Executive Summary : | Designing metal-organic compounds (MOC) has become one of the most sought after research target because of their innumerous applications in various fields of material chemistry including biomaterials [Coord. Chem. Rev. 2022, 451, 214262; Angew. Chem. Int. Ed. 2021, 60, 23975–24001; Nat. Protocols 2023, 18, 136–156; Angew. Chem. Int. Ed. 2022, 61, e202209110 and references cited therein]. Ease of synthesis through crystallization and characterization by single crystal X-ray diffract make these class of compound attractive for applications. The present proposal aims at developing MOC based anti-cancer biomaterials in the form of supramolecular gels/nano-crystals that would work as carrier-free-drug-delivery (CFDD) systems. By creating reactive oxygen species (ROS) imbalance via triggering of intracellular Fenton reactions and glutathione (GSH) depletion, such CFDD systems are expected to cause cancer cell death – a process known as ferroptosis [Cell 2012, 149, 1060.] The metal ion of the MOC based gels/nanocrystals is expected to trigger Fenton reactions by reacting with H2O2 present in relatively high concentration in cancer cells [Chem. Sci., 2019, 10, 7068–7075] producing hydroxyl and perhydroxyl radicals (.OH/.OOH). This, in turn, increases the level of intracellular ROS causing accumulation lipid peroxides (LPO) that disrupts the cell membrane and promotes CD8+ T cell infiltration thereby killing tumour cells. However, in rapidly growing cancer cells, intracellular glutathione peroxidase 4 (GPX4) converts harmful LPO to nontoxic lipid hydroxyl compounds (LOH) at the expense of GSH to GSSG (oxidized glutathione) thereby maintaining intracellular redox balance preventing LPO mediated cell damage [Mol. Cell 2019, 73, 354.; Nat. Chem. Biol. 2018, 14, 507.; Coord. Chem. Rev. 2019, 382, 160.; Free Radical Biol. Med. 2019, 133, 144.; Nature 2017, 551, 247.] Thus, effective ferroptosis inducing CFDD system should perform both i.e. triggering Fenton reaction and inhibiting GPX4 by depleting intracellular GSH, which is a challenging job. By exploiting the design strategies for synthesizing supramolecular gelators developed by PI’s group,[Chem. Soc. Rev., 2008, 37, 2699–2715.; Gels 2019, 5, 15.; Cryst. Growth Des., 2010, 10, 4976–4986; Cryst. Growth Des., 2011, 11, 328–336] a series of MOC equipped with suitable metal ions (Fe(III)/Fe(II)/Cu(II)), disulfide ligands (RS-SR) and gelation promoting ligands and/or anti-cancer, immunomodulatory drugs will be synthesized and characterized. The corresponding gels and/or nanocrystals can then be evaluated in vitro for their anti-cancer properties. While the metal ion is expected to trigger Fenton reaction, the disulfide ligand would help deplete GSH by sulfide exchange reaction converting GSH to GSSG thereby inhibiting GPX4 triggering ferroptosis. In vivo evaluation of the gels/nanocrystals can be achieved via topical/subcutaneous (for gels) and intravenous (for nanocrystals) routes on suitable mice model. |