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Peptide -mediated targeting of glioma gene delivery systems Nano

Author: KeWeiLun
Tutor: JiangChen
School: Fudan University
Course: Pharmacy
Keywords: CTX Angiopep Polyamide - amine Nanoparticles BBB Gene therapy Matrix metalloproteinase-2 Low-density lipoprotein receptor-related protein Glioma
CLC: R739.41
Type: Master's thesis
Year: 2010
Downloads: 371
Quote: 0
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Abstract

Glioma is the highest incidence of brain tumors, but also the highest mortality rate of 10 categories of cancer. Since their infiltrative glioma growth characteristics and blood-brain barrier (BBB) ??presence, making the most commonly used treatments include surgery, radiotherapy, chemotherapy etc. is difficult to achieve a good therapeutic effect. Gene therapy is a potential means of treatment, but it is difficult to self-medication to glioma gene enrichment, need to build properties with active gene targeting Drug Delivery release system, making the drugs exogenous gene expression in the lesion site to achieve widespread . This topic glioma growth process for the BBB physiological characteristics, it is envisaged to build two kinds of genes Drug Delivery release system strategy: (1) in glioma late, BBB is damaged, this time gliomas and other tumors Similarly, with the EPR effect, based on the use of this head-modified targeting glioma is able to further enhance intracellular drug concentration glioma; (2) in the early glioma, BBB intact, the choice of BBB, glioma cells as targeting high-affinity peptide head group may leap BBB, targeting gliomas. Based on the above two strategies, the subject through pharmacy, molecular and biological means of cross-applications to cationic polymer polyamide - amine (PAMAM)-based polymer carrier via a hydrophilic polymer polyethylene glycol (PEG) to connect glioma or BBB-targeting peptide CTX glioma dual targeting peptide Angiopep, and the gene complex formation PAMAM-PEG-CTX/DNA and PAMAM-PEG-Angiopep/DNA nanoparticles. Both nanoparticle delivery system has the following characteristics: (a) gene vector PAMAM adopted in recent years developed a new type of cationic polymer materials, easy modification, genes containing higher ability; (2) is a specific choice of CTX glioma cell binding peptide nanoparticles can improve the targeting of glioma; (3) optional Angiopep is a glioma cells with the BBB and have high affinity peptides that can help nanoparticles across the BBB After further concentrated to glioma cells. The first chapter on the physiological characteristics of glioma and treatment are outlined. Intracranial glioma as the most common and most difficult to cure the disease, in addition to the basic features of a general tumor, there own characteristics, mainly as invasive growth and the \With the process of tumorigenesis and tumor cells and endothelial cells, astrocytes interaction BBB gradually being destroyed. Now commonly used in the treatment of glioma means, including surgery, radiotherapy and chemotherapy, but their shortcomings and poor efficacy. Gene therapy is a potential new treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TNF related apoptosis inducing ligand, TRAIL) is a recently discovered mediated apoptosis signaling molecules, TNF family members have many features to specific cell surface by glioma binding induce apoptosis, but do not kill normal cells. In this study, a plasmid encoding TRAIL protein pORF-TRAIL as a gene drugs to PAMAM-based carrier for glioma growth during the physiological characteristics of the BBB, and BBB-taking targeting glioma glioma pairs targeting two kinds of strategies constructed two genes Drug Delivery release system. Angiopep CTX and two were selected as a target peptide head group, which CTX through with glioma cells express high levels of matrix metalloproteinase -2 (MMP-2) combine to form MMP-2-CTX complex after glial tumor cell-specific uptake, with glioma targeting; while Angiopep is through BBB glioma cells and expression on both low-density lipoprotein receptor-related protein (LRP) mediates entry into cells, enabling BBB-gum Dual targeting stromal tumors. Section I, Chapter II of this article on the PAMAM-PEG-CTX polymer carrier and in vitro characterization of gene-loaded nanoparticles were evaluated. CTX-modified polymeric carrier can specifically increase in the uptake of C6 glioma cells, but not in normal cells (293 cells) on the intake is unaffected. C6 cells on the polymer carrier in the uptake was inhibited at 4 ℃ described carrier may enter cells by endocytosis. CTX modified gene-carrying nanoparticles uptake in C6 cells also increased significantly. Section II examines the PAMAM-PEG-CTX/DNA nanoparticles containing gene in glioma bearing mice in vivo distribution of brain expression, and the treatment of cerebral gliomas nanoparticles were pharmacodynamic evaluation. The unmodified PAMAM / DNA nanoparticles compared, PAMAM-PEG-CTX/DNA nanoparticles can be increased in the tumor bearing mice glioma aggregation. Frozen sections showed, PAMAM-PEG-CTX/DNA nanoparticles in glioma tumor tissue edges more visible expression, whereas PAMAM / DNA edges in glioma part of a small amount of normal tissue expression, which may and tumor angiogenesis associated with blood-brain barrier. Pharmacodynamic evaluation results show, PAMAM-PEG-CTX/pORF-TRAIL nanoparticles can induce tumor-bearing mice inside glioma tumor cell apoptosis, the effect of the commercially available oral drug temozolomide considerably, while PAMAM/pORF- TRAIL is able to induce apoptosis in glioma Edge PAMAM-PEG-CTX/pORF-TRAIL and temozolomide group of mice with a median survival time was 59.5 days and 49 days, and PAMAM-PEG-CTX/pORF- TRAIL group, 50% of the mice survived longer than 70 days and temozolomide group, the survival time of less than 70 days. These results suggest PAMAM-PEG-CTX/pORF-TRAIL effective in treating gliomas. Chapter III Section on PAMAM-PEG-Angiopep polymer carrier and its load in vivo gene nanoparticles properties were evaluated. Angiopep vector modified to increase in the brain capillary endothelial cells (BCECs) on the uptake, and in a certain range showing concentration-dependent. Study showed uptake mechanism, PAMAM-PEG-Angiopep vector containing genes polymer and nanoparticles may be mediated by LRP endocytosis pathway is BCECs intake. Angiopep modified gene containing nanoparticles can improve the transport efficiency across BCECs monolayer. Biodistribution results showed, Angiopep nanoparticles modified gene can increase the load distribution in the brain, and with the increase in the proportion Angiopep modification increases; while, Angiopep modification can effectively increase the foreign gene in the mouse brain expression efficiency of each part. PAMAM-PEG-Angiopep/DNA gene containing nanoparticles show a good brain targeting efficiency. Section II examines the PAMAM-PEG-Angiopep/DNA nanoparticles containing gene in glioma bearing mice in vivo distribution, and treatment of cerebral gliomas nanoparticles were pharmacodynamic evaluation. Unmodified PAMAM / DNA nanoparticles compared, PAMAM-PEG-Angiopep/DNA can increase the nanoparticles in tumor bearing mice glioma aggregation of nanoparticles possible reason is mediated in Angiopep further after crossing the BBB concentrated to glioma cells, showing BBB-glioma dual targeting. Pharmacodynamic evaluation results show, PAMAM-PEG-Angiopep/pORF-TRAIL nanoparticles can induce tumor-bearing mice inside glioma tumor cell apoptosis; PAMAM-PEG-Angiopep/pORF-TRAIL and temozolomide group tumor The median survival time of mice was 56.5 days and 49 days respectively, both overall survival time considerably. These results suggest that PAMAM-PEG-Angiopep/pORF-TRAIL is an effective treatment of cerebral gliomas release non-viral gene delivery system drugs.

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