Rauta, Pradipta RanjanMackeyev, YuriSanders, KeithKim, Joseph B.K.Gonzalez, Valeria V.Zahra, YasminShohayeb, Muhammad A.Abousaida, BelalVijay, Geraldine V.Tezcan, OkanDerry, PaulLiopo, Anton V.Zubarev, Eugene R.Carter, RickeySingh, PankajKrishnan, Sunil2022-12-132022-12-132022Rauta, Pradipta Ranjan, Mackeyev, Yuri, Sanders, Keith, et al.. "Pancreatic tumor microenvironmental acidosis and hypoxia transform gold nanorods into cell-penetrant particles for potent radiosensitization." <i>Science Advances,</i> 8, no. 45 (2022) AAAS: https://doi.org/10.1126/sciadv.abm9729.https://hdl.handle.net/1911/114128Coating nanoparticles with stealth epilayers increases circulation time by evading opsonization, macrophage phagocytosis, and reticuloendothelial sequestration. However, this also reduces internalization by cancer cells upon reaching the tumor. We designed gold nanorods (GNRs) with an epilayer that retains stealth properties in circulation but transforms spontaneously in the acidotic tumor microenvironment to a cell-penetrating particle. We used a customized stoichiometric ratio of l-glutamic acid and l-lysine within an amphiphilic polymer of poly(l-glutamic acid-co-l-lysine), or P(Glu-co-Lys), to effect this transformation in acidotic environments. P(Glu-co-Lys)-GNRs were internalized by cancer cells to facilitate potent in vitro radiosensitization. When administered intravenously in mice, they accumulate in the periphery and core of tumors without any signs of serum biochemical or hematological alterations, normal organ histopathological abnormalities, or overt deterioration in animal health. Furthermore, P(Glu-co-Lys)-GNRs penetrated the tumor microenvironment to accumulate in the hypoxic cores of tumors to potently radiosensitize heterotopic and orthotopic pancreatic cancers in vivo.engThis is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Journal articlesciadv-abm9729https://doi.org/10.1126/sciadv.abm9729