, was first synthesized and assembled with PGG-PTX into RGE-PEG/PGG-PTX NPs based on the hydrophobic interaction between the groups of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) and PTX. The NPs exhibited a uniform spherical morphology with particle size of around 90 nm, as shown by the dynamic light scattering and transmission electron microscopy results. The NPs showed good in vitro stability at 4 °C for over 3 weeks, sustained drug release within 120 h, and good hemocompatibility. The cellular-uptake study displayed that the NPs showed increased uptake by U87 MG cells and human umbilical vein endothelial cells (HUVECs) compared to the unmodified PGG-PTX. The cytotoxicity test demonstrated that RGE-PEG/PGG-PTX NPs produced a stronger growth inhibitory effect against U87 MG cells and HUVECs than PGG-PTX, which was consistent with the cellular uptake results. Finally, the pharmacodynamic study proved that RGE-PEG/PGG-PTX NPs significantly prolonged the median survival time of nude mice bearing intracranial glioblastoma. The results indicated the effectiveness of RGE-PEG/PGG-PTX NPs in the treatment of glioblastoma as well as the feasibility of the "modular" design strategy in the preparation of active-targeting PDCs.

[Indexed for MEDLINE]

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