药学学报

Classification	Application	Excitation/emission wavelength	Ref.
A ratiometric H₂S-activated fluorescent probe	HS-CG functions as a ratiometric near-infrared probe by exhibiting low F₇₂₈/F₈₁₆ in its native state. Upon hydrogen sulfide (H₂S) activation, the fluorescence at 728 nm increases sharply, leading to a marked rise in the F₇₂₈/F₈₁₆ ratio. This enables highly sensitive and accurate ratiometric detection and imaging of H₂S in vivo	IR-HS: λ_ex = 680 nm; λ_em = 728 nm ICG: λ_ex = 780 nm; λ_em = 816 nm	[37]
Membrane and pH-sensitive fluorescent probes	A 1, 8-naphthalimide-based pH probe (ND6) with a pronounced fluorescence response between pH 6 and 7 was developed for live-cell imaging. It offers a potent means to study membrane dynamics and synaptic functions in neurons and secretory cells	λ_ex = 399 nm; λ_em = 514 nm	[38]
On-off fluorescent probe	The antibody-conjugated DAE@CB7 supramolecular probe enables reversible super-resolution imaging of intracellular proteins. CB7 encapsulation enhances the aqueous fluorescence and switching durability of the DAE photoswitch, allowing for repeated on/off cycling in cells under confocal and nanoscopy modes	λ_ex = 365 nm; λ_em = 519 nm/548 nm	[39]
pH-sensitive and hypoxia-responsive fluorescent probes	The semi-quinone probe Val-Hcys, activated by acidic pH through its amide side chain, serves as a sensitive sensor for hypoxic regions. It exhibits a rapid and strong (4-fold) fluorescence turn-on in hypoxic cells, confirming its utility for mapping the tumor microenvironment	λ_ex = 532 nm; λ_em = 559-574 nm	[40]
Ratio and pH-sensitive fluorescent probes	A guanine-quenched, dual-labeled DNA probe demonstrates high pH sensitivity (49-fold fluorescence change) upon hybridization. It serves as a general platform for simultaneously tracking oligonucleotide localization and reporting the local pH microenvironment, as evidenced by monitoring vesicular dynamics in living cells	FAM: λ_ex = 488 nm; λ_em = 515-520 nm Cy5: λ_ex = 633/640 nm; λ_em = 660-670 nm	[41]
Fe³⁺ sensitive fluorescent probe	CS-TPE is an AIE-active fluorescent probe that dually acts as a sensitive Fe³⁺ sensor and a potent antibacterial agent. It allows for real-time monitoring of Fe³⁺ levels and antibacterial efficacy, showcasing great theranostic potential	λ_ex = 365 nm; λ_em = 473 nm	[42]
Chlorite-sensitive fluorescent probe	JDK is a FRET-based fluorescent probe characterized by a large stokes shift and robust photostability. It serves as a highly sensitive tool for tracking hypochlorite in biological systems	λ_ex = 415 nm; λ_em = 475/580 nm	[43]
pH-responsive fluorescent probe	P24-mid is a pH-sensitive FRET biosensor that targets mitochondria and undergoes a reversible structural change, enabling real-time sensing of mitochondrial pH and monitoring of mitophagy	λ_ex = 545 nm; λ_em = 570/660-670 nm	[44]

Classification	Application	Excitation/emission wavelength	Ref.
A ratiometric H₂S-activated fluorescent probe	HS-CG functions as a ratiometric near-infrared probe by exhibiting low F₇₂₈/F₈₁₆ in its native state. Upon hydrogen sulfide (H₂S) activation, the fluorescence at 728 nm increases sharply, leading to a marked rise in the F₇₂₈/F₈₁₆ ratio. This enables highly sensitive and accurate ratiometric detection and imaging of H₂S in vivo	IR-HS: λ_ex = 680 nm; λ_em = 728 nm ICG: λ_ex = 780 nm; λ_em = 816 nm	[37]
Membrane and pH-sensitive fluorescent probes	A 1, 8-naphthalimide-based pH probe (ND6) with a pronounced fluorescence response between pH 6 and 7 was developed for live-cell imaging. It offers a potent means to study membrane dynamics and synaptic functions in neurons and secretory cells	λ_ex = 399 nm; λ_em = 514 nm	[38]
On-off fluorescent probe	The antibody-conjugated DAE@CB7 supramolecular probe enables reversible super-resolution imaging of intracellular proteins. CB7 encapsulation enhances the aqueous fluorescence and switching durability of the DAE photoswitch, allowing for repeated on/off cycling in cells under confocal and nanoscopy modes	λ_ex = 365 nm; λ_em = 519 nm/548 nm	[39]
pH-sensitive and hypoxia-responsive fluorescent probes	The semi-quinone probe Val-Hcys, activated by acidic pH through its amide side chain, serves as a sensitive sensor for hypoxic regions. It exhibits a rapid and strong (4-fold) fluorescence turn-on in hypoxic cells, confirming its utility for mapping the tumor microenvironment	λ_ex = 532 nm; λ_em = 559-574 nm	[40]
Ratio and pH-sensitive fluorescent probes	A guanine-quenched, dual-labeled DNA probe demonstrates high pH sensitivity (49-fold fluorescence change) upon hybridization. It serves as a general platform for simultaneously tracking oligonucleotide localization and reporting the local pH microenvironment, as evidenced by monitoring vesicular dynamics in living cells	FAM: λ_ex = 488 nm; λ_em = 515-520 nm Cy5: λ_ex = 633/640 nm; λ_em = 660-670 nm	[41]
Fe³⁺ sensitive fluorescent probe	CS-TPE is an AIE-active fluorescent probe that dually acts as a sensitive Fe³⁺ sensor and a potent antibacterial agent. It allows for real-time monitoring of Fe³⁺ levels and antibacterial efficacy, showcasing great theranostic potential	λ_ex = 365 nm; λ_em = 473 nm	[42]
Chlorite-sensitive fluorescent probe	JDK is a FRET-based fluorescent probe characterized by a large stokes shift and robust photostability. It serves as a highly sensitive tool for tracking hypochlorite in biological systems	λ_ex = 415 nm; λ_em = 475/580 nm	[43]
pH-responsive fluorescent probe	P24-mid is a pH-sensitive FRET biosensor that targets mitochondria and undergoes a reversible structural change, enabling real-time sensing of mitochondrial pH and monitoring of mitophagy	λ_ex = 545 nm; λ_em = 570/660-670 nm	[44]

Multimodal combination	Technical advantage	Research content	Typical case	Ref.
PET-CT	Integrating the ultra-high sensitivity of PET with the sub-millimeter anatomical resolution of CT; providing whole-body dynamic quantitative analysis and mechanistic modeling	Systemic pharmacokinetics of nanomedicines; quantitative analysis of targeting efficiency and organ distribution	⁸⁹Zr-labeled PEGylated liposomes: PET-CT quantitatively demonstrated anti-PEG antibody-mediated accelerated blood clearance, showing significantly reduced systemic exposure and enhanced hepatic accumulation. This data validated a PBPK model, establishing immune response as a critical regulator of nanocarrier fate beyond conventional EPR effects	[65]
PET-MRI	Combining PET molecular metabolic information with MRI's non-radiative soft tissue resolution; multi-parameter functional imaging	Nanodelivery to the brain/soft tissues; long-term dynamic monitoring of the integrity of the carrier	PLGA nanocapsules: enabled simultaneous quantification of whole-body biodistribution by PET and high-resolution hepatic tracking by MRI, collectively mapping the hepatobiliary clearance pathway of nanocarriers	[84]
MRI-FLI	MRI provides anatomical positioning of deep tissues, while FLI acquires information on the distribution and interactions at the cellular/subcellular level; no radiation, high spatial and temporal dynamic monitoring	Cell uptake mechanism and intracellular transport; the distribution of the carrier in the subcellular components of the organ	PEG-PCL micelles (encapsulating SPIONs + VivoTag 680XL): MRI-labeled micelles for liver accumulation, FLI reveals cell-specific uptake by the reservoir cells	[85]
PET-MALDI IMS	PET imaging reveals the overall distribution throughout the body, while MALDI IMS provides the spatial distribution of chemical components of drugs/vehicles at the µm level	Analysis of the correlation between drug release and carrier dissociation; dose heterogeneity in the microenvironment of tissues	Lipo680 liposomal antibiotic: PET tracked whole-body carrier distribution, while MALDI IMS spatially resolved drug and lipid components in infected tissues, validating tissue-level co-localization and confirming intact carrier delivery to the target site	[86]
MSI-IMC	MSI enables label-free, high-resolution spatial mapping of drugs (from nanocarriers) and their metabolites; IMC enables high-plex, single-cell mapping of nanocarrier distribution and tissue microenvironment	The distribution mechanism of nanomedicines in the tumor microenvironment; the correlation between carrier distribution and immune cells/matrix	PLA-PEG nanoparticles: MSI locates the free drug and the differential distribution of the nanoparticle drug at the tumor core/margin, IMC reveals its spatial association with the macrophage infiltration area	[87]

