NRP-1 靶向治疗性 AGuIX 纳米颗粒用于脑胶质瘤光动力治疗的多尺度选择性和体内生物分布。

Multiscale Selectivity and in vivo Biodistribution of NRP-1Targeted Theranostic AGuIX Nanoparticles for PDT of Glioblastoma.

机构信息

Université de Lorraine, Centre National de la Recherche Scientifique (CNRS), Research Center for Automatic Control of Nancy (CRAN), Nancy, France.

Université de Lyon, CNRS, Institut Lumière Matière, Lyon, France.

出版信息

Int J Nanomedicine. 2020 Nov 9;15:8739-8758. doi: 10.2147/IJN.S261352. eCollection 2020.

DOI:10.2147/IJN.S261352

PMID:33223826

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7673487/

Abstract

BACKGROUND

Local recurrences of glioblastoma (GBM) after heavy standard treatments remain frequent and lead to a poor prognostic. Major challenges are the infiltrative part of the tumor tissue which is the ultimate cause of recurrence. The therapeutic arsenal faces the difficulty of eradicating this infiltrating part of the tumor tissue while increasing the targeting of tumor and endogenous stromal cells such as angiogenic endothelial cells. In this aim, neuropilin-1 (NRP-1), a transmembrane receptor mainly overexpressed by endothelial cells of the tumor vascular system and associated with malignancy, proliferation and migration of GBM, highlighted to be a relevant molecular target to promote the anti-vascular effect of photodynamic therapy (VTP).

METHODS

The multiscale selectivity was investigated for KDKPPR peptide moiety targeting NRP-1 and a porphyrin molecule as photosensitizer (PS), both grafted onto original AGuIX design nanoparticle. AGuIX nanoparticle, currently in Phase II clinical trials for the treatment of brain metastases with radiotherapy, allows to achieve a real-time magnetic resonance imaging (MRI) and an accumulation in the tumor area by EPR (enhanced permeability and retention) effect. Using surface-plasmon resonance (SPR), we evaluated the affinities of KDKPPR and scramble free peptides, and also peptides-conjugated AGuIX nanoparticles to recombinant rat and human NRP-1 proteins. For in vivo selectivity, we used a cranial window model and parametric maps obtained from T2*-weighted perfusion MRI analysis.

RESULTS

The photophysical characteristics of the PS and KDKPPR molecular affinity for recombinant human NRP-1 proteins were maintained after the functionalization of AGuIX nanoparticle with a dissociation constant of 4.7 μM determined by SPR assays. Cranial window model and parametric maps, both revealed a prolonged retention in the vascular system of human xenotransplanted GBM. Thanks to the fluorescence of porphyrin by non-invasive imaging and the concentration of gadolinium evaluated after extraction of organs, we checked the absence of nanoparticle in the brains of tumor-free animals and highlighted elimination by renal excretion and hepatic metabolism.

CONCLUSION

Post-VTP follow-ups demonstrated promising tumor responses with a prolonged delay in tumor growth accompanied by a decrease in tumor metabolism.

摘要

背景

胶质母细胞瘤（GBM）在经过标准的高强度治疗后仍会频繁复发，导致预后不良。主要的挑战是肿瘤组织的浸润部分，这是复发的根本原因。治疗手段面临着在消除肿瘤浸润部分的同时增加对肿瘤和内源性基质细胞（如血管生成内皮细胞）靶向性的困难。在这一目标中，神经纤毛蛋白-1（NRP-1），一种主要在肿瘤血管系统的内皮细胞中过度表达的跨膜受体，与 GBM 的恶性程度、增殖和迁移有关，被突出为促进光动力疗法（VTP）抗血管作用的一个相关分子靶点。

方法

研究了靶向 NRP-1 的 KDKPPR 肽部分和原 AGuIX 设计纳米颗粒上的卟啉分子作为光敏剂（PS）的多尺度选择性。AGuIX 纳米颗粒目前正在进行 II 期临床试验，用于放射治疗脑转移，通过 EPR（增强渗透和保留）效应实现实时磁共振成像（MRI）和在肿瘤区域的积累。我们使用表面等离子体共振（SPR）评估了 KDKPPR 和无乱序对照肽以及与 AGuIX 纳米颗粒缀合的肽与重组大鼠和人 NRP-1 蛋白的亲和力。为了进行体内选择性研究，我们使用了颅窗模型和从 T2*-加权灌注 MRI 分析获得的参数图。

结果

通过 SPR 分析确定的解离常数为 4.7 μM，表明 PS 的光物理特性和 KDKPPR 分子对重组人 NRP-1 蛋白的亲和力在 AGuIX 纳米颗粒功能化后得以保持。颅窗模型和参数图均显示出在人异种移植 GBM 的血管系统中滞留时间延长。通过非侵入性成像检测卟啉的荧光和提取器官后的钆浓度，我们检查了无肿瘤动物大脑中是否存在纳米颗粒，并强调了通过肾脏排泄和肝脏代谢进行消除。