Alpha-v integrins and neuropilin-1 (αv-integrins/NRP1)

Alpha-v integrins (αvβ3, αvβ5, αvβ6, αvβ8) and neuropilin-1 (NRP1) are cell surface receptors that are frequently overexpressed in the tumor microenvironment, particularly on tumor-associated endothelial cells and various solid tumor cells [1, 4, 6]. Alpha-v integrins are heterodimeric transmembrane proteins that mediate cell-extracellular matrix interactions and are essential for angiogenesis, cell migration, and survival [6, 9]. Neuropilin-1 is a transmembrane glycoprotein that acts as a co-receptor for vascular endothelial growth factor (VEGF) and class 3 semaphorins, playing a pivotal role in vascular permeability and tissue penetration [1, 17]. Together, these molecules form a functional axis that regulates the transport of substances across the vascular wall and into the tumor parenchyma [4, 14]. This dual-target system is the basis for a novel class of tumor-penetrating peptides, such as iRGD (CEND-1), which utilize a multi-step mechanism to enhance drug delivery [2, 5]. The process begins with the peptide binding to αv-integrins, followed by proteolytic cleavage that exposes a C-end Rule (CendR) motif, which then binds to NRP1 to trigger an active, endocytic transport pathway [1, 10]. This mechanism significantly increases the penetration of co-administered chemotherapeutic agents, such as gemcitabine and nab-paclitaxel, into dense tumor tissues like those found in pancreatic ductal adenocarcinoma [5, 15]. Therapeutic strategies targeting this axis aim to overcome the high interstitial fluid pressure of tumors, thereby improving the efficacy and reducing the systemic toxicity of anti-cancer treatments [4, 16].

Other names

αv-integrins/NRP1 complexiRGD targetCendR pathway targetsAlpha-v integrin and Neuropilin-1

Dual-step targeting where initial binding to αv-integrins is followed by proteolytic cleavage and subsequent binding to neuropilin-1 to trigger the CendR tissue penetration pathway.