Multimodal combination	Technical advantage	Research content	Typical case	Ref.
PET-CT	Integrating the ultra-high sensitivity of PET with the sub-millimeter anatomical resolution of CT; providing whole-body dynamic quantitative analysis and mechanistic modeling	Systemic pharmacokinetics of nanomedicines; quantitative analysis of targeting efficiency and organ distribution	⁸⁹Zr-labeled PEGylated liposomes: PET-CT quantitatively demonstrated anti-PEG antibody-mediated accelerated blood clearance, showing significantly reduced systemic exposure and enhanced hepatic accumulation. This data validated a PBPK model, establishing immune response as a critical regulator of nanocarrier fate beyond conventional EPR effects	[65]
PET-MRI	Combining PET molecular metabolic information with MRI's non-radiative soft tissue resolution; multi-parameter functional imaging	Nanodelivery to the brain/soft tissues; long-term dynamic monitoring of the integrity of the carrier	PLGA nanocapsules: enabled simultaneous quantification of whole-body biodistribution by PET and high-resolution hepatic tracking by MRI, collectively mapping the hepatobiliary clearance pathway of nanocarriers	[84]
MRI-FLI	MRI provides anatomical positioning of deep tissues, while FLI acquires information on the distribution and interactions at the cellular/subcellular level; no radiation, high spatial and temporal dynamic monitoring	Cell uptake mechanism and intracellular transport; the distribution of the carrier in the subcellular components of the organ	PEG-PCL micelles (encapsulating SPIONs + VivoTag 680XL): MRI-labeled micelles for liver accumulation, FLI reveals cell-specific uptake by the reservoir cells	[85]
PET-MALDI IMS	PET imaging reveals the overall distribution throughout the body, while MALDI IMS provides the spatial distribution of chemical components of drugs/vehicles at the µm level	Analysis of the correlation between drug release and carrier dissociation; dose heterogeneity in the microenvironment of tissues	Lipo680 liposomal antibiotic: PET tracked whole-body carrier distribution, while MALDI IMS spatially resolved drug and lipid components in infected tissues, validating tissue-level co-localization and confirming intact carrier delivery to the target site	[86]
MSI-IMC	MSI enables label-free, high-resolution spatial mapping of drugs (from nanocarriers) and their metabolites; IMC enables high-plex, single-cell mapping of nanocarrier distribution and tissue microenvironment	The distribution mechanism of nanomedicines in the tumor microenvironment; the correlation between carrier distribution and immune cells/matrix	PLA-PEG nanoparticles: MSI locates the free drug and the differential distribution of the nanoparticle drug at the tumor core/margin, IMC reveals its spatial association with the macrophage infiltration area	[87]

现代成像技术在纳米制剂体内命运研究中的应用进展及展望

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董硕 ¹^,² , 李智楠 ¹^,² , 陈彦 ¹^,²^,^* , 李晓琦 ¹^,²^,^*

药学学报 | 综述 2026,61(4): 1120-1133

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药学学报 |综述 2026 , 61 (4) : 1120 -1133

现代成像技术在纳米制剂体内命运研究中的应用进展及展望

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董硕¹^,², 李智楠¹^,², 陈彦¹^,²^,^*, 李晓琦¹^,²^,^*

作者信息

¹南京中医药大学附属中西医结合医院, 江苏南京 210028

²江苏省中医药研究院, 中药组分与微生态研究中心, 江苏南京 210028

通讯作者:

陈彦, E-mail: ychen202@hotmail.com

李晓琦, Tel: 86-25-52362155, E-mail: xiaoqili8619@163.com

作者简介:

作者贡献:

董硕负责文献检索、图片制作、数据核对、综述初稿撰写及修改; 李智楠负责稿件修改及信息核对; 陈彦负责为综述撰写提供思路及基金支持; 李晓琦负责为综述撰写提供思路并对稿件进行修改和审校及基金支持。

Advances and perspectives of modern imaging technologies in the in vivo fate of nanomedicines

Shuo DONG¹^,², Zhi-nan LI¹^,², Yan CHEN¹^,²^,^*, Xiao-qi LI¹^,²^,^*

Affiliations

¹Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China

²Multi-component of Traditional Chinese Medicine and Microecology Research Center, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China

出版时间: 2026-04-12 doi: 10.16438/j.0513-4870.2025-0785

文章导航

摘要

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纳米制剂体内命运的不明确, 是阻碍其临床转化的核心瓶颈。近年来, 多种成像技术如荧光成像、光声成像、放射性成像、磁共振成像及多模态成像技术的飞速发展, 为纳米制剂体内行为(形态变化、释药动力学、分布与代谢等) 的实时、原位解析提供了强大工具。然而, 如何实现对纳米制剂体内形态变化的全过程动态监测及在生理微环境下的精准定量分析, 仍是纳米制剂体内研究面临的重大挑战。本文聚焦于纳米制剂体内命运研究最新进展, 对上述多种成像技术的基本原理、应用、优势及局限进行了综述, 并对创新探针设计、多种成像技术融合等未来发展方向进行了深入探讨。旨在为优化纳米递药系统设计、加速其临床转化提供坚实的理论与技术支撑。

关键词

纳米制剂 / 体内命运 / 药物递送 / 成像技术 / 临床转化

Abstract

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The elusive in vivo fate of nanomedicines represents a critical barrier to their clinical translation. Recent rapid advancements in imaging technologies, such as fluorescence imaging (FLI), photoacoustic imaging (PAI), radionuclide imaging (RI), magnetic resonance imaging (MRI), and multimodal imaging (MI) have provided powerful tools for real-time and in situ analysis of nanomedicine behavior in vivo, encompassing morphological evolution, drug release kinetics, distribution, metabolic and so on. However, significant challenges persist, particularly in continuously tracking dynamic morphological changes throughout their entire lifecycle and achieving accurate quantitative analysis within the physiological microenvironment. This review focuses on recent progress in understanding the in vivo fate of nanomedicines, systematically summarizing the fundamental principles, applications, advantages and limitations of these imaging technologies. It also highlights recent breakthroughs in utilizing these technologies to decipher the in vivo fate of nanomedicines and explores future perspectives, such as the development of innovative probes and the integration of multimodal imaging platforms. The objective is to offer robust theoretical and technical foundations for optimizing the design of nanodrug delivery systems and promoting their clinical translation.

Key words

nanomedicine / in vivo fate / drug delivery / imaging technique / clinical translation

引用本文

董硕, 李智楠, 陈彦, 李晓琦. 现代成像技术在纳米制剂体内命运研究中的应用进展及展望. 药学学报, 2026 , 61 (4) : 1120 -1133 . DOI: 10.16438/j.0513-4870.2025-0785

Shuo DONG, Zhi-nan LI, Yan CHEN, Xiao-qi LI. Advances and perspectives of modern imaging technologies in the in vivo fate of nanomedicines[J]. Acta Pharmaceutica Sinica, 2026 , 61 (4) : 1120 -1133 . DOI: 10.16438/j.0513-4870.2025-0785

正文

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纳米递药系统的快速发展显著提升了药物的靶向递送效率和治疗效果^[1]。然而, 其体内命运的复杂性及不明确性, 如药物递送过程中的形态演变、药物的体内释放动力学、制剂在靶部位或胞内的分布及代谢等, 都是制约其临床转化的关键问题^[2-4]。尤其在抗肿瘤领域, 纳米制剂在体内递送过程中可能发生药物的提前泄漏或制剂的提前解离, 从而导致药效降低并引发潜在安全隐患^[5]。因此, 发展具备高灵敏度和高时空分辨率的体内可视化技术, 对实现纳米制剂体内行为的全程、动态、精准示踪具有重大意义^[6]。

