Therapeutic Strategies for Anticancer Immune Response and Stemness Modulation via Light-Activated or Metal-Assisted Systems

Ghosh, Shilpendu (2026) Therapeutic Strategies for Anticancer Immune Response and Stemness Modulation via Light-Activated or Metal-Assisted Systems. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Shilpendu Ghosh (20RS015)) 20RS015.pdf - Submitted Version Restricted to Repository staff only Download (144MB)

Abstract

The development of next-generation therapeutics requires molecular platforms capable of addressing complex and evolving biological challenges, including cancer progression, immune evasion, and viral infections. This thesis presents a comprehensive strategy based on drug-directed metallodrug design, integrating clinically relevant pharmacophores with transition metal chemistry to generate multifunctional small molecules with enhanced therapeutic potential. Chapter 1 outlines the conceptual framework of metallodrug design, emphasizing the limitations of conventional single-target therapeutics and the need for multi-mechanistic approaches. It establishes the rationale for incorporating bioactive organic scaffolds into metal-based architectures to achieve synergistic biological activity. Chapter 2 describes the development of a sunitinib-derived Ru(II) complex (complex 5) that induces ROS-independent immunogenic cell death (ICD). The complex simultaneously inhibits VEGFR2, EGFR, NF-κB signaling, and telomerase activity, leading to apoptosis and immune activation. Encapsulation into folate-targeted polymeric micelles (5@PFC) enhances tumor selectivity and in vivo efficacy, demonstrating significant tumor suppression and increased T-cell infiltration in murine models . Chapter 3 focuses on the design of iridium(III)-based complexes targeting apoptosis-resistant cancers through redox modulation and non-apoptotic cell death pathways, highlighting their potential to overcome multidrug resistance. Chapter 4 reports a series of lenalidomide-derived Ru(II) complexes as broad-spectrum antiviral agents. These complexes exhibit potent activity against Influenza A (H1N1), HCoV-OC43, and SARS-CoV-2, with lead compounds demonstrating both intracellular antiviral effects and direct virucidal activity. Mechanistic studies reveal a dual mode of action involving metal-mediated reactivity and ligand-directed biological interactions, while maintaining low cytotoxicity and a high therapeutic index . Chapter 5 introduces a Limantrafin-conjugated BODIPY photosensitizer designed for Type-I photodynamic therapy (PDT) under hypoxic conditions. The lead compound selectively generates superoxide radicals upon green light irradiation, exhibiting an exceptionally high phototherapeutic index (>3700) in triple-negative breast cancer cells. Glycopolymer-based nanoparticle delivery further enhances selectivity and efficacy, while simultaneously suppressing cancer stemness markers and oncogenic signaling pathways . Chapter 6 investigates mechanistic aspects of cell death, including mitochondrial dysfunction, ROS generation, and apoptosis pathways, providing insights into structure–activity relationships and biological responses across the developed systems. Overall, this thesis establishes a unified design paradigm for multifunctional metallodrugs, demonstrating how the integration of metal centers with pharmacologically active ligands enables simultaneous targeting of multiple disease pathways. The findings highlight the potential of these systems to overcome drug resistance, enhance selectivity, and expand therapeutic scope across oncology and antiviral applications, offering a versatile platform for next-generation drug discovery.

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