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

Abstract

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.

• Authors: Jing Yu, Lei Sun, Jinge Zhou, Lipeng Gao, Lijuan Nan, Shimin Zhao, Ting Peng, Lin Han, Jing Wang, Weiyue Lu, Lin Zhang, Yiting Wang, Zhiqiang Yan, Lei Yu
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 28 Issue 11 Pg. 2823-2831 (11 15 2017) ISSN: 1520-4812 [Electronic] United States
• PMID: 28968068 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Peptides
• Proteins
• poly(gamma-glutamylglutamine)paclitaxel
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (chemistry, pharmacology, therapeutic use)
• Brain (drug effects, pathology)
• Brain Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Drug Delivery Systems
• Glioblastoma (drug therapy, pathology)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Nanoparticles (chemistry)
• Paclitaxel (analogs & derivatives, chemistry, pharmacology, therapeutic use)
• Peptides (chemistry)
• Proteins (chemistry, pharmacology, therapeutic use)
• Rats