Supramolecular assembly is ubiquitous in living systems, thus enabling construction of a range of fascinating structures with intricate biological functions that meet the essential needs of organisms [1, 2]. A typical example is metal-organic coordination assembly: in the light-harvesting complexes of photosynthetic systems, chromophores with metal-ion centers are assembled via coordination with histidineimidazole in proteins, thus forming particular arrangements that absorb light energy [3]. Furthermore, phenolic-iron coordination bonding has been implicated in various properties (e.g., mechanical and adhesive functions) of mussel byssus cuticle [4]. These natural phenomena may provide valuable inspiration for developing metal-organic-assembly materials and strategies for biomedical applications [5–7].
Given the unique chemistry and biological functions of iron, recent research endeavors have paid particular attention to iron-based supramolecular assembly in vitro and in vivo, aiming at the development of desirable agents and nanomaterials for disease diagnosis and treatment [8, 9]. In in biological systems, iron ions are usually bound to molecules with electron-donating atoms (e.g., oxygen and sulfur). This characteristic has inspired pioneering work on in vitro nanomaterial assembly using iron-based coordination, wherein interactions between FeIII and various oxygen- and/or sulfur-containing therapeutics lead to the assembly of multifunctional theranostic nanoparticles. For example, co-assembly of photosensitizers (sinoporphyrin sodium) and chemotherapeutics (doxorubicin) with FeIII has enabled the formulation of metal-organic nanodrugs [10]. The reversible nature of coordination bonding has enabled biological barriers to nanoparticle delivery to be overcome. The metal-organic nanodrugs maintain their structures in the blood circulation under neutral pH (∼ 4) but steadily decompose into small drug complexes under the acidic (pH 5.5) tumor microenvironment, thereby enhancing intratumor drug permeability for effective image-guided photodynamic/chemo combinational therapy.
To address the limited tissue penetration of photodynamic therapeutics, researchers have engineered metal-organic nanostructures for cancer sonodynamic therapy using ultrasound, whose deep tissue penetration triggers generation of reactive oxygen species (ROS), which kill cancer cells [11, 12]. Several smart cancer sonotheranostics have been fabricated through co-assembly of FeIII and organic sonosensitizers with a sulfonate group [e.g., meso-tetrakis (4-sulfonatophenyl) porphyrin, indocyanine green (ICG)], and other compounds and therapeutics [13, 14]. In a recent study, Lin et al. have reported microbubbles (MBs) loaded with FeIII/ICG coordination complexes for cancer sonotheranostics [14]. Ultrasound not only triggers in situ conversion of MBs into small FeIII/ICG nanocomplexes with better tissue penetration but also induces transient opening of leaky tumor vessels. These multiple benefits contribute to a 1.3-fold enhancement in tumoral deposition of FeIII/ICG@MBs, thus increasing ultrasound-mediated ROS generation for tumor ablation.
Encouraged by the positive results regarding in vitro material assembly, Lin et al. subsequently applied in vivo iron-based assembly to noninvasive diagnosis and treatment of iron-overload diseases ( Figure 1 ) [15]. Iron-overloaded organs have abundant FeIII ions available for assembly with administered organic ligands and/or dyes. Such in situ assembly can alter iron and ligand forms (e.g., from free to aggregated), thus amplifying alterations in molecular-imaging signals and enabling iron detection. Specifically, the authors have designed an elegant ICG/lecithin (ICG/Leci) system in which the interaction between ICG and local FeIII in the iron-overloaded liver is accelerated by co-administered Leci, thus forming FeIII/ICG/Leci aggregates. The free-to-aggregate conversion by the ICG/Leci system offers several notable advantages as multimodal theranostics: ⅰ) the FeIII/ICG/Leci aggregation obstructs the water exchange rate with FeIII and significantly decreases MRI signals in the iron-overloaded liver, thereby enabling the detection of FeIII through MRI; ⅱ) π-π stacking between ICG and Leci results in UV-visible absorption at 890 nm, thus allowing for FeIII quantification through photoacoustic imaging with strong contrast and high sensitivity; ⅲ) the FeIII/ICG/Leci assembly alters the iron excretion pathway and facilitates twice the iron depletion of deferoxamine (a commonly investigated iron chelator), thus achieving better kinetics while avoiding toxicity.
Schematic graph showing recent advances in iron-based coordination assembly, from nanotherapeutic assembly in vitro to in situ iron-based assembly in vivo for iron quantification and depletion [15].
This study provides a promising example of how iron-based coordination assembly can be leveraged to address unmet clinical needs. Liver biopsy, which remains the current gold standard for diagnosis of iron-overload diseases, is limited by sampling errors due to the nonuniform iron distribution in organs, and the possible risk of hospitalization (1–3%) [16]. Although MRI is becoming a more acceptable approach, its low sensitivity restricts its accuracy in iron quantification. The developed ICG/Leci system, with its enhanced MRI sensitivity and superior photoacoustic-imaging contrast, may aid in addressing the above issues and providing accurate, noninvasive diagnosis of iron-overloaded liver. When coupled with augmented iron depletion, the ICG/Leci system offers a powerful imaging-guided theranostic platform for iron-overload disorders. Interdisciplinary knowledge is highly desired for nanomedicine design, in which the properties of agents and nanomaterials are tailored according to biological and medical needs. This successful work is expected to inspire the development of more smart probes based on metal-organic assembly for diagnosis and therapeutic purposes.