传统的离体表征技术(如透射电子显微镜、原子力显微镜) 虽能精细解析纳米粒子的初始形貌, 却无法实现对纳米粒子在生物体内的动态变化过程的实时监测^[1-7]。现代成像技术, 如荧光成像(fluorescence imaging, FLI)、光声成像(photoacoustic imaging, PAI)、放射性成像(radioactive imaging, RI)、磁共振成像(magnetic resonance imaging, MRI)、多模态成像(multimodal imaging, MI) 技术等在纳米药物的体内形态示踪与药物定量方面展现出明显优势和潜力(图1), 但同时也存在一定的局限性^[8-11]。FLI具有亚细胞水平的超高时空分辨率和实时动态监测能力, 但其组织穿透深度有限且易受生物组织自发荧光背景干扰^[12-14]; PAI虽融合了光学对比度与超声的深层组织穿透能力(厘米级) 的优势, 但其空间分辨率却受到声学探测器性能限制, 同时存在潜在热损伤风险, 且图像重建算法复杂^[15]; RI主要分为正电子发射断层扫描(positron emission tomography, PET) 和单光子发射计算机断层扫描(single-photon emission computed tomography, SPECT), 其具备pmol/fmol的检测灵敏度, 且在药代动力学研究上有一定优势, 但空间分辨率却相对较低且存在电离辐射的安全隐患^[16]; MRI能提供较高的软组织对比度, 无电离辐射, 安全性较高, 较适合长期重复监测, 但其体内组织成像通常要依赖造影剂增强信号, 设备成本高昂且扫描时间较长^[17,18]。现有研究表明, 单一模态的成像技术难以全面深入解析纳米制剂在复杂动态生理环境中的多维信息, 而MI技术通过整合互补单一模态技术的优势, 在纳米制剂的体内命运研究等各方面展现出巨大的发展潜力, 但由于其设备较复杂, 需要多源数据融合与解读, 因此其应用面临较大的挑战。

本文以纳米制剂的体内命运研究为着眼点, 聚焦于FLI、PAI、RI、MRI及MI等多种现代成像技术, 系统评述了各技术的核心原理与技术优势, 深入剖析了其在纳米制剂体内命运研究中的最新应用与局限, 并对未来发展趋势进行了多层次展望, 以期能促进更高效、更安全的纳米递药系统的设计研发, 以及推动其临床转化。

1　FLI技术

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1.1　技术原理与特点

FLI是一种基于荧光探针吸收特定波长激发光后发射更长波长荧光的非侵入性成像技术, 是高分辨率动态监测的核心技术^[19]。其关键过程包括特定波长光激发、电子能级跃迁、非辐射弛豫、荧光发射及信号捕获与图像生成。其超高时空分辨率、实时动态监测能力及高灵敏度使其成为研究纳米制剂胞内转运路径、亚细胞器定位及载体结构完整性的首选技术^[12,20,21]。但有限的组织穿透深度、生物组织自发荧光干扰及进行外源性荧光标记可能引入的潜在干扰使得其应用受到较大限制。

1.2　新型荧光探针

探针性能是决定FLI应用效能的关键因素。近年来, 新型探针的大量涌现极大拓展了其应用边界。

1.2.1　聚集导致猝灭探针

聚集导致猝灭(aggregation-caused quenching, ACQ) 探针材料, 如吲哚菁绿(indocyanine green, ICG) 及其衍生物、硼二吡咯(boron-dipyrromethene, BODIPY) 类染料, 在聚集状态下因分子间π-π堆积作用导致荧光猝灭^[22,23]。巧妙利用此特性, 该类探针被广泛应用于纳米载体的完整性示踪研究。当ACQ探针被包封于完整的纳米载体内部时, 因物理隔离抑制聚集而呈现强荧光; 当载体降解导致探针释放至水性环境中并发生聚集时, 荧光显著猝灭。这种“信号关闭”机制可特异性区分完整载体信号, 有效降低背景干扰。Xia等^[24]利用ACQ探针(P2/P4) 标记自微乳给药系统(self-microemulsifying drug delivery systems, SMEDDS), 通过探针的荧光猝灭特性克服了传统荧光标记的背景噪声问题, 特异性区分完整载体信号, 证实SMEDDS可跨上皮转运至淋巴和肝脏, 发现约2%~4%的SMEDDS通过淋巴途径转运, 主要蓄积于肝脏, 精准示踪了SMEDDS在胃肠道的滞留、脂解及跨上皮转运至淋巴和肝脏的过程。Wang等^[25]利用ICG类脂(DiD/DiI) 和荧光磷脂(Cy3/Cy5-DSPE) 双标记脂质体, 通过比较不同标记位点的荧光分布差异, 揭示了不同标记策略对正确解读纳米制剂肿瘤外渗和蓄积行为的潜在影响, 也反映了探针选择在纳米制剂体内分布解析中的重要性。现今, 近红外二区(near infrared-Ⅱ, NIR-Ⅱ, 1 000~1 700 nm) ACQ探针凭借更深的组织穿透能力和更低的自发荧光背景, 已成为活体深层成像研究的热点。

1.2.2　聚集诱导发光探针

聚集诱导发光(aggregation-induced emission, AIE) 探针材料, 如四苯基乙烯(tetraphenylethylene, TPE)、四苯基吡嗪(tetraphenylpyrazine, TPP), 在分散态(溶液) 荧光微弱, 而在聚集态或分子内运动受限时(如被纳米载体包封或束缚) 荧光显著增强(“点亮”特性)^[26-28]。此特性使其极其适用于无创、长时程示踪纳米载体的体内分布、肿瘤蓄积及结构完整性。Cao等^[29]研究发现, 相较于传统商用探针(如PKH-26外泌体示踪染料), AIE探针(DPA-SCP) 标记的外泌体等纳米囊泡展现出更长的体内滞留时间、更优的生物相容性, 且有效避免了因染料聚集淬灭导致的假阴性结果, 为长时程、高保真地示踪纳米囊泡的体内动力学行为提供了可靠工具。Qi等^[30]开发了一种新型的具有优异光稳定性和高信噪比的AIE纳米探针, 利用该探针通过活体成像清晰揭示了纳米粒子穿越血脑屏障并在脑瘤组织中累积的动态过程, 展现了AIEgens在示踪纳米制剂复杂体内分布中的显著优势。

1.2.3　共振能量转移探针

共振能量转移(förster resonance energy transfer, FRET) 探针发生在距离1~10 nm、光谱重叠 > 30%的供体-受体荧光对之间。当纳米载体结构变化(如解离、药物释放) 导致供受体间距改变时, FRET效率随之变化, 体现为供体荧光增强/受体荧光减弱(或反之)^[31]。常用FRET对包括DiO/DiI、DiD/DiR、Cy5.5/Cy7等花菁染料对, 以及量子点、上转换纳米粒等^[26,27,32]。利用精心设计的FRET对(如Cy5.5/Cy7), 可实时、原位监测聚合物胶束的组装/解组装动力学、药物释放速率等关键过程^[33,34]。Yang等^[35]使用Cy5.5和Cy7作为FRET对来监测聚合物胶束的形成和药物递送, 通过共价连接Cy5.5和Cy7实现对胶束组装过程中结构变化的实时示踪。Jutkova等^[6]以抗癌药物姜黄素(curcumin, CUR) 和光敏剂金丝桃素(hypericin, HYP) 为FRET对, 研究了CUR载入脂蛋白中的分子互作模式。

1.2.4　环境响应型智能探针

在遵循生物相容性和非免疫原性的基本原则, 并确保足够低的细胞毒性的前提下, 荧光探针的设计正朝着实现“更敏感、更具选择性、更少损伤和更好生物相容性”的目标迈进, 且不满足于荧光探针用于诊断的单一功能, 还通过分子修饰、连接基团等手段, 将荧光探针与药物分子连接, 合成了具有诊断和治疗等功能的荧光探针。离子敏感型(如Ca²⁺、Zn²⁺)、pH敏感型、可激活型(“开-关”)、比率型等智能荧光探针^[36], 能够响应特定的生理或病理微环境变化(如肿瘤微酸环境、特定酶活性升高、活性氧水平变化), 为在复杂生物微环境下精准解析纳米制剂的命运(如药物在靶点的特异性释放行为) 提供了强有力的工具(表1^[37-44])。

