Nanoscale Metal–Organic Layers for Biomedical Applications

Abstract

Conspectus As a monolayer version of nanoscale metal organic frameworks (nMOFs), nanoscale metal–organic layers (nMOLs) have recently emerged as a novel class of two-dimensional (2D) molecular nanomaterials. nMOLs are built from metal-oxo secondary building units (SBUs) with suitable coordination modes and organic linkers with proper geometries in a bottom-up fashion by carefully controlling the reaction temperature, capping agents, water concentration, and other parameters. M6-BTB and related nMOLs are formed by linking M6(μ3-O)4(μ3-OH)4 (M = Zr4+, Hf4+, Ce4+) SBUs and planar tricarboxylate bridging ligands such as 1,3,5-benzene-tribenzoate (BTB), while M12-nMOLs are constructed from M12(μ3-O)8(μ3-OH)8 (μ2-OH)6 (M = Zr4+, Hf4+) SBUs and linear dicarboxylate ligands such as 5,15-di­(p-benzoato)­porphyrin (DBP). Mechanistic studies revealed the important roles of capping agents and water on the growth of nMOLs and the stepwise growth process involving the partial hydrolysis of metal ions to form metal-oxo clusters with capping agents and the subsequent replacement of capping agents by bridging ligands. The 2D nature of nMOLs facilitates the postsynthetic modification of bridging ligands and the exchange of capping agents to simultaneously incorporate multi­functional­ities into nMOLs. In this Account, we discuss the design principles, growth mechanisms, and postsynthetic functionalization strategies for nMOLs and summarize our research efforts to design nMOLs for various biological and biomedical applications. We first outline the strategies for the design and synthesis of M6- and M12-nMOLs via a dimensional reduction strategy and discuss the growth mechanisms of nMOLs. We then highlight the methods for the postsynthetic functionalization of nMOLs. We demonstrate the application of nMOLs in two broad categories. We first show the design and development of nMOLs for radiotherapy–radiodynamic therapy (RT–RDT) and further combination with checkpoint blockade immunotherapy. The evolution of Hf6-nMOLs to Hf12-nMOLs illustrates the control of nMOL morphology and photosensitizer loading for optimal RT–RDT effects. The nMOL-mediated RT–RDT is further combined with checkpoint blockade cancer immunotherapy to enable the treatment of systemic diseases via local X-ray irradiation. We next demonstrate nMOLs as a versatile platform for ratiometric sensing/imaging and drug delivery. The easily accessible sites on SBUs and ligands in nMOLs provide conjugation sites for multifunctional sensors and drugs, allowing for simultaneous ratiometric sensing of the pH and oxygen concentration or pH and glutathione concentration in mitochondria as well as highly effective photodynamic therapy with insoluble conjugated zinc phthalocyanine. We discuss the limitations of currently available nMOLs in terms of a lack of structural diversity and lower stability compared to nMOFs. We also point out the untapped potential of using the inherent hierarchy of SBU and bridging ligand structures to integrate multiple functionalities for synergistic func...

A 2D Nanoradiosensitizer Enhances Radiotherapy and Delivers STING Agonists to Potentiate Cancer Immunotherapy

“…Hf 12 ‐Ir MOL has exchangeable sites on the Hf 12 SBUs for further functionalization. [ 31 ] The weakly‐bound TFA capping groups on the Hf 12 SBUs can be substituted by other small molecules with strongly‐binding carboxyl groups or phosphate groups. [ 23 ] We hypothesized that phosphate groups on cGAMP could bind to Hf 12 SBUs by replacing TFA groups to afford cGAMP/MOL ( Figure a,c).…”

“…[47][48][49] As radiosensitizing effects correlate to the surface areas of the nanoparticles, 2D MOL particles maximally increase the surface area for enhanced radiosensitization and ROS diffusion. [31] The linking of high-Z secondary building units with photosensitizing ligands in crystalline MOL particles further enabled RT-RDT to not only generate multiple ROS for stronger cancer cell killing but also induce ICD to release TAAs and DAMPs. [22,38] In addition, the high density of exchange sites on the MOL allows the delivery of cGAMP for TME activation to enhance the antitumor efficacy of MOL-mediated RT-RDT.…”

“…[50][51][52][53][54][55] MOFs and MOLs have been applied to load small molecules or macromolecules by pore loading or surface modification. [31,56,57] By coordinatively binding cGAMP to SBUs on the MOL, cGAMP/MOL increased the intracellular uptake and intratumoral retention of cGAMP by more than an order of magnitude. cGAMP/MOL also enabled the controlled release of cGAMP inside immune cells by taking advantage of the large difference in intracellular and extracellular phosphate concentrations.…”

Recent advances in metal-organic frameworks for X-ray detection

“…Meanwhile, nanoscale MOFs can be used for X-ray dynamic therapy to treat deep-seated tumors [75]. By synthesizing novel non bio-toxicity nanoscale MOFs with X-ray-excited photodynamic chemical reaction ability ( 1O 2 or •OH generation), several kinds of cancer cells can be killed in vitro and in vivo [76,77].…”

Dimensional Reduction Enhances Photodynamic Therapy of Metal–Organic Nanophotosensitizers

“…Nanoscale metal–organic frameworks (nMOFs) have recently emerged as a novel class of nanophotosensitizers. − In nMOFs, PSs are periodically arranged as ligands in three-dimensional (3-D) crystalline frameworks to afford high PS loadings and are spatially isolated by metal–oxo secondary building units (SBUs) to prevent self-quenching. − We hypothesized that the PDT performance of nMOFs could be further enhanced via dimensional reduction to increase the energy transfer from photoexcited PSs to oxygen molecules and the diffusion of singlet oxygen ( 1 O 2 ) from the nanophotosensitizers to intracellular organelles for maximal cytotoxicity. − …”