Integrin Targeting and Beyond: Enhancing Cancer Treatment with Dual-Targeting RGD (Arginine-Glycine-Aspartate) Strategies

Abstract

Integrins, an important superfamily of cell adhesion receptors, play an essential role in cancer progression, metastasis, and angiogenesis, establishing them as prime targets for both diagnostic and therapeutic applications. Despite their significant potential, integrin-targeted therapies have faced substantial challenges in clinical trials, including variable efficacy and unmet high expectations. Nevertheless, the consistent expression of integrins on tumor and stromal cells underscores their ongoing relevance and potential. Traditional RGD-based imaging and therapeutic agents have faced limitations, such as inconsistent target expression and rapid systemic clearance, which have reduced their effectiveness. To overcome these challenges, recent research has focused on advancing RGD-based strategies and exploring innovative solutions. This review offers a thorough analysis of the latest developments in the RGD-integrin field, with a particular focus on addressing previous limitations. It delves into new dual-targeting approaches and cutting-edge RGD-based agents designed to improve both tumor diagnosis and therapeutic outcomes. By examining these advancements, this review illuminates new pathways for enhancing the specificity and efficacy of integrin-targeted therapies, paving the way for more effective cancer diagnosis and treatment strategies.

Keywords: PET imaging; RGD-binding integrin; dual targeting; solid tumors; theranostic; αvβ3.

Figure 1

Schematic representation of tumors with high RGD-binding integrin expression, which drives tumor progression, metastasis, and angiogenesis. The figure illustrates various strategies targeting RGD-binding integrins, such as drug delivery through nanoparticles and liposomes, imaging and radiotherapy with radiopharmaceuticals, and pharmacological intervention using RGD inhibitors. Additionally, dual-targeting approaches are shown, which combine the targeting of RGD-binding integrins with other molecular targets. These dual-targeting strategies aim to improve the specificity and efficacy of both diagnostic and therapeutic interventions by simultaneously addressing multiple pathways involved in tumor growth and resistance, offering enhanced therapeutic outcomes compared to traditional single-target approaches.