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BACKGROUND: Prostate cancer affects 1 in 6 men, and it is the secondleading cause of cancer-related death in American men. Surgery is one of the main treatment modalities for prostate cancer, but it often results in incomplete resection margins or complete resection that leads to nerve damage and undesirable side effects. In the present work, we have developed a new bimodal tracer, NODAGA-sCy7.5 PSMAi (prostate-specific membrane antigen inhibitor), labeled with the true matched theranostic pair 64Cu/67Cu and a near-infrared fluorescent dye. This agent could potentially be used for concomitant PET imaging, optical surgical navigation, and targeted radiopharmaceutical therapy. METHODS: A prostate-specific membrane antigen (PSMA)-targeting urea derivative was conjugated to NODAGA for copper radiolabeling and to the near-infrared fluorophore sulfo-Cy7.5 (sCy7.5). Binding studies were performed in PSMA-positive PC-3 PIP cells, as well as uptake and internalization assays in PC-3 PIP cells and PSMA-negative PC-3 wild type cells. Biodistribution studies of the 64Cu-labeled compound were performed in PC-3 PIP- and PC-3 tumor-bearing mice, and 67Cu biodistributions of the agent were obtained in PC-3 PIP tumor-carrying mice. PET imaging and fluorescence imaging were also performed, using the same molar doses, in the two mouse models. RESULTS: The PSMA conjugate bound with high affinity to PSMA-positive prostate cancer cells, as opposed to cells that were PSMA-negative. Uptake and internalization were rapid and PSMA-mediated in PC-3 PIP cells, while only minimal non-specific uptake was observed in PC-3 cells. Biodistribution studies showed specific uptake in PC-3 PIP tumors, while accumulation in PC-3 tumor-bearing mice was low. Furthermore, tumor uptake of the 67Cu-labeled agent in the PC-3 PIP model was statistically equivalent to that of 64Cu. PET and fluorescence imaging at 0.5 nmol per mouse also demonstrated that PC-3 PIP tumors could be clearly detected, while PC-3 tumors showed no tumor accumulation. CONCLUSIONS: NODAGA-sCy7.5-PSMAi was specific and selective in detecting PSMA-positive, as opposed to PSMA-negative, tumors in mouse models of prostate cancer. This bioconjugate could potentially be used for PET staging with 64Cu, targeted radiopharmaceutical therapy with 67Cu, and/or image-guided surgery with sCy7.5.
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We report on a two-dimensional hexagonal "honeycomb" network comprising barium-seamed metal-organic nanocapsules involving a hexameric assembly of pyrogallol[4]arene ligands. The incorporated barium ions act as spacers to generate a solvent-accessible void, hierarchical self-assembly having an individual void volume near 13 000 Å3. This work illustrates the surprising chemistry that remains to be discovered by integrating large or classically non-reactive metal ions within supramolecular assemblies, networks, and organic nanocapsules.
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The inception of an unprecedented class of voluminous Platonic solids displaying hierarchical geometry based on pyrogallol[4]arene moieties seamed by divalent calcium ion is described. Single-crystal X-ray structural determination has established the highly conserved geometry of two original Ca2+-seamed nanocapsules to be essentially cubic in shape with C-ethylpyrogallol[4]arene units located along the twelve edges of the cube which are then bridged by metallic polyatomic cations ([Ca4Cl]7+ or [Ca(HCO2)Na4]5+) at the six cube faces. The accessible volume of the nanocapsules is ca. 3500 Å3 and 2500 Å3 and is completely isolated from the exterior of the capsules. These remarkable nanocapsule discoveries cast a spotlight on a marginalized area of synthetic materials chemistry and encourage future exploration of diversiform supramolecular assemblies, networks, and capsules built on calcium, with clear benefits deriving from the intrinsic biocompatibility of calcium. Finally, a proof-of-concept is demonstrated for fluorescent reporter encapsulation and sustained release from the calcium-seamed nanocapsules, suggesting their potential as delivery vehicles for drugs, nutrients, preservatives, or antioxidants.
