In vivo biodistribution of kinetically stable Pt2L4 nanospheres that show anti-cancer activity

Bobylev, Eduard O.; Knol, Renzo A.; Mathew, Simon; Poole, David A.; Kotsogianni, Ioli; Martin, Nathaniel I.; de Bruin, Bas; Kros, Alexander; Reek, Joost N. H.

doi:10.1039/d3sc01086d

Cited by 8 publications

(7 citation statements)

References 54 publications

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“…In the future, one promising alternative for developing more stable metallacages is the use of more kinetically inert metal–ligand bonds, e.g., by using Pt(II) as a substitute for Pd(II). This approach has been demonstrated to yield systems with enhanced stability . Overall, our results show that, although challenging, the synthesis of SCC-based radiopharmaceuticals is possible and, upon optimization, can render systems with increased functionality that can be foreseen as a new generation of theranostic agents.…”

Section: Discussionmentioning

confidence: 80%

“…Relatively few examples exist where SCCs have been employed as molecular imaging agents, despite the plethora of strategies for achieving light-emitting scaffolds . For example, SCCs can include ligands, metal centers, or pendant functional groups that confer luminescent properties on the SCCs in order to study their cellular accumulation, subcellular distribution, and overall fate in biological systems by optical imaging methods. − In this context, two-dimensional (2D) SCCs as boron dipyrromethene (BODIPY)-based, highly emissive Pt(II) supramolecular triangles ( Pt-BODIPY , Figure a) have been reported, which were endowed with combined phototherapy–chemotherapy effects. Moreover, the near-infrared (NIR)-II emissive Ru(II) metallacycle ( Ru1085 , Figure b), which shows precise fluorescence imaging-guided and long-term monitored chemophototherapy against A549 lung tumors, is highlighted.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of ¹⁷⁷Lu-Labeled, Somatostatin-2 Receptor-Targeted Metalla-Assemblies: Challenges in the Design of Supramolecular Radiotherapeutics

Deiser,

Drexler,

Moreno-Alcántar

et al. 2023

Inorg. Chem.

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Self-assembled supramolecular coordination complexes (SCCs) hold promise for biomedical applications in cancer therapy, although their potential in the field of nuclear medicine is still substantially unexplored. Therefore, in this study an exo-functionalized cationic [Pd2L2]4+ metallacycle (L = 3,5-bis(3-ethynylpyridine)phenyl), targeted to the somatostatin-2 receptor (sst2R) and featuring the DOTA chelator (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) in order to bind the β–- and γ-emitter lutetium-177, was synthesized by self-assembly following ligand synthesis via standard solid-phase peptide synthesis (SPPS). This metallacycle was then characterized by reverse-phase high-performance liquid chromatography (RP-HPLC), electrospray ionization mass spectrometry (ESI-MS), and 1H and 1H-DOSY NMR (DOSY = diffusion-ordered spectroscopy). A procedure for the radiolabeling of the metallacycle with 177Lu was also optimized. The resulting [nat/177Lu]Lu-DOTA-metallacycle, termed [nat/177Lu]Lu-Cy, was evaluated concerning its stability and in vitro properties. The compound was more lipophilic compared to the reference [177Lu]Lu-DOTA-TATE (logP Oct/H2O = −0.85 ± 0.10 versus −3.67 ± 0.04, respectively). While [natLu]Lu-Cy revealed low stability in a DMEM/F12 GlutaMax medium, it demonstrated good stability in other aqueous media as well as in DMSO. A high sst2R binding affinity (expressed as IC50) was determined in CHOsst2 cells (Chinese hamster ovary cells that were stably transfected with human sst2R). Moreover, the metallacycle exhibited high human serum albumin binding, as assessed by high-performance affinity chromatography (HPAC), and moderate stability in human serum compared to [177Lu]Lu-DOTA-TATE (TATE = (Tyr3)-octreotate). In order to improve stability, a heteroleptic approach was used to develop a less sterically hindered cage-like SCC that is potentially endowed with host–guest chemistry capability, which has been preliminarily characterized by RP-HPLC and ESI-MS. Overall, our initial results encourage future studies on sst2R-directed SCCs and have led to new insights into the chemistry of ss2R-directed SCCs for radiopharmaceutical applications.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Synthesis of ¹⁷⁷Lu-Labeled, Somatostatin-2 Receptor-Targeted Metalla-Assemblies: Challenges in the Design of Supramolecular Radiotherapeutics

Deiser,

Drexler,

Moreno-Alcántar

et al. 2023

Inorg. Chem.