1.3　FLI的技术优势及在纳米制剂体内命运中的应用进展

相较于PET、SPECT、MRI等技术, FLI在时空分辨率、灵敏度及实时动态成像方面具有显著优势, 且操作相对简便, 比较适用于细胞及亚细胞水平的精细机制研究。技术层面, 一方面, FLI可提供极高的时空分辨率, 能够清晰示踪细微的生物结构及其快速动态变化过程, 表现出较好的实时动态成像特性, 能够以高时间分辨率(理论上可达亚秒级) 快速实时捕捉生物体内瞬间发生的生理或病理事件; 另一方面, FLI具有优异的分子特异性与高灵敏度, 通过特异性靶向设计, 荧光探针能够实现对特定生物标志物、细胞类型或分子事件的高选择性、高灵敏度检测。其分子尺寸相对较小, 易于进行化学修饰, 即使在复杂的生物微环境中也能维持高效的靶标(如特定蛋白质) 结合能力与识别特异性。尤其在近红外(near infrared, NIR) 波段, 荧光探针表现出在可见光范围内相对优异的组织穿透能力, 可实现一定深度的组织/器官无创活体成像。FLI操作相对简便, 成像过程通常无需复杂的图像重建算法。基于上述特性, 荧光探针已广泛应用于多种疾病的诊断、疾病进程的实时监测及生物标志物的检测, 正日益成为现代生物医学成像领域的核心工具之一, 推动着医学影像技术向更高效率与精度的方向发展。

综上, FLI凭借其超高时空分辨率, 通过ACQ、AIE、FRET及环境响应型等智能探针, 实现对纳米载体的结构完整性变化(如解离、降解等) 及纳米制剂在体内、器官、组织乃至胞内分布与转运路径的实时示踪, 在揭示纳米制剂早期体内行为, 特别是与细胞相互作用和胞内命运相关的过程中发挥着重要作用。

2　PAI技术

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2.1　成像原理与技术特点

PAI是一种结合了激光光子激发分子的光谱选择性与高分辨率超声成像技术的混合成像技术。使用短脉冲激光照射生物组织, 激光光子被组织内源性吸收体(如氧合/脱氧血红蛋白、黑色素) 或外源性造影剂(如纳米材料) 吸收, 导致瞬时局部温度升高, 热弹性膨胀, 产生宽带超声波(光声波), 这种现象称为光声效应。组织产生的光声波被超声换能器阵列接收, 通过重建算法生成反映组织内部光学吸收分布的高对比度断层图像, 上述整个过程即为PAI^[45]。PAI主要有两个方法实现重建图像, 第一种为直接成像, 是基于聚焦单元超声波换能器的机械扫描, 通常用于高分辨率光声显微镜(optical resolution photoacoustic microscope, OR-PAM)。第二种为重建图像, 是基于多元素换能器阵列的机械/电子扫描, 用于深层组织光声计算机断层扫描(photoacoustic computed tomography, PACT)。

PAI是一种新兴技术, 能够通过丰富的光学对比度增强超声成像, 并且可以作为一种便携式且相对低代价的独立模态, 用于区域性血管和其他光学对比剂的成像, 具有极大的应用和发展潜力。该技术的核心优势在于突破了纯光学成像的深度极限(在生物组织中可达数厘米), 同时兼具光学吸收对比度与超声的良好组织穿透性和空间分辨率; 无电离辐射风险, 且可通过多波长激发实现功能与分子成像(如血氧饱和度测绘、特定生物标志物表达可视化)。PAI同时也存在很多局限, 如空间分辨率通常低于高分辨率光学显微技术(受限于超声波长和探测器性能), 高功率激光潜在的局部热损伤风险需严格控制, 图像重建算法复杂且计算量大, 成像对比度高度依赖吸收体的浓度、分布与吸收特性^[46,47]。

2.2　PAI在纳米制剂体内命运中的应用进展

PAI凭借其独特的深度-分辨率平衡、多重对比度来源(内源性/外源性) 和无辐射安全性, 在肿瘤血管生成成像、药物分布可视化及炎症反应监测等领域展现出巨大的应用前景和独特价值。PAI能够实时、无创地追踪纳米制剂在体内的分布, 可用于监测纳米制剂对细胞功能的影响、评估纳米制剂在不同器官中的潜在毒性、评估纳米制剂的靶向性; 将光声成像技术与药代动力学研究相结合, 可用于确定纳米制剂的最佳给药剂量和给药频率, 从而促进纳米制剂临床转化。Liang等^[48]利用PAI定量监测经呼吸道雾化递送的纳米佐剂(ICG-牛血清白蛋白标记的氢氧化铝AlOOH纳米佐剂) 在小鼠气管层的动态转运过程, 为新型疫苗的开发与评价提供了关键数据。Uthaman等^[49]开发了靶向特异性受体CD44的纳米造影剂——ICG包封的透明质酸微泡, 利用PAI实现了对荷瘤小鼠体内肿瘤病灶的特异性识别与信号增强, 并结合随时间变化的PAI信号强度, 实现了对该纳米造影剂靶向富集效率及其在肿瘤部位滞留情况的定量评估。Jokerst等^[50]通过设计金纳米棒等智能响应型PAI探针, 实现了对纳米药物在肿瘤部位行为(富集与释放) 的实时、原位监测。该方法的核心原理在于利用探针聚集状态或微环境变化所引发光声信号的改变, 来直观反映药物的动态过程, 为利用PAI精准解析纳米制剂的释放动力学提供了关键技术支撑。

凭借厘米级的深层组织穿透能力, PAI可实现对纳米制剂在活体肿瘤等深部组织中宏观分布与蓄积的直接可视化, 为定量评估其靶向效率提供了关键依据。此外, PAI还可通过对血管结构与血氧饱和度等功能参数的成像, 间接反映纳米制剂对局部微环境及组织代谢状态的调节作用。尽管该技术在直接解析纳米载体自身形态变化方面分辨率有限, 但其独特的深部成像与功能信息获取能力, 为揭示纳米制剂在主要靶器官中的整体归宿提供了不可或缺的研究视角。

3　RI技术

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3.1　技术原理与特点

放射性成像技术通过将放射性同位素(如¹⁸F、^99mTc、⁶⁴Cu、¹¹¹In) 标记于药物分子或纳米载体材料, 利用其衰变释放的γ射线(SPECT) 或正电子湮灭产生的特征γ光子对(PET) 进行探测成像^[51], 从而非侵入性、动态、定量地可视化纳米制剂的吸收、分布、代谢和排泄(absorption, distribution, metabolism, and excretion, ADME) 全过程。其最核心的优势是极高的检测灵敏度(可达皮摩尔甚至飞摩尔水平), 允许使用亚治疗剂量的示踪剂(通常 < 10 nmol·kg^-1), 最大限度减少对正常生理过程的干扰, 是定量药代动力学研究的核心工具^[15]。放射性标记策略取决于载体材料的理化特性。有机纳米载体(脂质体、聚合物纳米粒等) 常采用¹¹C、¹⁸F等非金属同位素进行共价标记, 而⁶⁴Cu、⁸⁹Zr、^99mTc、¹¹¹In等金属同位素则需通过双功能螯合剂(如DOTA、NOTA、DTPA) 共价连接实现稳定标记, 或采用物理包埋/表面吸附法^[52]。而现代多功能纳米载体更支持多模态成像, 如PET/MRI双模态探针实现解剖与功能协同成像。

3.2　PET

PET基于正电子湮灭原理: 正电子发射核素(如 ¹⁸F、⁶⁴Cu、⁸⁹Zr) 衰变产生的正电子, 在组织中迁移数毫米距离(通常1~3 mm, 具体取决于核素能量) 后与电子湮灭, 产生一对运动方向相反、能量均为511 keV的γ光子; 探测器环通过符合探测技术捕获这些时间符合事件(即几乎同时到达的γ光子对), 经迭代重建算法(如有序子集最大期望值算法, OSEM) 生成示踪剂的三维分布图像^[53]。PET示踪剂的设计遵循“靶向分子-放射性核素”二元结构原则。靶向分子(如FDG中的脱氧葡萄糖结构) 决定生物靶点特异性, 放射性核素(如¹⁸F、⁶⁸Ga等) 提供信号源, 其中非金属核素(如¹¹C、¹³N等) 通过共价键直接标记, 金属类核素(如⁶⁴Cu、⁸⁹Zr等) 则需借助DOTA、NOTA等螯合剂实现稳定标记^[54]。以临床最常用的¹⁸F-FDG为例, 其通过葡萄糖转运体(recombinant glucose transporter 1, GLUT1) 在代谢活跃的肿瘤组织富集, 标准化摄取值(standardized uptake value, SUV) 可量化肿瘤糖酵解活性。PET的核心优势在于其皮摩尔级超高灵敏度, 支持微量药物示踪及绝对定量分析, 优异的时间分辨率(秒级) 可用于动态药代动力学建模。但其同时也存在电离辐射暴露(典型检查有效剂量5~10 mSv)、短半衰期核素(如¹⁵O: 2 min, ¹¹C: ≈ 20 min) 依赖现场回旋加速器产生, 以及相对较低的空间分辨率(临床全身扫描仪通常1~4 mm, 小动物专用系统可达 < 1 mm) 等局限性。PET/CT技术将功能代谢信息(PET) 与精细解剖结构(computed tomography, CT) 信息完美融合, 显著提升病灶定位精确性和诊断准确性; CT提供的衰减校正图(μ-map) 可有效减少定量误差; 采用低剂量CT扫描方案可将总辐射剂量控制在合理水平(如 < 15 mSv)^[55-59]。

