Stimulating photosensitizers (PS) by Cerenkov radiation (CR) can overcome the light penetration limitation in traditional photodynamic therapy. However, separate injection of radiopharmaceuticals and PS cannot guarantee their efficient interaction in tumor areas, while co‐delivery of radionuclides and PS face the problem of nonnegligible phototoxicity in normal tissues. Here, we describe a 131I‐labeled smart photosensitizer, composed of pyropheophorbide‐a (photosensitizer), a diisopropylamino group (pH‐sensitive group), an 131I‐labeled tyrosine group (CR donor), and polyethylene glycol, which can self‐assemble into nanoparticles (131I‐sPS NPs). The 131I‐sPS NPs showed low phototoxicity in normal tissues due to aggregation‐caused quenching effect, but could self‐produce reactive oxygen species in tumor sites upon disassembly. Upon intravenous injection, 131I‐sPS NPs showed great tumor inhibition capability in subcutaneous 4T1‐tumor‐bearing Balb/c mice and orthotopic VX2 liver tumor bearing rabbits. We believed 131I‐sPS NPs could expand the application of CR and provide an effective strategy for deep tumor theranostics.
Stimulating photosensitizers (PS) by Cerenkov radiation (CR) can overcome the light penetration limitation in traditional photodynamic therapy. However, separate injection of radiopharmaceuticals and PS cannot guarantee their efficient interaction in tumor areas, while co‐delivery of radionuclides and PS face the problem of nonnegligible phototoxicity in normal tissues. Here, we describe a 131I‐labeled smart photosensitizer, composed of pyropheophorbide‐a (photosensitizer), a diisopropylamino group (pH‐sensitive group), an 131I‐labeled tyrosine group (CR donor), and polyethylene glycol, which can self‐assemble into nanoparticles (131I‐sPS NPs). The 131I‐sPS NPs showed low phototoxicity in normal tissues due to aggregation‐caused quenching effect, but could self‐produce reactive oxygen species in tumor sites upon disassembly. Upon intravenous injection, 131I‐sPS NPs showed great tumor inhibition capability in subcutaneous 4T1‐tumor‐bearing Balb/c mice and orthotopic VX2 liver tumor bearing rabbits. We believed 131I‐sPS NPs could expand the application of CR and provide an effective strategy for deep tumor theranostics.
Overexpression of fibroblast activation protein (FAP) in cancer-associated fibroblasts in a wide variety of tumors enables a highly selective targeting strategy using FAP inhibitors (FAPIs). Quinoline-based FAPIs labeled with radionuclides have been widely developed for tumor-targeted nuclear medicine imaging. However, the short retention time of FAPIs at the tumor site limits their application in radionuclide therapy. In this study, a novel FAPI-04 dimer was synthesized and labeled with radionuclides to prolong the retention time in tumors for imaging and therapy. To prepare the FAPI-04 dimer complex, DOTA-Suc-Lys-(FAPI-04) 2 , we used Fmoc-Lys(Boc)−OH as the linker to conjugate two FAPI-04 structures by an amide reaction. The resulting product was further modified by DOTA groups to allow for conjugation with radioactive metals. Both [ 68 Ga]Ga-(FAPI-04) 2 and [ 177 Lu]Lu-(FAPI-04) 2 showed a radiochemical purity of >99% and remained stable in vitro. In vivo, micro-PET images of SKOV3, A431, and H1299 xenografts revealed that the tumor uptake of [ 68 Ga]Ga-(FAPI-04) 2 was about twice that of [ 68 Ga]Ga-FAPI-04 and that the accumulation of [ 68 Ga]Ga-(FAPI-04) 2 at the tumor site did not significantly decrease even 3h after injection. The tumor−abdomen ratio of [ 68 Ga]Ga-(FAPI-04) 2 images was significantly higher than that of [ 18 F]F-FDG images. For radionuclide therapy, [ 177 Lu]Lu-(FAPI-04) 2 effectively retarded tumor growth and displayed good tolerance. In conclusion, the DOTA-Suc-Lys-(FAPI-04) 2 design enhanced its uptake in FAP-expressing tumors, improved its retention time at the tumor site, and produced high-contrast imaging in xenografts after radionuclide labeling. Furthermore, it showed a noticeable antitumor effect. DOTA-Suc-Lys-(FAPI-04) 2 provides a new approach for applying FAPI derivatives in tumor theranostics.
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