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“…To track the distribution of the nanoplatforms, Cy5-labeled BP-PGA 50 and PGA 50 NPs were administered via intranasal instillation in the mouse model, and the biodistribution was monitored at 0, 1, and 7 d postadministration. 44 The fluorescence signals in the nose and lungs decreased quickly at 1 day after instillation, particularly for PGA 50 NP-treated mice (Figure 5A). Then, the mice were sacrificed, and the MBs, lungs, and other major organs were isolated.…”

Section: Resultsmentioning

confidence: 98%

“…Collectively, our findings demonstrated that BP-PGA 50 nanosheets with their 2D nanostructure effectively inhibited both TLR9 stimulation and NET formation via cfDNA scavenging. 44 The fluorescence signals in the nose and lungs decreased quickly at 1 day after instillation, particularly for PGA 50 NP-treated mice (Figure 5A). Then, the mice were sacrificed, and the MBs, lungs, and other major organs were isolated.…”

Section: Analysis Of Cfdna and Net Levels In Nasalmentioning

confidence: 98%

Tackling Severe Neutrophilic Inflammation in Airway Disorders with Functionalized Nanosheets

Tu,

Zhu,

Gao

et al. 2024

ACS Nano

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Severe airway inflammatory disorders impose a significant societal burden, and the available treatments are unsatisfactory. High levels of neutrophil extracellular trap (NET) and cell-free DNA (cfDNA) were detected in the inflammatory microenvironment of these diseases, which are closely associated with persistent uncontrolled neutrophilic inflammation. Although DNase has proven to be effective in mitigating neutrophilic airway inflammation in mice by reducing cfDNA and NET levels, its clinical use is hindered by severe side effects. Here, we synthesized polyglycerol-amine (PGA) with a series of hydroxyl/amine ratios and covered them with black phosphorus (BP) nanosheets. The BP nanosheets functionalized with polyglycerol-50% amine (BP-PGA 50 ) efficiently lowered cfDNA levels, suppressed tolllike receptor 9 (TLR9) activation and inhibited NET formation in vitro. Importantly, BP-PGA 50 nanosheets demonstrated substantial accumulation in inflamed airway tissues, excellent biocompatibility, and potent inflammation modulation ability in model mice. The 2D sheet-like structure of BP-PGA 50 was identified as a crucial factor for the therapeutic efficacy, and the hydroxyl/amine ratio was revealed as a significant parameter to regulate the protein resistance, cfDNA-binding efficacy, and cytotoxicity. This study shows the promise of the BP-PGA 50 nanosheet for tackling uncontrolled airway inflammation, which is also significant for the treatment of other neutrophilic inflammatory diseases. In addition, our work also highlights the importance of proper surface functionalization, such as hydroxyl/amine ratio, in therapeutic nanoplatform construction for inflammation modulation.

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“…Therefore, to enhance these types of applications there is a need to develop more kinetically robust MSAs. [195][196][197][198] The majority of heterometallic MSAs developed to date feature both inert and liable metal ions. Thus, it would be expected that those systems would be more robust than the related homometallic systems.…”

Section: Discussionmentioning

confidence: 99%

Heterometallic cages: synthesis and applications

Moree,

Faulkner,

Crowley

2024

Chem. Soc. Rev.

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In vivo biodistribution of kinetically stable Pt₂L₄ nanospheres that show anti-cancer activity

Abstract: There is an increasing interest in the application of coordination-based spherical assemblies (CBSAs) in a bio medicinal context, as they can offer non-classical distribution in organisms compared to molecular substrates...

Cited by 8 publications

References 54 publications

Synthesis of ¹⁷⁷Lu-Labeled, Somatostatin-2 Receptor-Targeted Metalla-Assemblies: Challenges in the Design of Supramolecular Radiotherapeutics

Synthesis of ¹⁷⁷Lu-Labeled, Somatostatin-2 Receptor-Targeted Metalla-Assemblies: Challenges in the Design of Supramolecular Radiotherapeutics

Tackling Severe Neutrophilic Inflammation in Airway Disorders with Functionalized Nanosheets

Heterometallic cages: synthesis and applications

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In vivo biodistribution of kinetically stable Pt2L4 nanospheres that show anti-cancer activity

Abstract: There is an increasing interest in the application of coordination-based spherical assemblies (CBSAs) in a bio medicinal context, as they can offer non-classical distribution in organisms compared to molecular substrates...

Cited by 8 publications

References 54 publications

Synthesis of 177Lu-Labeled, Somatostatin-2 Receptor-Targeted Metalla-Assemblies: Challenges in the Design of Supramolecular Radiotherapeutics

Synthesis of 177Lu-Labeled, Somatostatin-2 Receptor-Targeted Metalla-Assemblies: Challenges in the Design of Supramolecular Radiotherapeutics

Tackling Severe Neutrophilic Inflammation in Airway Disorders with Functionalized Nanosheets

Heterometallic cages: synthesis and applications

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Product

Resources

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In vivo biodistribution of kinetically stable Pt₂L₄ nanospheres that show anti-cancer activity

Synthesis of ¹⁷⁷Lu-Labeled, Somatostatin-2 Receptor-Targeted Metalla-Assemblies: Challenges in the Design of Supramolecular Radiotherapeutics

Synthesis of ¹⁷⁷Lu-Labeled, Somatostatin-2 Receptor-Targeted Metalla-Assemblies: Challenges in the Design of Supramolecular Radiotherapeutics