PET/CT在纳米药物的体内命运研究中主要聚焦于纳米药物体内稳定性与药物释放动力学解析、靶向效率与生物屏障穿越机制及蛋白冠介导的纳米制剂体内命运调控机制研究3个方面问题^[60]。Ludtke等^[61]通过双标记策略(用¹⁸F分别标记载体聚乙烯亚胺PEI和荷载物siRNA) 研究PEI/siRNA复合物的体内命运, PET/CT动态成像结果表明PEI/siRNA复合物在体内被肝脾网状内皮系统快速捕获, 并观察到部分复合物在循环中发生解离释放出siRNA (¹⁸F-siRNA标记组在肾脏和膀胱的放射性显著高于背景水平)。Rajora等^[62]用 ⁶⁴Cu标记含卟啉脂质的微泡外壳(pDefs, Definity^®类似物), 通过PET/CT精确量化其在0~48 h内的全身生物分布, 发现其具有较长的血液循环时间(24~48 h) 和主要累积器官(肝脏、脾脏), 并证明PET结果比荧光成像能更精确地反映聚焦超声(focused ultrasound surgery, FUS) 对肿瘤外渗的增强效果(1.5倍vs荧光显示的2~15倍), 展现了PET在定量评估纳米制剂体内分布与行为中的准确性。Villacorta等^[63]采用¹³¹I标记牛血清白蛋白(bovine serum albumin, BSA) 构建聚乳酸-羟基乙酸共聚物纳米颗粒[poly (lactic-co-glycolic acid) nanoparticles, PLGA NPs] 的软蛋白冠(soft corona, SC) 与硬蛋白冠(hard corona, HC), 结合PET/CT动态成像技术, 精准揭示了两者在健康小鼠体内0~150 min的分布差异, 明确了软、硬蛋白冠在体内代谢途径的关键区别。

3.3　SPECT

SPECT通过物理准直器对单光子γ射线(如^99mTc: 140 keV, ¹¹¹In: 171 & 245 keV, ¹²³I: 159 keV) 进行空间定位和角度选择^[64]。其系统空间分辨率(R ≈ 1.5 ×准直孔直径) 通常低于PET (临床系统约8~10 mm, 专用小动物系统可达0.35~1 mm)。探测器核心通常为NaI (Tl) 闪烁晶体耦合光电倍增管, 通过步进旋转采集多角度投影数据, 经迭代重建算法(如OSEM) 获得三维断层图像^[65,66]。^99mTc因其近乎理想的物理性质(半衰期t_1/2 = 6 h, γ射线能量140 keV) 及便捷的⁹⁹Mo/^99mTc发生器获取方式, 占据临床SPECT应用的90%以上^[67]; 其他常用核素包括¹²³I (t_1/2 = 13 h) 常用于神经受体显像, ¹¹¹In (t_1/2 = 2.8 d) 适合长效监测。相较于PET/CT, SPECT的优势在于支持多核素同时成像(利用不同γ射线能谱进行区分)、设备购置与维护成本显著降低、^99mTc等常用核素标记相对简便等, 但其主要劣势是灵敏度远低于PET (通常低一个数量级或更多), 限制了其定量分析的精度和弱信号的检测能力^[64,66,68]。

SPECT在纳米制剂研发中主要用于解决体内生物分布定量(误差 < 15%)、靶向效率评估和治疗核素剂量学优化等问题。Jha等^[69]采用^99mTc标记金纳米簇(gold nanoparticles, GNPC), 获得高达4.7 ± 0.3的肿瘤/本底摄取比值(tumor-to-background ratio, TBR), 显著优于同期进行的荧光成像结果(TBR = 1.8 ± 0.2)。Jasim等^[70]利用¹¹¹In通过DOTA螯合物标记不同横向尺寸的聚乙二醇(polyethylene glycol, PEG) 功能化氧化石墨烯(graphene oxide-DOTA, GO-DOTA), SPECT/CT定量研究表明: 所有尺寸的氧化石墨烯(graphene oxide, GO) 主要被肝脏和脾脏摄取, 大尺寸GO在肺部表现出明显的尺寸依赖性滞留; 拉曼光谱证实所有尺寸的GO均能通过尿液以完整片层结构排泄, 且大尺寸GO的排泄速率较慢, 该研究清晰地揭示了纳米材料尺寸对其体内分布、滞留与清除行为的系统性影响。Chung等^[71]利用^99mTc标记间充质干细胞来源外囊泡, 首次精确量化其在肝脏和脾脏的清除半衰期(t_1/2 ≈ 1.2 h), 为优化给药剂量和频率提供了关键依据。

RI技术(如PET/SPECT) 对评估纳米制剂体内靶向效率、解析其在不同器官中的滞留与清除规律至关重要。一方面, 该技术具有超高灵敏度, 可对放射性标记的纳米制剂进行全身、动态、定量追踪, 实现对纳米制剂体内分布、蓄积与清除图谱的精准绘制; 另一方面, 通过双标记等策略, 该技术还可实现对纳米载体与所载药物体内行为的进一步区分, 揭示纳米制剂的解离动力学。综上, RI技术是连接纳米制剂微观递送机制与宏观体内行为的关键桥梁。

4　MRI

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4.1　成像原理与技术特点

MRI是一种利用强静磁场(B₀) 和射频(radio frequency, RF) 脉冲激发生物体组织内富含的氢原子核(质子), 并接收其弛豫过程中释放的射频信号, 经傅里叶变换算法重建, 生成高分辨率的体内组织解剖和功能图像的非侵入性成像技术^[72,73]。自1973年由Lauterbur首次实现以来, MRI技术已广泛应用于生物医学研究及临床诊断^[74,75]。MRI技术在纳米制剂体内研究中的核心优势在于能够实现无创性与长时程追踪, 观察纳米载体从给药到清除的全过程; 具有高空间分辨率与解剖背景, 能够提供亚毫米级分辨率的软组织解剖结构信息, 表现出极为优越的软组织对比度, 尤其适用于脑部、脊髓、心脏、关节及腹部器官成像, 精确定位纳米载体在器官、组织甚至细胞水平的富集位置(如肿瘤内部、特定脑区、肝脏区域); 成像过程不涉及X射线或γ射线, 无电离辐射, 安全性高, 适合长期、重复监测和特殊人群(如儿童、孕妇) 检查; 可通过调整序列参数获取T₁、T₂、扩散加权(diffusion weighted imaging, DWI)、灌注加权(perfusion weighted imaging, PWI) 等多种对比度图像, 同时提供丰富的解剖和功能信息, 如脑功能成像(functional magnetic resonance imaging, fMRI) 及弥散张量成像(diffusion tensor imaging, DTI) 等, 实现多参数、多功能成像; 可直接获取横断面、冠状面、矢状面及任意斜面的二维或三维图像, 具有多平面成像能力^[16,17,76]。但是设备昂贵、扫描时间长、对铁磁性金属植入物敏感、检查过程中噪声大, 以及钆基(Gd³⁺) 造影剂在肾功能不全患者中可能引发肾源性系统性纤维化(nephrogenic systemic fibrosis, NSF) 的风险等问题也给其应用带来了一定的局限性^[77]。

