Brachytherapy, as an effective setting for precise cancer therapy in clinic, can lead to serious DNA damage. However, its therapeutic efficacy is always limited by the DNA self‐repair property, tumor hypoxia‐associated radiation resistance as well as inhomogeneous distribution of the radioactive material. Herein, a multifunctional hybrid hydrogel (131I‐hydrogel/DOX/GNPs aggregates) is developed by loading gold nanoparticle aggregates (GNPs aggregates) and DOX into a radionuclide iodine‐131 (131I) labelled polymeric hydrogels (131I‐PEG‐P(Tyr)8) for tumor destruction by completely damaging DNA self‐repair functions. This hybrid hydrogel exhibits excellent photothermal/radiolabel stability, biocompatibility, and fluorescence/photothermal /SPECT imaging properties. After local injection, the sustained releasing DOX within tumor greatly inhibits the DNA replication. Meanwhile, GNPs aggregates as a radiosensitizer and photosensitizer show a significant improvement of brachytherapeutic efficacy and cause serious DNA damage. Simultaneously, GNPs aggregates induce mild photothermal therapy under 808 nm laser irradiation, which not only inhibits self‐repair of the damaged DNA but also effectively relieves tumor hypoxic condition to enhance the therapeutic effects of brachytherapy, leading to a triple‐synergistic destruction of DNA functions. Therefore, this study provides a highly efficient tumor synergistic therapy platform and insight into the synergistic antitumor mechanism in DNA level.
Background: Ursolic acid is a promising anticancer agent. The current study aims to evaluate the single-and multiple-dose pharmacokinetics (PK) as well as the safety of ursolic acid nanoliposomes (UANL) in healthy volunteers and in patients with advanced solid tumors. Methods: Twenty-four healthy volunteers in the single-dose PK study were divided into three different groups, which received 37, 74, and 98 mg/m 2 of UANL. Eight patients in the multiple-dose PK study were administered with 74 mg/m 2 of UANL daily for 14 days. The UA plasma concentrations were determined using ultra-performance liquid chromatograph-tandem mass spectrometry.
Results:The plasma concentration profiles of all subjects were characterized by a biexponential decline after infusion. The mean peak plasma concentration (C max ) increased linearly as a function of the dose (r = 0.999). The mean area under the plasma concentration-time curve (AUC) from 0 to 16 hours also increased proportionally with dose escalation (r = 0.998). However, the clearance was constant over the specific dose interval. In the multiple-dose PK study, the trough and average concentrations remained low. The mean AUC, half-life, C max , time to C max , and the volume of distribution on the first day were similar to those on the last day. All subjects tolerated the treatments well. Most UANL-associated adverse events varied from mild to moderate. Conclusions: UANL exhibits relatively linear PK behavior with dose levels from 37 mg/m 2 to 98 mg/m 2 . No drug accumulation was observed with repeated doses of UANL. The intravenous infusion of UANL was well tolerated by healthy volunteers and patients with advanced tumors.
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