Recent Developments of Supramolecular Metal-based Structures for Applications in Cancer Therapy and Imaging

Abstract

The biomedical application of discrete supramolecular metal-based structures, including supramolecular coordination complexes (SCCs), is still an emergent field of study. However, pioneering studies over the last 10 years demonstrated the potential of these supramolecular compounds as novel anticancer drugs, endowed with different mechanisms of action compared to classical small-molecules, often related to their peculiar molecular recognition properties. In addition, the robustness and modular composition of supramolecular metal-based structures allows for an incorporation of different functionalities in the same system to enable imaging in cells via different modalities, but also active tumor targeting and stimuli-responsiveness. Although most of the studies reported so far exploit these systems for therapy, supramolecular metal-based structures may also constitute ideal scaffolds to develop multimodal theranostic agents. Of note, the host-guest chemistry of 3D self-assembled supramolecular structures - within the metallacages family - can also be exploited to design novel drug delivery systems for anticancer chemotherapeutics. In this review, we aim at summarizing the pivotal concepts in this fascinating research area, starting with the main design principles and illustrating representative examples while providing a critical discussion of the state-of-the-art. A section is also included on supramolecular organometallic complexes (SOCs) whereby the (organic) linker is forming the organometallic bond to the metal node, whose biological applications are still to be explored. Certainly, the myriad of possible supramolecular metal-based structures and their almost limitless modularity and tunability suggests that the biomedical applications of such complex chemical entities will continue along this already promising path.

Keywords: supramolecular metal-based complexes - metallacages - cancer - drug delivery - theranostics..

Figure 1

Different types of metal-based assemblies (examples): Coordination polymers and networks formed by divergent (left) and discreet supramolecular complexes formed by convergent combinations of metal nodes and organic linkers (right).

Figure 2

Classification of supramolecular organometallic assemblies into different groups: (A) Assemblies with organometallic nodes (i.e. carbon metal bond within metal node) -. (B) Assemblies with organometallic linker molecules (i.e. carbon metal bond within linker molecule) , . (C) Supramolecular Organometallic Complexes (SOCs, i.e. assemblies with a carbon metal bond between node and linker) , , . Green: location of organometallic bond.

Figure 3

A) Schematic representation of a [Pt₃L₃]⁶⁺ hexagon exo-functionalised with three moieties of a Pt(IV) prodrug . B) The amphiphilic polymer Pt-PAZMB-b-POEGMA, containing glutathione (GSH)-responsive deblock copolymers as the arms and an aggregation-induced emissive Pt(II) metallacycle as the core unit .

Figure 4

A) Schematic representation and corresponding X-ray structures of a cylindrical [Ni₂L₃]⁴⁺ helicate (CCDC n° 722438) and a [Fe₂L₃]⁴⁺ helicate (CCDC n° 622770); B) Schematic representation of a multinuclear Pt(II) metallacycle acting as quadruplex binder and telomerase inhibitor and its adduct with a G4 structure studied by molecular modeling (Adapted with permission from 'J. Am. Chem. Soc. 2008, 130 (31), 10040-10041'. Copyright 2008 American Chemical Society.); C) Schematic representation of a Ru₈ cage bearing porphyrin ligands studied as nucleic acid binder .

Figure 5

X-ray structures of rectangles (A) ⁴⁺ and (B) ⁴⁺ from ref. .

Figure 6

A) Schematic representation and corresponding X-ray structure (CCDC n° 673229) of a [[Ru₂L']₃L₂]⁶⁺ cage encapsulating [Pt^II(acac)₂] (acac = acetylacetonato) . B) Schematic representation and corresponding X-ray structure (CCDC n° 853227) of an exo-functionalised [Pd₂L₄]⁴⁺ metallacage encapsulating two equivalents of cisplatin . C) Schematic representation and corresponding X-ray structure (CCDC n° 902397) of a [Pd₂L₄]⁴⁺ capsule encapsulating two equivalents of corannulene .

Figure 7

Schematic representations of A) two arene-Ru(II) metallacycles (left: 2D rectangular geometry; right: 'metalla-bowl' geometry) and of B) a rhomboidal Pt(II) metallacycle, studied in vivo for their anticancer properties.

Figure 8

A) Schematic diagrams of the MNPs serving as a multifunctional theranostic platform. Structures of TPP, cPt, DSTP, M, mPEG-b-PEBP, and RGD-PEG- b-PEBP . B) Ex vivo image of the main organs separated from U87MG tumor-bearing mice at 24 h post injection of MNPs. C) PET image of U87MG tumor-bearing nude mice at 2, 4, 6, 12, 24 and 48 h post injection of ⁶⁴Cu@MNPs (150 μCi). The white circle denotes the tumor site. D) In vivo T₁-weighted axial MRI images (7T) of the mice pre-injection and after injection of Mn@MNPs. The white circle denotes the tumor site. (Adapted with permission from 'Nature Comm. 2018, 9, 4335-4335', licensed under a Creative Commons Attribution 4.0 International License. Copyright 2018 Springer Nature Publishing AG.)

Figure 9

A) Structure of anion-binding Co^III₄L₆ cages shown exemplarily at the X-ray structure of a tetrahedral SCC, featuring an encapsulated ReO₄^- (CCDC n° 1864366) ; B) Comparison of free [^99mTc]TcO₄^- uptake in naïve mice (left) vs SCC-encapsulated [^99mTc]TcO₄^- (right) monitored by SPECT imaging . Encapsulation results in reduced thyroid and stomach uptake, and increased liver uptake. Images are maximum intensity coronal projections. S = Stomach, Th = Thyroid, L = Liver. (Adapted with permission from 'J. Am. Chem. Soc. 2018, 140, 16877-16881'. Copyright 2018 American Chemical Society.)