4.2　MRI在纳米制剂体内命运中的应用进展

MRI凭借其无辐射、可深层组织穿透及优越的软组织结构对比能力, 成为纳米递药系统体内研究中极为重要的工具和手段。随着高灵敏度造影剂、智能响应型探针和先进成像序列的发展, MRI从静态解剖成像转向动态分子示踪, 为纳米制剂的体内命运多维度实时解析提供了更多更独特的视角和技术。Said等^[78]利用共价连接Gd³⁺螯合物(Gd-DOTA) 标记的可注射自修复透明质酸水凝胶, 在4.7T MRI下成功追踪其脑内注射后的分布长达31天, 证实了Gd标记的稳定性及该技术在脑内递送系统分布监测的应用价值。Rong等^[79]构建了可同时递送治疗药物和MRI造影剂(Gd-DOTA) 的纳米粒乳糖酸修饰脂质体LA-LNPs, 实现了肝癌的治疗与MRI监测一体化。Ajayi等^[80]通过将SPIONs封装于阳离子PLGA纳米粒并偶联Alexa Fluor荧光探针, 对比MRI与FLI成像结果, 揭示了传统荧光标记的局限性: FLI仅能检测到约14天的信号, 且肝脏出现探针解离所致假阳性荧光; 而MRI显示载SPIONs纳米粒在关节腔内稳定滞留≥ 42天, 且未在肝脾检出, 证实其未被系统清除。该研究展现了MRI在实现深度穿透、无探针解离干扰的长时程精准示踪方面的独特优势。此外, 对纳米制剂体内分布异质性的认识是理解其体内命运的关键。早期临床研究^[81]利用核医学成像揭示了PEG化脂质体在患者肿瘤中的蓄积存在显著的瘤内和瘤间异质性, 该研究为后续采用高分辨率、多参数的MRI技术研究体内分布提供了重要的理论和技术基础, 有效促进了临床前研究中纳米制剂体内分布图谱的精准绘制, 及其与肿瘤血管功能、间质压力等微环境因素关系的定量研究, 为优化纳米制剂设计以克服体内递送屏障提供了关键依据。

MRI适用于对纳米制剂在脑、肝、肿瘤等复杂软组织中分布的长时程、高精度定位与追踪; 结合DWI与PWI等功能序列, 可实现纳米制剂对组织微环境(如局部细胞密度、血流灌注) 潜在影响的评估。尽管其在对纳米载体自身形态变化的直接示踪方面存在一定局限, 且多依赖于造影剂增强信号, 但所提供的精细解剖定位和长期动态信息, 对评价纳米制剂的靶向持久性、体内分布及安全性具有重要价值。

5　MI技术

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5.1　多模态策略与技术特点

在纳米药物递送研究中, 现行单一成像技术存在诸多局限, 如FLI虽能精确定位却易受组织深度局限, MRI具备卓越的解剖分辨能力但对分子层面的分析却较为欠缺, PET/SPECT灵敏度极高却牺牲了空间细节。为克服这些单模态技术各自的局限, 以获取更全面、更精准的生物信息, MI技术应运而生^[82]。该技术通过整合两种或多种互补的成像模态, 如FLI-MRI、PET-CT、PET-MRI、PAI-MRI等, 实现各模态之间的协同作用, 充分发挥各模态自身优势, 实现对纳米制剂体内分布、代谢及微环境响应等的多维、动态解析, 对推动纳米制剂体内命运研究起到了重要作用^[83]。MI的核心优势在于“优势互补, 协同增强”, 表2^[65,84-87]和图2^[84-87]列举了应用于纳米制剂体内命运研究的部分代表性多模态成像策略及其特点, 例如, 将FLI的高时空分辨率、分子特异性与MRI的深层穿透、优异软组织对比度相结合(FLI-MRI), 或将PAI的光学吸收对比度、功能成像能力与MRI的解剖细节相结合(PAI-MRI)^[88], 可在细胞/亚细胞水平精确定位纳米制剂的同时, 获取其在深层组织或器官中的宏观分布信息, 实现光学特异性和深层穿透/解剖定位的; 结合放射性成像(PET/SPECT) 的全身动态定量示踪能力与其他模态(如FLI、MRI) 的空间信息, 可更全面地检测纳米制剂的药代动力学(pharmacokinetics, PK) 特征和生物分布模式, 实现对纳米制剂的体内动态追踪和定量分析。同时, MI技术在疾病诊断方面也具有独特优势。将PET的超高灵敏度(检测限可达皮摩尔级) 和功能性代谢信息与CT的亚毫米级解剖结构信息(空间分辨率~0.5 mm) 相结合(PET-CT)^[89], 或与MRI优异的软组织分辨率和无辐射特性相结合(PET-MRI), 可显著提升对肿瘤等病灶的早期检出、精确定位、分期及疗效评估的准确性。PET-MRI尤其适用于神经系统和软组织肿瘤的研究。

5.2　MI策略选择及在纳米制剂体内命运研究中的应用

对纳米制剂体内命运(如分布、代谢及释放过程等) 的机制认知匮乏, 是制约其临床转化的关键瓶颈。传统单模态成像技术(FLI、MRI、PET等) 虽各具优势, 却难以同时满足体内研究对高灵敏度、高分辨率及深层组织穿透的需求。MI技术通过协同整合互补模态(如PET-MRI、FLI-PAI), 为动态、多维度解析纳米制剂的体内行为提供了强大工具, 在实现动态定量监测、推动智能探针创新及发展诊疗一体化平台等方面展现出突破性潜力, 有望成为加速纳米制剂临床转化的关键突破点^[90,91]。选择最优的多模态成像策略至关重要, 需系统考量纳米制剂自身的理化性质(如粒径、表面修饰、材料构成)、研究核心目标(如细胞追踪侧重分辨率, 全身分布依赖灵敏度)、生物安全性(如辐射暴露累积、对比剂潜在毒性) 及设备可及性与成本效益等多重因素。

在纳米制剂体内命运解析方面, MI技术通过整合互补的成像模式, 为系统解析纳米制剂的体内命运提供了强大工具。例如, FLI与MRI结合, 可在捕捉纳米载体亚细胞定位的同时, 获取其在深层组织中的宏观分布与解剖背景^[85]; PET与MRI融合, 既能实现全身药代动力学的灵敏定量, 又可获得高分辨的软组织结构和功能信息^[84]; PET-CT则兼具全身定量分布分析与精确解剖定位能力^[65]。这种多层次信息的有机融合, 使研究人员能够从时空与功能维度完整揭示纳米制剂的体内分布、载体形态演化、药物释放动力学及代谢清除途径, 从而全面阐释其体内命运。

尽管MI在揭示纳米制剂的体内命运方面具有显著优势并得到广泛应用, 但其发展仍面临严峻挑战^[92,93]。在技术层面, 现有技术难以完全规避各单模态的固有局限: 例如, PET/SPECT的空间分辨率通常为1~2 mm, 低于高分辨率解剖成像; 部分组合(如PET-CT) 会导致辐射剂量叠加, 显著增加受试者(患者或实验动物) 的总暴露量(典型临床全身PET-CT检查的有效剂量约为10~25 mSv); 此外, 不同模态图像间因分辨率差异、对比度机制不同、采集时间点不一致等导致的精确空间配准问题(尤其在活体动态研究中), 以及多源异构信息的高效融合、解读与生物学意义挖掘, 仍是当前面临的主要技术障碍。同时, 开发兼具高灵敏度、高特异性、良好生物相容性与可降解性, 并能被多种模态高效、稳定检测的“理想”纳米探针也极具挑战性。另一方面, 硬件一体化集成存在显著困难: 以PET-MRI为例, 需解决强静磁场和射频干扰对PET探测器性能的制约, 这导致设备成本极其高昂(价格约300~500万美元) 且单次扫描时间延长(常超过30 min)。

随着超灵敏探测器(如硅光电倍增管PET)、智能响应探针(如代谢通路激活型探针) 及人工智能驱动的大数据分析技术的发展, MI将逐步实现从“描述性成像”向“机制驱动型成像”的跃迁, 为纳米制剂的理性设计与临床转化提供不可替代的平台支撑^[94,95]。

6　结语与展望

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现代成像技术, 如FLI、PAI、RI、MRI及MI策略, 为纳米制剂的体内命运解析提供了日益强大且多样化的途径。FLI凭借亚细胞至纳米级的超高时空分辨率与实时动态成像能力, 在揭示纳米载体胞内转运机制、药物亚细胞释放位点及利用智能探针(ACQ、AIE、FRET、环境响应型) 精准示踪载体结构完整性方面发挥着关键作用, 但其有限的活体穿透深度与背景干扰是进行深层组织或全身尺度研究的掣肘。PAI创新性地融合了光学吸收对比度与声学的深层穿透能力, 在肿瘤血管网络成像、药物分布可视化及无辐射功能与分子成像方面展现出巨大潜力, 然而其空间分辨率(尤其深层)、潜在热效应控制及复杂图像重建仍需持续优化。RI作为高灵敏度定量药代动力学的核心工具, 在纳米制剂全身分布图谱测绘、靶向效率绝对量化及纳米复合物体内稳定性评估中不可或缺, 但其相对较低的空间分辨率、电离辐射暴露及设备/放射性核素的可及性与成本限制了其更广泛的应用。MRI提供卓越的软组织对比度与分辨率、无电离辐射安全性及丰富的多功能信息, 是进行长期监测、精细解剖定位和部分功能成像(如扩散、灌注) 的理想选择, 但对高性能造影剂开发(尤其需规避钆剂潜在风险) 的依赖、高昂的设备与运行成本及相对较低的时间分辨率是其面临的主要挑战。MI通过策略性地整合互补技术的优势(如PET-MRI、FLI-PAI、SPECT-CT), 是纳米制剂体内研究未来发展的主要方向, 有望为纳米制剂体内行为解析提供最全面的时空与功能信息, 但其设备复杂度、高昂成本、辐射剂量叠加(如含PET/SPECT/CT的组合) 及多源数据的有效融合与解读仍是亟待解决的关键问题。

