Theranostic Nanoparticles in Prostate Cancer: Disrupting Hypoxia‐Induced Glycolysis by Targeting Hypoxia‐Inducible Factor‐1 Alpha and Downstream Metabolites

ABSTRACT Background Prostate cancer (PCa) is a major cause of cancer‐associated death in men. A crucial factor in its development and treatment resistance is tumor hypoxia, which drives metabolic reprogramming (especially reconfiguration towards glycolysis), mediated to a great extent by hypoxia‐inducible factor‐“HIF‐1 alpha” (HIF‐1a). Aims The present review summarizes (i) the mechanisms underlying hypoxia‐induced glycolysis that enhances the aggressiveness of and treatment failure in PCa and (ii) recent developments in the field of theranostic nanoparticles (TNPs) with dual actions of inhibiting HIF‐1a and downstream metabolic targets, while facilitating the imaging and treatment of the tumor. Materials and Methods We summarize available evidence for the hypoxia‐glycolysis signaling in PCa and assess nanotechnology achievable theranostic approaches (i.e., liposomal‐, polymer‐ and metallic nanoplatforms) to promote drug delivery, real‐time tumor picture and modulation of hypoxic tumor microenvironments. Results Hypoxia‐inducible factor‐1 alpha (HIF‐1a) driven hypoxia is a common phenotypic feature that underlies the increased glycolysis and aggressive tumor phenotype. TNPs have been developed with the aim of (a) enhancing the drug bioavailability, (b) enabling the selectivity of tumor and imaging, and (c) reducing the hypoxia‐linked metabolic pathways. The use of PCa as a model for TNP development is especially timely as hypoxia crosses the intersection of androgen receptor (AR) signaling heavens (hormone therapy resistance) leading to progression to castration‐resistant PCa (CRPC) and as the Prostate‐Specific Membrane Antigen (PSMA) is greatly overexpressed and is a validated target for custom imaging and treatment. Discussion Compared with other hypoxia mediated solid tumors, hypoxia AR axis and PSMA overexpression have unique biological leverage for precision theranostics in PCa. Nevertheless, translation is limited by the issues of biocompatibility, complexities resulting from systematic regulations and constraints of scale‐up manufacturing. Conclusion TNPs are a promising platform to integrate diagnosis and treatment of PCa as they incorporate features of targeted delivery, on‐line monitoring and interference with HIF‐1a regulated glycolysis. Future advances will require interdisciplinary optimization, development of better tumor‐targeting approaches, and artificial intelligence guided nanoparticle design to facilitate clinical scale up and regulation of technically and clinically acceptable theranostics of nanomedicines for PCa.