TY - JOUR
T1 - Manganese-Templated Nontrivial Structures for MRI and Therapy
AU - Benyettou, Farah
AU - Prakasam, Thirumurugan
AU - Khair, Mostafa
AU - Abdullah, Osama
AU - Lusi, Matteo
AU - Paterson, Haidee
AU - Alkaabi, Maryam
AU - Thomas, Sneha
AU - Straubinger, Rainer
AU - Al Damook, Nosayba
AU - Boitet, Maylis
AU - Abelbaki, Mamoun
AU - Del Monte, Judalyn
AU - Yu, Diana
AU - Heinz, Rick E.
AU - Holmen, Sheri L.
AU - Hsu, Edward
AU - Platas-Iglesias, Carlos
AU - Esposito, Gennaro
AU - Trabolsi, Ali
N1 - Publisher Copyright:
© 2026 The Authors. Published by American Chemical Society
PY - 2026/4/22
Y1 - 2026/4/22
N2 - Manganese (Mn)-based metal–organic architectures offer a unique avenue for integrating magnetic resonance imaging (MRI) and cancer therapy within a single molecular platform. We report three topologically distinct Mn-templated structures─Mn-[2]Catenate (Mn-[2]C), Mn-Trefoil Knot (Mn-TK), and Mn-Borromean Rings (Mn-BR)─that combine high relaxivity with tumor-selective cytotoxicity. The design leverages their geometrical complexity and electropositive, pH-labile coordination framework to ensure kinetic stability and lipophilicity at physiological pH while enabling Mn2+ release in the acidic tumor microenvironment. Among the three, Mn-BR and Mn-TK exhibit superior longitudinal relaxivities (r1 = 10.1 and 6.8 mM–1.s–1 at 3 T) and produce bright T1-weighted contrast exceeding that of Gd-DTPA and Mn-DPDP. In vitro, they show high cancer selectivity and potency in glioblastoma (U251-MG) cells, with IC50 values of 3.0 ± 0.9 μM (Mn-BR) and 5.6 ± 1.9 μM (Mn-TK), outperforming cisplatin (12.7 ± 2.5 μM) while sparing normal cells (SI > 3.9 for Mn-TK; SI > 9.4 for Mn-BR). Mechanistically, their uptake proceeds via energy-dependent endocytosis─caveolae-mediated for Mn-TK and clathrin/macropinocytosis-driven for Mn-BR─culminating in lysosomal acidification, pH-triggered disassembly, Mn2+ release, ROS accumulation, and caspase-dependent apoptosis. In vivo, Mn-TK and Mn-BR achieve tumor-specific accumulation, strong MRI contrast, and pronounced growth inhibition in subcutaneous glioblastoma models, while Mn-[2]C shows minimal selectivity and higher systemic toxicity. Importantly, in a spontaneous orthotopic glioblastoma model, both Mn-TK and Mn-BR provided robust BBB permeability and persistent, tumor-specific MRI enhancement, confirming their potential for precise MRI-guided tumor visualization. This research marks a major leap forward in medical nanotechnology, unveiling a new class of metal–organic structures that seamlessly integrates imaging and therapy. By unlocking their full potential, these structures promise to revolutionize MRI diagnostics, precision medicine, and next-generation cancer treatments, paving the way for unparalleled clinical outcomes.
AB - Manganese (Mn)-based metal–organic architectures offer a unique avenue for integrating magnetic resonance imaging (MRI) and cancer therapy within a single molecular platform. We report three topologically distinct Mn-templated structures─Mn-[2]Catenate (Mn-[2]C), Mn-Trefoil Knot (Mn-TK), and Mn-Borromean Rings (Mn-BR)─that combine high relaxivity with tumor-selective cytotoxicity. The design leverages their geometrical complexity and electropositive, pH-labile coordination framework to ensure kinetic stability and lipophilicity at physiological pH while enabling Mn2+ release in the acidic tumor microenvironment. Among the three, Mn-BR and Mn-TK exhibit superior longitudinal relaxivities (r1 = 10.1 and 6.8 mM–1.s–1 at 3 T) and produce bright T1-weighted contrast exceeding that of Gd-DTPA and Mn-DPDP. In vitro, they show high cancer selectivity and potency in glioblastoma (U251-MG) cells, with IC50 values of 3.0 ± 0.9 μM (Mn-BR) and 5.6 ± 1.9 μM (Mn-TK), outperforming cisplatin (12.7 ± 2.5 μM) while sparing normal cells (SI > 3.9 for Mn-TK; SI > 9.4 for Mn-BR). Mechanistically, their uptake proceeds via energy-dependent endocytosis─caveolae-mediated for Mn-TK and clathrin/macropinocytosis-driven for Mn-BR─culminating in lysosomal acidification, pH-triggered disassembly, Mn2+ release, ROS accumulation, and caspase-dependent apoptosis. In vivo, Mn-TK and Mn-BR achieve tumor-specific accumulation, strong MRI contrast, and pronounced growth inhibition in subcutaneous glioblastoma models, while Mn-[2]C shows minimal selectivity and higher systemic toxicity. Importantly, in a spontaneous orthotopic glioblastoma model, both Mn-TK and Mn-BR provided robust BBB permeability and persistent, tumor-specific MRI enhancement, confirming their potential for precise MRI-guided tumor visualization. This research marks a major leap forward in medical nanotechnology, unveiling a new class of metal–organic structures that seamlessly integrates imaging and therapy. By unlocking their full potential, these structures promise to revolutionize MRI diagnostics, precision medicine, and next-generation cancer treatments, paving the way for unparalleled clinical outcomes.
UR - https://www.scopus.com/pages/publications/105036523215
U2 - 10.1021/jacs.5c19016
DO - 10.1021/jacs.5c19016
M3 - Article
C2 - 41919314
AN - SCOPUS:105036523215
SN - 0002-7863
VL - 148
SP - 15529
EP - 15549
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 15
ER -