尽管现代成像技术在纳米制剂的形态动态示踪、药物释放动力学研究、体内分布定量及靶向效率评估方面已取得显著进展, 但现有研究仍面临诸多挑战, 例如, 如何在复杂动态生理环境下实现超高灵敏度、超高分辨率(尤其在活体全身尺度) 的全程动态监测? 如何开发更安全(低毒、可降解)、更智能(微环境响应、可激活)、多功能(多模态兼容) 的探针以显著提升成像特异性、信噪比和信息维度?如何有效克服多模态融合中的技术壁垒(兼容性、配准) 与成本障碍? 如何将海量、多尺度的成像数据转化为对纳米制剂体内行为的深刻机制理解与精准预测能力? 上述种种难题对纳米制剂的体内命运解析具有重要作用, 未来可考虑从以下几个方面继续深入研究: ①新型探针与造影剂的研发: 如开发NIR-Ⅱ/Ⅲ区荧光探针以提升组织穿透深度与信噪比, 设计可响应肿瘤微环境特征的环境激活型智能探针, 开发超高弛豫率、高生物安全性MRI造影剂, 以及优化放射性标记策略等; ② MI深度优化与AI赋能: 利用深度学习、人工智能, 显著提升图像重建速度与质量, 实现多模态数据的智能化精准配准、深度融合与自动特征提取及生物学解读, 推动便携式、高度集成化、低成本多模态成像设备的研发, 促进技术普及; ③动态监测与精准建模结合: 将超分辨率显微技术(stimulated emission depletion, STED、photoactivated Localization Microscopy, PALM等) 与活体成像模态结合, 实现对纳米制剂亚细胞行为(如特定内吞途径、胞内细胞器定位、药物原位释放动力学) 的纳米级时空解析; 整合生理药代动力学(physiologically based pharmacokinetic, PBPK) 模型与药效动力学(pharmacodynamics, PD) 模型, 结合MI获取的时空分布数据, 构建“数字孪生”虚拟生物系统, 实现对纳米制剂体内命运的精准预测, 辅助虚拟筛选及优化个体化给药方案; ④兼顾生物安全性与临床转化潜力: 探针设计必须严格遵守高生物相容性、低系统毒性及可生物降解的核心原则, 通过表面工程化策略, 如优化PEG结构与密度、引入高亲和力靶向配体及仿生膜修饰等, 有效降低免疫原性、延长血液循环时间、增强靶向特异性, 从而减少探针的脱靶分布与潜在不良反应; ⑤推动诊疗一体化与精准纳米医学: 构建可智能响应肿瘤微环境、兼具精准成像与高效治疗(如化疗、放疗增敏、光热/光动力/声动力等) 功能的智能化纳米诊疗系统; 利用MI实时动态监控治疗反应, 指导临床用药方案的及时调整, 推动精准纳米医学的临床实现。

现代成像技术, 特别是MI技术的快速发展, 不仅深化了对纳米制剂体内命运的理解, 且极大推动了其临床转化。在药物研发体系中, MI技术在不同阶段均发挥着关键作用。在临床前研究阶段, MI技术通过提供纳米制剂吸收、分布、代谢、排泄(ADME) 的全面定量数据, 为制剂优化提供直接依据, 如利用PET-MRI评估不同处方的靶向效率与滞留特性; 在转化研究阶段, MI基于成像数据所获得的生物分布与药代动力学特征, 可筛选出最具优势的候选药物, 并对其在人体中的药代行为进行合理预测; 进入临床研究后, MI可用于患者分层、早期疗效评估和个体化给药方案优化, 为实现精准医疗提供支撑。随着纳米材料、分子影像、人工智能与生物医学工程的深度交叉融合, 纳米制剂的体内研究正逐步实现系统化、动态化、精准化及可视化。这一发展趋势将显著推进下一代纳米药物向更安全、高效与智能的方向发展, 并为癌症等重大疾病的精准诊疗体系构建奠定坚实的理论及技术基础。

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2026年第61卷第4期

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doi: 10.16438/j.0513-4870.2025-0785

接收时间：2025-07-08
首发时间：2026-09-21
出版时间：2026-04-12

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收稿日期：2025-07-08
修回日期：2025-12-02

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¹南京中医药大学附属中西医结合医院, 江苏南京 210028

²江苏省中医药研究院, 中药组分与微生态研究中心, 江苏南京 210028

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Classification	Application	Excitation/emission wavelength	Ref.
A ratiometric H₂S-activated fluorescent probe	HS-CG functions as a ratiometric near-infrared probe by exhibiting low F₇₂₈/F₈₁₆ in its native state. Upon hydrogen sulfide (H₂S) activation, the fluorescence at 728 nm increases sharply, leading to a marked rise in the F₇₂₈/F₈₁₆ ratio. This enables highly sensitive and accurate ratiometric detection and imaging of H₂S in vivo	IR-HS: λ_ex = 680 nm; λ_em = 728 nm ICG: λ_ex = 780 nm; λ_em = 816 nm	[37]
Membrane and pH-sensitive fluorescent probes	A 1, 8-naphthalimide-based pH probe (ND6) with a pronounced fluorescence response between pH 6 and 7 was developed for live-cell imaging. It offers a potent means to study membrane dynamics and synaptic functions in neurons and secretory cells	λ_ex = 399 nm; λ_em = 514 nm	[38]
On-off fluorescent probe	The antibody-conjugated DAE@CB7 supramolecular probe enables reversible super-resolution imaging of intracellular proteins. CB7 encapsulation enhances the aqueous fluorescence and switching durability of the DAE photoswitch, allowing for repeated on/off cycling in cells under confocal and nanoscopy modes	λ_ex = 365 nm; λ_em = 519 nm/548 nm	[39]
pH-sensitive and hypoxia-responsive fluorescent probes	The semi-quinone probe Val-Hcys, activated by acidic pH through its amide side chain, serves as a sensitive sensor for hypoxic regions. It exhibits a rapid and strong (4-fold) fluorescence turn-on in hypoxic cells, confirming its utility for mapping the tumor microenvironment	λ_ex = 532 nm; λ_em = 559-574 nm	[40]
Ratio and pH-sensitive fluorescent probes	A guanine-quenched, dual-labeled DNA probe demonstrates high pH sensitivity (49-fold fluorescence change) upon hybridization. It serves as a general platform for simultaneously tracking oligonucleotide localization and reporting the local pH microenvironment, as evidenced by monitoring vesicular dynamics in living cells	FAM: λ_ex = 488 nm; λ_em = 515-520 nm Cy5: λ_ex = 633/640 nm; λ_em = 660-670 nm	[41]
Fe³⁺ sensitive fluorescent probe	CS-TPE is an AIE-active fluorescent probe that dually acts as a sensitive Fe³⁺ sensor and a potent antibacterial agent. It allows for real-time monitoring of Fe³⁺ levels and antibacterial efficacy, showcasing great theranostic potential	λ_ex = 365 nm; λ_em = 473 nm	[42]
Chlorite-sensitive fluorescent probe	JDK is a FRET-based fluorescent probe characterized by a large stokes shift and robust photostability. It serves as a highly sensitive tool for tracking hypochlorite in biological systems	λ_ex = 415 nm; λ_em = 475/580 nm	[43]
pH-responsive fluorescent probe	P24-mid is a pH-sensitive FRET biosensor that targets mitochondria and undergoes a reversible structural change, enabling real-time sensing of mitochondrial pH and monitoring of mitophagy	λ_ex = 545 nm; λ_em = 570/660-670 nm	[44]

Classification

Structure

Application

Excitation/emission wavelength

Ref.