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Coordination polymers, commonly known as infinite crystalline lattices, are versatile networks and have diverse potential applications in the fields of gas storage, molecular separation, catalysis, optics, and drug delivery, among other areas. Secondary building blocks, mainly incorporating rigid polydentate organic linkers and metal ions or clusters, are commonly employed to construct coordination polymers. Recently, novel building blocks such as coordination polyhedra have been utilized as metal nodes to fabricate coordination polymers. Benefiting from the rigid porous structure of the coordination polyhedron, prefabricated designer "pores" can be incorporated in this type of coordinate polymer. In this Account, coordination polymers built by pyrogallol[4]arene-assembled metal-organic nanocapsules are summarized. This class of metal-organic nanocapsule possesses the following advantages that make them excellent candidates in the construction of coordination polymers: (i) Various geometrical shapes with different volumes of the inner cavities can be obtained from these capsules. Among them, the two main categories illustrated are dimeric and hexameric capsules, which comprise two and six pyrogallol[4]arenes units, respectively. (ii) A wide range of possible metal ions ranging from main group metals to transition metals and even lanthanides have been demonstrated to seam the capsules. Therefore, these coordination polymers can be endowed with fascinating functionalities such as magnetism, semiconductivity, luminescence, and radioactivity. (iii) Up to 24 metal ions have been successfully embedded on the surface of the nanocapsule, each a potential reaction site in the construction of coordination polymers, opening up pathways for the formation of multidimensional frameworks.In this Account, we focus primarily on the synthesis and the structural information on pyrogallol[4]arene-derived coordination polymers. Coordination polymers can be formed by introducing linkers with two coordination sites, using pyrogallol[4]arenes with coordination sites on the tail, or even via metal ions cross-linking with each other. Machine learning was recently developed to help us predict and screen the structures of the coordination polymers. With single crystal analysis in hand, detailed structural information provides a molecular-level perspective. Significantly, following the formation of coordination polymers, the overall shape and structure of the discrete metal-organic nanocapsules remains essentially unchanged, with full retention of the prefabricated pores. If a rigid linker is used to connect capsules, more than one lattice void with different volumes can be found within the framework. Thus, molecules with different sizes could potentially be encapsulated within these coordination polymers. In addition, flexible ligands can also be employed as linkers. For example, polymers have been employed as large linkers that transform the crystalline coordination polymers into polymer matrices, paving the way toward the synthesis of advanced functional materials. Overall, coordination polymers constructed with pyrogallol[4]arene-assembled metal-organic nanocapsules show wide diversity and tunability in structure and fascinating properties, as well as the promise of built-in functionality in the future.
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A hexameric metal-organic nanocapsule is assembled from pyrogallol[4]arene units, which are stitched together with indium ions. This indium-seamed capsule is the first instance of a M24 L6 type hexameric coordination cage held together exclusively by trivalent metal ions. Explicitly, unlike previously reported pyrogallol[4]arene-based metal-seamed capsules, the current In3+ seamed capsule is entirely supported by OâIn coordinate bonds. This work demonstrates the important proof of concept of the ability of pyrogallol[4]arene to react with metals in higher oxidation states to assemble into atomically-precise hexameric coordination cages. As such, these results open up exciting avenues toward the assembly of previously unanticipated metal-organic capsules, for example offering inspiration for tackling metals exhibiting high valence states such as in the lanthanide and actinide series.
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We present here the preparation of a M18L6 hexameric metal-organic nanocapsule using a pyrogallol[3]resorcin[1]arene mixed macrocycle. The introduction of resorcinol moieties within the assembly leads to the formation of two open windows. This study demonstrates that introducing defects into the existing structure of nanocapsules may act as an effective method to tailor the composition and geometry, and introduce new properties.
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Crystalline hydrates of macrocyclic compounds such as pyroagllol[4]arenes (PgCs) and resorcin[4]arenes (RsCs) are rare owing to their lower water solubility. Functionalization of these macrocyclic compounds is an affordable way to enhance water solubility. However, functionalization also encounters the formation of multiple conformers and subsequent difficulty in purification of the product. Herein, four novel crystalline hydrates of functionalized PgCs and RsCs were synthesized. Formation of water channels and the effects of intermolecular interactions on the physical properties of these novel hydrates are discussed.
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The solvothermal synthesis of two M7L2 metal-organic nanocapsules from C-alkyl pyrogallol[3]resorcin[1]arene is reported. Using mixed macrocycles as building blocks shows great potential in the discovery of new metal-organic nanocapsules with novel properties.