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Jin-Shuai Lan,1,2,* Yan-Hong Qin,2,* Li Liu,2 Rui-Feng Zeng,2 Yang Yang,3 Kai Wang,3 Yue Ding,1,2 Tong Zhang,1,2 Rodney JY Ho4 1Experiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 3Science and Technology Experimental Center, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 4Department of Pharmaceutics, University of Washington, Seattle, WA, 98195, USA*These authors contributed equally to this workCorrespondence: Tong Zhang; Yue DingExperiment Centre of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong New District, Shanghai, 201203, People’s Republic of ChinaTel +86 21 5132 2318; Tel +86 21 5132 2325Email zhangtongshutcm@hotmail.com; dingyue1640@shutcm.edu.cnPurpose: To avoid undefined metabolic mechanisms and to eliminate potential side effects of traditional nanocarriers, new green carriers are urgently needed in cancer treatment. Carrier-free nanoparticles (NPs) based on ursolic acid (UA) have attracted significant attention, but the UA NPs targeting the folate receptor have never been explored. We designed a novel self-assembled UA-Methotrexate (MTX) NPs targeting the folate-receptor and its synergetic anticancer activity was studied in vitro and in vivo.Methods: UA-MTX NPs were prepared using the solvent precipitation method. Characterization of the UA-MTX NPs preparation was performed using a size analyzer, transmission electron microscopy, and UV-vis spectrophotometry. The in vitro pH-responsive drug release capability of UA-MTX NPs was tested at different pH values. The UA-MTX NPs targeting of folates was determined by comparing the endocytosis rates of cell lines with low or overexpression of the folate receptor (A549 and MCF-7 cells). The cytotoxicity and cell apoptosis of UA-MTX NPs were also studied to determine the in vitro synergistic effects. Combination chemotherapy of UA-MTX NPs in vivo was evaluated using MCF-7 xenografted tumor models.Results: Compared with free UA or MTX, the water solubility of UA-MTX NPs improved significantly. Drug-release from the UA-MTX NPs was faster at pH 5.0 than pH 7.4, suggesting MTX-UA NPs could rapidly release MTX in the acidic conditions of the tumor microenvironment. Confocal laser scanning microscopy revealed the excellent folate receptor targeting of UA-MTX NPs in MCF-7 cells. Cytotoxicity and cell apoptosis results demonstrated greater antiproliferative capacity of UA-MTX NPs than that of free drug in folate receptor overexpressing MCF-7 cells. Anticancer effects in vivo suggested MTX-UA NPs exhibited good biological safety and could enhance antitumor efficacy due to the combination therapy.Conclusion: Our findings indicate that the UA-MTX NPs targeting folate-receptors is an efficient strategy for combination chemotherapy.Keywords: ursolic acid, methotrexate, anticancer, carrier free, targeted drug delivery

Terbium-161 (161Tb) is a potential radiolanthanide due to its favorable properties for treatment small size of cancer. Preliminary study on radiochemical separation of 161Tb from Gd/Tb matrix using Ln resin column based on extraction chromatography method has been carried out. 161Tb radionuclide was produced by irradiation of natural Gd2O3 target through neutron thermal bombardment at G.A. Siwabessy Multipurpose Reactor. Fractions eluted from the column containing Gd/Tb matrix of irradiated natural Gd2O3 target were identified and quantified using a γ-rays spectrometer with HP-Ge detector coupled to a multichannel analyzer. The results show that the optimum condition on 161Tb separation from irradiated Gd2O3 target with radionuclide purity 99.27 ± 0.30% was obtained using HNO3 solution with concentration of 0.8 and 3 N to separate gadolinium and terbium isotope, respectively. The yield of 161Tb obtained from the separation was 61.21 ± 2.05% and Gd recovered was 97.15 ± 2.23%. Based on this experiment, 161Tb has been separated from irradiated natural gadolinium oxide target with high radionuclide purity.