A ratiometric H₂S-activated fluorescent probe

HS-CG functions as a ratiometric near-infrared probe by exhibiting low F₇₂₈/F₈₁₆ in its native state. Upon hydrogen sulfide (H₂S) activation, the fluorescence at 728 nm increases sharply, leading to a marked rise in the F₇₂₈/F₈₁₆ ratio. This enables highly sensitive and accurate ratiometric detection and imaging of H₂S in vivo

IR-HS:
λ_ex = 680 nm;
λ_em = 728 nm
ICG:
λ_ex = 780 nm;
λ_em = 816 nm

[37]

Membrane and pH-sensitive fluorescent probes

A 1, 8-naphthalimide-based pH probe (ND6) with a pronounced fluorescence response between pH 6 and 7 was developed for live-cell imaging. It offers a potent means to study membrane dynamics and synaptic functions in neurons and secretory cells

λ_ex = 399 nm;
λ_em = 514 nm

[38]

On-off fluorescent probe

The antibody-conjugated DAE@CB7 supramolecular probe enables reversible super-resolution imaging of intracellular proteins. CB7 encapsulation enhances the aqueous fluorescence and switching durability of the DAE photoswitch, allowing for repeated on/off cycling in cells under confocal and nanoscopy modes

λ_ex = 365 nm;
λ_em = 519 nm/548 nm

[39]

pH-sensitive and hypoxia-responsive fluorescent probes

The semi-quinone probe Val-Hcys, activated by acidic pH through its amide side chain, serves as a sensitive sensor for hypoxic regions. It exhibits a rapid and strong (4-fold) fluorescence turn-on in hypoxic cells, confirming its utility for mapping the tumor microenvironment

λ_ex = 532 nm;
λ_em = 559-574 nm

[40]

Ratio and pH-sensitive fluorescent probes

A guanine-quenched, dual-labeled DNA probe demonstrates high pH sensitivity (49-fold fluorescence change) upon hybridization. It serves as a general platform for simultaneously tracking oligonucleotide localization and reporting the local pH microenvironment, as evidenced by monitoring vesicular dynamics in living cells

FAM:
λ_ex = 488 nm;
λ_em = 515-520 nm
Cy5:
λ_ex = 633/640 nm;
λ_em = 660-670 nm

[41]

Fe³⁺ sensitive fluorescent probe

CS-TPE is an AIE-active fluorescent probe that dually acts as a sensitive Fe³⁺ sensor and a potent antibacterial agent. It allows for real-time monitoring of Fe³⁺ levels and antibacterial efficacy, showcasing great theranostic potential

λ_ex = 365 nm;
λ_em = 473 nm

[42]

Chlorite-sensitive fluorescent probe

JDK is a FRET-based fluorescent probe characterized by a large stokes shift and robust photostability. It serves as a highly sensitive tool for tracking hypochlorite in biological systems

λ_ex = 415 nm;
λ_em = 475/580 nm

[43]

pH-responsive fluorescent probe

P24-mid is a pH-sensitive FRET biosensor that targets mitochondria and undergoes a reversible structural change, enabling real-time sensing of mitochondrial pH and monitoring of mitophagy

λ_ex = 545 nm;
λ_em = 570/660-670 nm

[44]

Multimodal combination	Technical advantage	Research content	Typical case	Ref.
PET-CT	Integrating the ultra-high sensitivity of PET with the sub-millimeter anatomical resolution of CT; providing whole-body dynamic quantitative analysis and mechanistic modeling	Systemic pharmacokinetics of nanomedicines; quantitative analysis of targeting efficiency and organ distribution	⁸⁹Zr-labeled PEGylated liposomes: PET-CT quantitatively demonstrated anti-PEG antibody-mediated accelerated blood clearance, showing significantly reduced systemic exposure and enhanced hepatic accumulation. This data validated a PBPK model, establishing immune response as a critical regulator of nanocarrier fate beyond conventional EPR effects	[65]
PET-MRI	Combining PET molecular metabolic information with MRI's non-radiative soft tissue resolution; multi-parameter functional imaging	Nanodelivery to the brain/soft tissues; long-term dynamic monitoring of the integrity of the carrier	PLGA nanocapsules: enabled simultaneous quantification of whole-body biodistribution by PET and high-resolution hepatic tracking by MRI, collectively mapping the hepatobiliary clearance pathway of nanocarriers	[84]
MRI-FLI	MRI provides anatomical positioning of deep tissues, while FLI acquires information on the distribution and interactions at the cellular/subcellular level; no radiation, high spatial and temporal dynamic monitoring	Cell uptake mechanism and intracellular transport; the distribution of the carrier in the subcellular components of the organ	PEG-PCL micelles (encapsulating SPIONs + VivoTag 680XL): MRI-labeled micelles for liver accumulation, FLI reveals cell-specific uptake by the reservoir cells	[85]
PET-MALDI IMS	PET imaging reveals the overall distribution throughout the body, while MALDI IMS provides the spatial distribution of chemical components of drugs/vehicles at the µm level	Analysis of the correlation between drug release and carrier dissociation; dose heterogeneity in the microenvironment of tissues	Lipo680 liposomal antibiotic: PET tracked whole-body carrier distribution, while MALDI IMS spatially resolved drug and lipid components in infected tissues, validating tissue-level co-localization and confirming intact carrier delivery to the target site	[86]
MSI-IMC	MSI enables label-free, high-resolution spatial mapping of drugs (from nanocarriers) and their metabolites; IMC enables high-plex, single-cell mapping of nanocarrier distribution and tissue microenvironment	The distribution mechanism of nanomedicines in the tumor microenvironment; the correlation between carrier distribution and immune cells/matrix	PLA-PEG nanoparticles: MSI locates the free drug and the differential distribution of the nanoparticle drug at the tumor core/margin, IMC reveals its spatial association with the macrophage infiltration area	[87]

Multimodal combination

Technical advantage

Research content

Typical case

Ref.

PET-CT

Integrating the ultra-high sensitivity of PET with the sub-millimeter anatomical resolution of CT; providing whole-body dynamic quantitative analysis and mechanistic modeling

Systemic pharmacokinetics of nanomedicines; quantitative analysis of targeting efficiency and organ distribution

⁸⁹Zr-labeled PEGylated liposomes: PET-CT quantitatively demonstrated anti-PEG antibody-mediated accelerated blood clearance, showing significantly reduced systemic exposure and enhanced hepatic accumulation. This data validated a PBPK model, establishing immune response as a critical regulator of nanocarrier fate beyond conventional EPR effects

[65]

PET-MRI

Combining PET molecular metabolic information with MRI's non-radiative soft tissue resolution; multi-parameter functional imaging

Nanodelivery to the brain/soft tissues; long-term dynamic monitoring of the integrity of the carrier

PLGA nanocapsules: enabled simultaneous quantification of whole-body biodistribution by PET and high-resolution hepatic tracking by MRI, collectively mapping the hepatobiliary clearance pathway of nanocarriers

[84]

MRI-FLI

MRI provides anatomical positioning of deep tissues, while FLI acquires information on the distribution and interactions at the cellular/subcellular level; no radiation, high spatial and temporal dynamic monitoring

Cell uptake mechanism and intracellular transport; the distribution of the carrier in the subcellular components of the organ

PEG-PCL micelles (encapsulating SPIONs + VivoTag 680XL): MRI-labeled micelles for liver accumulation, FLI reveals cell-specific uptake by the reservoir cells

[85]

PET-MALDI
IMS

PET imaging reveals the overall distribution throughout the body, while MALDI IMS provides the spatial distribution of chemical components of drugs/vehicles at the µm level

Analysis of the correlation between drug release and carrier dissociation; dose heterogeneity in the microenvironment of tissues

Lipo680 liposomal antibiotic: PET tracked whole-body carrier distribution, while MALDI IMS spatially resolved drug and lipid components in infected tissues, validating tissue-level co-localization and confirming intact carrier delivery to the target site

[86]

MSI-IMC

MSI enables label-free, high-resolution spatial mapping of drugs (from nanocarriers) and their metabolites; IMC enables high-plex, single-cell mapping of nanocarrier distribution and tissue microenvironment

The distribution mechanism of nanomedicines in the tumor microenvironment; the correlation between carrier distribution and immune cells/matrix

PLA-PEG nanoparticles: MSI locates the free drug and the differential distribution of the nanoparticle drug at the tumor core/margin, IMC reveals its spatial association with the macrophage infiltration area

[87]