Application of Cleavable Linkers to Improve Therapeutic Index of Radioligand Therapies

Radioligand therapy (RLT) is an emergent drug class for cancer treatment. The dose administered to cancer patients is constrained by the radiation exposure to normal tissues to maintain an appropriate therapeutic index. When a radiopharmaceutical or its radiometabolite is retained in the kidneys, radiation dose deposition in the kidneys can become a dose-limiting factor. A good exemplar is [¹⁷⁷Lu]Lu-DOTATATE, where patients receive a co-infusion of basic amino acids for nephroprotection. Besides peptides, there are other classes of targeting vectors like antibody fragments, antibody mimetics, peptidomimetics, and small molecules that clear through the renal pathway. In this review, we will review established and emerging strategies that can be used to mitigate radiation-induced nephrotoxicity, with a focus on the development and incorporation of cleavable linkers for radiopharmaceutical designs. Finally, we offer our perspectives on cleavable linkers for RLT, highlighting future areas of research that will help advance the technology.     

Synthesis and anti-leukaemic activity of pyrrolo[3,2,1-hi]indole-1,2-diones,pyrrolo[3,2,1-ij]quinoline-1,2-diones and other polycyclic isatin derivatives

To further expand the structure–cytotoxic activity relationships of isatin derivatives and to reduce flexibility in substituent groups at nitrogen, 20 analogues incorporating a ring system between the N1 and C7 atoms of isatin were prepared using a variety of synthetic strategies. This yielded pyrroloindole-, pyrroloquinoline-, pyrroloacridine-, pyrrolophenanthridine- and benzopyrrolophenanthridine-based systems with embedded isatin moieties, the latter possessing a novel carbon skeleton. These compounds were subsequently assessed for their in vitro cytotoxicity against human U937 lymphoma cells, with the brominated pyrroloacridine dione 27 showing the most promising activity (IC₅₀ 3.01 μM) after 24 h.     

Study of the centrally produced ωρ0 and ωω systems inpp interactions at 300 GeV/c

We have performed a search for vector-vector final states centrally produced in proton proton interactions at 300 GeV/c using the CERN Ω spectrometer. Evidence is found for ωρ⁰ production in the reactionpp→p _f (2π⁺2π^?2π⁰)p _s and for ωω production in the reactionpp→p _f (2π⁺2π^?2π⁰)p _s . However no evidence is found for ωø production in the reactionpp→p _f (K ⁺ K ^?π⁺π^?π⁰)p _s .     

Dense electron-positron plasmas and ultraintense γ rays from laser-irradiated solids

In simulations of a 10 PW laser striking a solid, we demonstrate the possibility of producing a pure electron-positron plasma by the same processes as those thought to operate in high-energy astrophysical environments. A maximum positron density of 10(26) m(-3) can be achieved, 7 orders of magnitude greater than achieved in previous experiments. Additionally, 35% of the laser energy is converted to a burst of γ rays of intensity 10(22) W cm(-2), potentially the most intense γ-ray source available in the laboratory. This absorption results in a strong feedback between both pair and γ-ray production and classical plasma physics in the new "QED-plasma" regime.     

In vivo label-free photoacoustic microscopy of cell nuclei by excitation of DNA and RNA

Imaging of cell nuclei plays a critical role in cancer diagnosis and prognosis. To image noninvasively cell nuclei in vivo without staining, we developed UV photoacoustic microscopy (UV-PAM), in which 266 nm wavelength UV light excites unlabeled DNA and RNA in cell nuclei to produce photoacoustic waves. We applied UV-PAM to ex vivo imaging of cell nuclei in a mouse lip and a mouse small intestine and to in vivo imaging of the cell nuclei in the mouse skin. The UV-PAM images of unstained cell nuclei match the optical micrographs of the histologically stained cell nuclei. Given intrinsic optical contrast and high spatial resolution, in vivo label-free UV-PAM has potential for unique biological and clinical application.     

Passive combination of multiple beams in an optical fiber via stimulated Brillouin scattering

We demonstrate passive combination of multiple beams in an optical fiber via stimulated Brillouin scattering (SBS). Four off-axis beams are combined in a long multimode optical fiber using a novel all-optical mount. The combined beam has the high spatial coherence properties of the LP(01) mode owing to the beam cleanup properties of SBS. The threshold for SBS when off-axis pumps are used is shown to be a factor of 13 times higher than for on-axis pump beams. We propose this method would improve the brightness of an array of fiber amplifiers.