Synergistic Image-guided Nanoparticles for Drug Delivery (SIN-Drug)

本项目旨在将无机-有机杂化纳米粒子(IOH-NPs)作为一种新型的、多功能的基础材料用于协同治疗肿瘤。IOH-NPs具有前所未有的高载药量(70-85wt-%)、低材料复杂性和水基合成等特点。挑战是将不同的细胞抑制剂(最多三种)和高载药量(每种药物的20wt-%)结合到均匀组成的纳米颗粒中。除了这些多药物IOH-NPs的细胞抑制作用外，它们还可以用于磁热和/或光激活的物理肿瘤治疗以及多模式成像(OI，MRI)。IOH-NPs有一种含有顺磁性、无机[GdO]+阳离子的盐水组成的[GdO]+[(R1CytostaticCOO)a(R2CytostaticCOO)b(R3CytostaticOPO3)c(RDyeSO3)d]–，以及最多四个功能阴离子(a+b+c+d=1)的组合，包括最多三个细胞抑制阴离子([R1CytostaticCOO]-，[R2CytostaticCOO]-，[R3CytostaticOPO3]2-)和一个荧光的、产生ROS的阴离子([RDyeSO3]-)。此外，还将进行详细的体外和体内研究(医学，这项研究旨在评估肿瘤的特异性摄取、生物相容性和生物分布、药物释放和药代动力学，以及IOH-NPs对胰腺导管腺癌(PDAC)这一最相关的肿瘤实体的细胞毒性(抗肿瘤)活性。作为最雄心勃勃的总体目标，多药物IOH-NPs旨在成为一个通用的多模式和多功能治疗和诊断平台的一部分，该平台可以转移到几乎所有类型的实体肿瘤，特别是允许减少副作用和最大限度地减少耐药性。

This project aims at inorganic-organic hybrid nanoparticles (IOH-NPs) as novel, multifunctional base materials for synergistic tumor therapy. IOH-NPs are designated by an unprecedentedly high drug load (70-85 wt-%), low material complexity and water-based synthesis. The challenge is to combine different cytostatic agents (up to three) with high drug load (>20 wt-% of each) into homogeneously composed nanoparticles. Besides the cytostatic effect of these multi-drug IOH-NPs, they are additionally intended to allow magnetothermal and/or photoactivated physical tumor treatment as well as multimodal imaging (OI, MRI). The IOH-NPs have a saline composition [GdO]+[(R1CytostaticCOO)a(R2CytostaticCOO)b(R3CytostaticOPO3)c(RDyeSO3)d]– with the paramagnetic, inorganic [GdO]+ cation and a combination of up to four functional anions (a+b+c+d = 1) including up to three cytostatic anions ([R1CytostaticCOO]–, [R2CytostaticCOO]–, [R3CytostaticOPO3]2–) and a fluorescent, ROS-generating anion ([RDyeSO3]–).Besides fundamental material synthesis and characterization (chemistry, Karlsruhe Institute of Technology), detailed in vitro and in vivo studies will be performed (medicine, University Medical Center Göttingen) to evaluate tumor-specific uptake, biocompatibility and biodistribution, drug release and pharmacokinetics, as well as the cytotoxic (anti-tumor) activity of the IOH-NPs in regard of pancreatic ductal adenocarcinoma (PDAC) as a most relevant tumor entity. As a most ambitions overall aim, the multi-drug IOH-NPs are intended to become part of a universal multimodal and multifunctional therapeutic and diagnostic platform that can be transferred to almost every type of solid tumor and that especially allows to reduce side effects and to minimize drug resistances.