Theranostic Platform: Integrating Stimuli-Responsive Prodrugs with Nanomaterial-Based Synergistic Therapy

Dutta, Sourav (2026) Theranostic Platform: Integrating Stimuli-Responsive Prodrugs with Nanomaterial-Based Synergistic Therapy. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Sourav Dutta (21RS079)) 21RS079.pdf - Submitted Version Restricted to Repository staff only Download (19MB)

Abstract

Cancer therapy is frequently limited by multidrug resistance, poor selectivity, and systemic toxicity associated with conventional chemotherapeutics. This thesis presents the development of stimuli-responsive theranostic platforms that integrate molecular prodrugs with nanomaterial-based strategies to achieve tumour-selective activation, organelle-specific targeting, and multimodal therapeutic intervention. The study begins with the design of a lysosome-targeted, esterase-responsive 5-fluorouracil (5-FU) prodrug capable of selective intracellular activation and fluorescence-based tracking of drug release. The system enables sustained intra-lysosomal liberation of 5-FU, resulting in enhanced anti-proliferative, anti-angiogenic, and three-dimensional tumour spheroid growth inhibition while significantly reducing off-target toxicity compared with free 5-FU. To complement molecular prodrug strategies, peptide-conjugated 2D 2H MoS2 nanosheets were engineered for mitochondrial targeting and near-infrared (NIR) photothermal therapy. Upon NIR irradiation, efficient heat generation (~52 °C) induces the extrinsic pathway of cancer cell apoptosis, while the nanofibre-forming mitochondria-targeting peptide disrupts mitochondrial membrane potential and induces the intrinsic pathway of apoptosis, selectively demonstrating the potential of organelle-directed nanomaterial-assisted tumour ablation. Further advancing tumour-selective drug delivery, dual-stimuli-responsive AND-Gated micellar systems incorporating folate receptor targeting and a co-operative cascade activation of Cathepsin B/Caspase-3-triggered intracellular doxorubicin release, were developed. These platforms combine tumour-specific accumulation with intracellular enzymatic activation, leading to enhanced cytotoxicity, apoptosis, and anti-angiogenic activity in relevant cellular models. Finally, a reactive oxygen species (ROS)-activated methylene-blue-based hierarchical construct was designed that self-assembles into a nanoplatform and remains inactive in normal cells. In ROS-rich tumour microenvironments, oxidative uncaging activates fluorescence and singlet oxygen generation, enabling mitochondria-localised photodynamic therapy with minimal dark toxicity. Collectively, this thesis establishes a modular design strategy combining enzyme-responsive prodrugs, peptide-engineered nanomaterials, dual-stimuli drug delivery systems, and ROS-activatable photosensitizers. These approaches highlight the potential of microenvironment-responsive, organelle-targeted theranostic systems for achieving more precise and effective cancer therapy.

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