[T1-weighted magnetic resonance imaging contrast agents and their theranostic nanoprobes]

Abstract

Magnetic resonance imaging (MRI) is an important imaging modality for clinical disease diagnosis, and nearly 50% of clinical MRI examinations require contrast agents to enhance the diagnostic sensitivity. This review provides a summary of the major MRI contrast agents and their classification, and the advantages and limits of the commercially available MRI contrast agents, and elaborates on the exceedingly small magnetic iron oxide nanoparticles (ES-MIONs), dotted core-shell iron and gadolinium hybrid nanoparticles (FeGd-HN) and exceedingly small gadolinium oxide nanoparticles (ES-GON). These nanoparticles can greatly improve the efficiency of T₁-weighted MRI due to their high r₁ value and low r₂/r₁ ratio, and are expected to be translated into clinical contrast agents for T₁-weighted MRI. The authors also review the diagnostic and therapeutic integration system that combines MRI contrast agents with various tumor therapies, such as MRI-guided ferroptosis therapy, radiosensitization therapy, and photothermal therapy, which allow efficient treatment as well as real-time monitoring of tumors and serve as potential cancer therapy strategies. The possible future research directions in the field of MRI-based multifunctional diagnostic and therapeutic formulations are also discussed.

Keywords: dotted coreshell iron and gadolinium hybrid nanoparticles; exceedingly small gadolinium oxide nanoparticles; exceedingly small magnetic iron oxide nanoparticles; magnetic resonance imaging contrast agents; tumor theranostics.

1

MRI造影剂的主要问题和优势^[23] Main problems and advantages of MRI contrast agents^[23].

2

ES-MIONs的TEM图像及r₁值或r₂/r₁比值与粒径（< 5 nm）的关系^[34] TEM images of ES-MIONs, and the relationships of r₁ value or r₂/r₁ ratio with particle size (< 5 nm) (Mean±SD, n=3). ^*P < 0.02^[34].

3

DOX@ES-MION@RGD2@mPEG复合纳米粒子的设计及降低正常细胞非特异性摄取纳米颗粒的原理^[34] Design of DOX@ES-MION@RGD2@mPEG composite nanoparticles and the mechanism to reduce nonspecific uptake of nanoparticles by normal cells^[34].

4

FeGd-HN-RGD2复合纳米粒子合成步骤示意图^[45] Schematic illustration of the procedures for synthesis of FeGd-HN-RGD2 composite nanoparticles^[45]. A: The seeds of ES-MIONs were synthesized using PAA as a stabilizer; B: Gd³⁺ions are adsorbed on the surfaces of ES-MION seeds via formation of ionic bonds between them and the -COOH groups from PAA, and then GdON are synthesized in situ on the surfaces of ES-MION seeds to form three different structures at different C_Gd; C: The targeted ligand RGD2 is conjugated onto the surface of the dotted core-shell type FeGd-HN to construct FeGd-HN-RGD2 nanoparticles.

5

FeGd-HN3的TEM图像及r₁值和r₂/r₁比值与Gd/Fe摩尔比的关系（B₀=7.0 T）^[45] An transmission electron microscopic image of FeGd-HN3 and the relationships of r₁ value or r₂/r₁ ratio with Gd/Fe molar ratio (Mean±SD, n=3)^[45].

6

ES-GON5-PAA@RGD2复合纳米粒子合成步骤示意图^[51] Schematic illustration of the synthesis of ES-GON5- PAA@RGD2 composite nanoparticles^[51]. A: Scheme for synthesis of the PAA-stabilized exceedingly small gadolinium oxide nanoparticles (ES-GON-PAA); B: With increasing PAA/Gd molar ratio, (1) the particle size of ES-GON-PAA decreases resulting in accelerated tumor accumulation, (2) r₁ value increases and r₂/r₁ ratio decreases leading to enhanced T₁- weighted MRI efficiency; C: RGD2-conjugated ES-GON-PAA (ES-GON-PAA@RGD2).

7

FeGd-HN@Pt@LF/RGD2的合成(A), MRI指导下原位脑肿瘤的铁凋亡治疗机制(B)^[100] Synthesis of FeGd-HN@PT@LF/RGD2 (A) and the mechanism illustration of MRI-guided ferroptosis therapy for orthotopic brain tumors(B)^[100].

8

不同治疗组原位脑肿瘤模型小鼠的生物发光图像(A-E)；不同治疗组原位脑瘤模型小鼠的存活率(F)；不同治疗组原位脑瘤模型小鼠的生长曲线(G)^[100] (A-E) Bioluminescence images of mice bearing orthotopic brain tumors in different treatment groups; (F) Percent survival of the mice bearing orthotopic brain tumors after different treatments; (G) Growth curves of the orthotopic brain tumors in different treatment groups (Mean±SE, n=5)^[100].

9

ES-GON-rBSA-FL-RGD2的合成(A)；MRI指导的脑肿瘤放射增敏治疗的机制(B)^[117] Synthesis of ES-GON-RBSA-FL-RGD2(A) and mechanism of MRI-guided radiosensitization therapy for brain tumors (B)^[117].

10

磁性AuNW的合成原理图(A), 磁性AuNW作为GSH响应型T₁-加权MRI造影剂和光热剂的应用(B)^[162] Schematic illustration of the synthesis of magnetic AuNW (A) and the applications of magnetic AuNW as GSH-responsive T₁- weighted MRI contrast agents and photothermal agents (B)^[162].

11

磁性AuNW的体内光声成像与光热治疗^[162] In vivo photoacoustic imaging and photothermal therapy with magnetic AuNWs^[162].