In this issue of the JCI, Liu et al. use irinotecan-loaded nanoparticles to treat pancreatic adenocarcinomas in mice. Encapsulating drugs into nanoparticles has distinct advantages: it can improve the pharmacokinetics of the drug, enhance efficacy, and reduce unwanted side effects. A drawback is that the large size of nanoparticles restricts their access to the tumor interior. Liu and colleagues show that the cyclic tumor-penetrating peptide iRGD, reported to be capable of enhancing tumor penetration by drugs, can overcome this limitation to a substantial degree when administered together with the nanoparticles. Pancreatic adenocarcinoma is a challenging malignancy to treat and in desperate need for improved treatments; therefore, advances like this are most welcome.
Intravenous iRGD penetrates tumor tissue in a 3-step process. First, iRGD binds to αv integrins. Second, protease cleavage of bound iRGD generates a C-terminal CendR–containing fragment of iRGD at the tumor site. Third, CendR fragment binds to NRP-1, which promotes silicasome uptake and transcytosis through the vessel endothelium, allowing delivery of cargo directly to the target tumor.