Abstract
The unique structure and physiology of a tumor microenvironment impede intra-tumoral penetration of chemotherapeutic agents. A novel iRGD peptide that exploits the tumor microenvironment can activate integrin-dependent binding to tumor vasculatures and neuropilin-1 (NRP-1)-dependent transport to tumor tissues. Recent studies have focused on its dual-targeting ability to achieve enhanced penetration of chemotherapeutics for the efficient eradication of cancer cells. Both the covalent conjugation and the co-administration of iRGD with chemotherapeutic agents and engineered delivery vehicles have been explored. Interestingly, the iRGD-mediated drug delivery also enhances penetration through the blood–brain barrier (BBB). Recent studies have shown its synergistic effect with BBB disruptive techniques. The efficacy of immunotherapy involving immune checkpoint blockades has also been amplified by using iRGD as a targeting moiety. In this review, we presented the recent advances in iRGD technology, focusing on cancer treatment modalities, including the current clinical trials using iRGD. The iRGD-mediated nano-carrier system could serve as a promising strategy in drug delivery to the deeper tumor regions, and be combined with various therapeutic interventions due to its novel targeting ability.
Highlights
Advancements in therapeutic techniques have increased the life expectancy of cancer patients, the growing rate of cancer incidence still remains a matter of concern [1,2]
NRP-1 is found to be overexpressed in many tumors, including breast cancer a co-receptor that enhances the binding of the vascular endothelial growth factor (VEGF)-A to[82], the melanoma
This study revealed that the use of nano-carriers, chemical modification of drugs, radiation, and active targeting using iRGD synergistically improved the penetration of drugs through the blood–brain barrier (BBB), and efficiently optimized the efficacy of immunotherapy
Summary
Advancements in therapeutic techniques have increased the life expectancy of cancer patients, the growing rate of cancer incidence still remains a matter of concern [1,2]. Studies have shown that the increased density of ECM in tumors results in the low penetration of anti-cancer drugs [12,13,14]. The enhanced stiffness of ECM has been considered to intensify the interstitial fluid pressure (IFP), impeding the effective penetration of anti-cancer drugs into the solid tumor [19,20,21]. Many studies have investigated whether the modulation of epithelial junctions and ECM structures can improve the intra-tumoral penetration of anti-cancer drugs beyond the passive targeting ability relying on the EPR effect. Chemotherapeutics targeting tumor vasculature can directly bind with the blood vessels or vascular endothelial cells, and have less possibility to cause drug resistance due to high genetic stability of endothelial cells [45]. Advantages of iRGD peptide will allow the resolution of problems present in chemotherapeutic agents, such as poor drug penetration and side effects, and improve the pharmacokinetic properties of the drug delivery system
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