Heat Shock Protein 90 as a Master Regulator of Multidrug Resistance: Small-molecule Inhibitors, Prodrugs, Hybrid Molecules, Antibody–drug Conjugates, and Nanotechnology-based Delivery Systems

INTRODUCTION/OBJECTIVE: Multidrug Resistance (MDR) remains a major obstacle to effective cancer chemotherapy, driven by multiple interconnected mechanisms, including overexpression of ATP-binding Cassette (ABC) transporters, enhanced DNA repair, apoptosis evasion, and protumorigenic microenvironmental factors. Heat Shock Protein 90 (HSP90) has emerged as a master regulator of MDR by chaperoning multiple client proteins involved in drug efflux, survival signaling pathways, and cellular stress responses. These mechanisms collectively decrease intracellular drug accumulation and promote tumor cell survival, leading to therapeutic failure. This review aims to summarize HSP90-targeted therapeutic strategies for overcoming MDR in cancer and evaluate their mechanistic basis, efficacy, and translational potential. METHODS: A systematic literature search was conducted in PubMed, Scopus, Web of Science, and Google Scholar up to 2010-2026. Keywords included "HSP90," "multidrug resistance," "cancer," "HSP90 inhibitors," "prodrug," "ADC," and "nanotechnology," combined using Boolean operators. Relevant preclinical and clinical studies on HSP90-targeted strategies to overcome MDR were included, while duplicates and studies that were irrelevant or insufficiently detailed were excluded. Eligible studies were screened and analyzed for mechanisms, therapeutic outcomes, and limitations. RESULTS: Small-molecule HSP90 inhibitors, including geldanamycin derivatives and resorcinol-based compounds, demonstrate potential in destabilizing MDR-associated client proteins such as P-glycoprotein, MRP1, BCRP, and survival kinases, thereby restoring sensitivity of resistant cancer cells to chemotherapy. Prodrug strategies improve bioavailability and reduce systemic toxicity while preserving HSP90 inhibitory activity. Hybrid molecules that integrate HSP90 inhibition with complementary mechanisms, such as HDAC inhibition and kinase inhibition, provide synergistic multi-targeted effects against resistance pathways. Antibody-drug conjugates facilitate tumor-selective delivery of HSP90 inhibitors, enabling receptormediated internalization and reducing the impact of efflux mechanisms. Furthermore, nanotechnology-based delivery platforms, including liposomes, polymeric nanoparticles, and stimuli-responsive carriers, enhance pharmacokinetics, enable co-delivery of HSP90 inhibitors with chemotherapeutic agents, and support controlled intratumoral drug release. DISCUSSION: HSP90-targeted strategies represent a promising approach for reversing MDR by simultaneously regulating multiple resistance-associated pathways. The ability of HSP90 inhibitors to disrupt drug efflux transporters, survival signaling networks, and stress adaptation mechanisms provides a strong rationale for their integration with conventional chemotherapy and emerging targeted therapies. However, clinical translation remains challenging due to tumor heterogeneity, biological barriers, dose-limiting toxicities, and variations in patient response. Rational combination strategies, biomarker-guided patient selection, and advanced delivery technologies are essential to maximize therapeutic benefits and improve clinical outcomes. CONCLUSION: HSP90-targeted therapeutic approaches offer significant potential for overcoming MDR in cancer by restoring drug sensitivity and enhancing treatment efficacy. Future progress will depend on optimized combination therapies incorporating MDR modulators, personalized treatment strategies guided by predictive biomarkers, and innovative technologies such as artificial intelligence-assisted drug design and CRISPR-based gene editing. Continued interdisciplinary research is required to translate HSP90- targeted innovations into effective clinical interventions for patients with drug-resistant cancers.