Nikitovic Dragana, Kukovyakina Ekaterina, Berdiaki Aikaterini, Tzanakakis Alexandros, Luss Anna, Vlaskina Elizaveta, Yagolovich Anne, Tsatsakis Aristides, Kuskov Andrey
Department of Histology-Embryology, Medical School, University of Crete, 71003 Heraklion, Greece.
Department of Technology of Chemical Pharmaceutical and Cosmetic Products, D. Mendeleev University of Chemical Technology of Russia, 125047 Moscow, Russia.
Cancers (Basel). 2024 Nov 8;16(22):3768. doi: 10.3390/cancers16223768.
Chemotherapy remains the primary therapeutic approach in treating cancer. The tumor microenvironment (TME) is the complex network surrounding tumor cells, comprising various cell types, such as immune cells, fibroblasts, and endothelial cells, as well as ECM components, blood vessels, and signaling molecules. The often stiff and dense network of the TME interacts dynamically with tumor cells, influencing cancer growth, immune response, metastasis, and resistance to therapy. The effectiveness of the treatment of solid tumors is frequently reduced due to the poor penetration of the drug, which leads to attaining concentrations below the therapeutic levels at the site. Cell-penetrating peptides (CPPs) present a promising approach that improves the internalization of therapeutic agents. CPPs, which are short amino acid sequences, exhibit a high ability to pass cell membranes, enabling them to deliver drugs efficiently with minimal toxicity. Specifically, the iRGD peptide, a member of CPPs, is notable for its capacity to deeply penetrate tumor tissues by binding simultaneously integrins ανβ3/ανβ5 and neuropilin receptors. Indeed, ανβ3/ανβ5 integrins are characteristically expressed by tumor cells, which allows the iRGD peptide to home onto tumor cells. Notably, the respective dual-receptor targeting mechanism considerably increases the permeability of blood vessels in tumors, enabling an efficient delivery of co-administered drugs or nanoparticles into the tumor mass. Therefore, the iRGD peptide facilitates deeper drug penetration and improves the efficacy of co-administered therapies. Distinctively, we will focus on the iRGD mechanism of action, drug delivery systems and their application, and deliberate future perspectives in developing iRGD-conjugated therapeutics. In summary, this review discusses the potential of iRGD in overcoming barriers to drug delivery in cancer to maximize treatment efficiency while minimizing side effects.
化疗仍然是治疗癌症的主要方法。肿瘤微环境（TME）是围绕肿瘤细胞的复杂网络，由各种细胞类型组成，如免疫细胞、成纤维细胞和内皮细胞，以及细胞外基质成分、血管和信号分子。TME通常僵硬且致密的网络与肿瘤细胞动态相互作用，影响癌症的生长、免疫反应、转移和对治疗的抗性。由于药物穿透性差，实体瘤的治疗效果常常降低，这导致在肿瘤部位达到低于治疗水平的浓度。细胞穿透肽（CPP）是一种很有前景的方法，可以提高治疗剂的内化。CPP是短氨基酸序列，具有很高的穿过细胞膜的能力，使其能够以最小的毒性有效地递送药物。具体而言，iRGD肽作为CPP的一员，因其能够同时结合整合素ανβ3/ανβ5和神经纤毛蛋白受体而深入穿透肿瘤组织而闻名。事实上，ανβ3/ανβ5整合素在肿瘤细胞中特异性表达，这使得iRGD肽能够归巢到肿瘤细胞上。值得注意的是，各自的双受体靶向机制大大增加了肿瘤血管的通透性，从而能够将共同给药的药物或纳米颗粒有效地递送至肿瘤块中。因此，iRGD肽有助于药物更深入地渗透，并提高共同给药疗法的疗效。特别地，我们将关注iRGD的作用机制、药物递送系统及其应用，并探讨开发iRGD缀合治疗剂的未来前景。总之，本综述讨论了iRGD在克服癌症药物递送障碍以在最小化副作用的同时最大化治疗效率方面的潜力。
