Self-Assembling Monomeric Nucleoside Molecular Nanoparticles Loaded with 5-FU Enhancing Therapeutic Efficacy against Oral Cancer.
Conventional oligonucleotide based drug delivery systems suffer from lengthy synthetic protocols, high cost, and poor chemical or enzymatic stability under certain circumstances. Canonical free individual nucleosides cannot form stable nanostructures in aqueous solution as drug vehicles. Here, we report the development of a monomeric self-assembled nucleoside nanoparticle (SNNP) into an efficient drug delivery system which has currently no parallel in such field. This was achieved using a l-configurational pyrimido[4,5-d]pyrimidine nucleoside building block that can form robust discrete nanoparticles in just one step with water as the sole solvent. Its high biocompatibility and low toxicity was demonstrated in vitro and in vivo. In mouse xenograft model of oral squamous cell carcinoma (OSCC), SNNP loaded with 5-fluoro-uracile (5-FU-SNNP) remarkably retarded the tumor growth compared with free 5-FU, albeit SNNP alone showed no antitumor effect. The stability in blood circulation and the effective concentration of 5-FU in tumor tissue were increased upon the loading with SNNP. TUNEL and immunohistochemistry analyses further indicated that the superior in vivo antitumor efficacy of 5-FU-SNNP compared to free 5-FU was associated with an enhanced degree of inhibition of cell proliferation and stimulation of cell apoptosis. Furthermore, SNNP alleviated the toxic side effects of 5-FU. These findings suggested that when loaded with SNNP, 5-FU has better antitumor efficacy and lower side effects, indicating that SNNP can efficiently act as a readily accessible, robust, biocompatible and low-toxic nanobiomaterial which may find wide therapeutic applications clinically in the future.
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.|Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, West China Hospital, West China Medical School, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Hang
H
Zhao
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.|XiangYa Stomatological Hospital, Central South University , Changsha, Hunan 410000, P. R. China.
Hui
H
Feng
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Dongjuan
D
Liu
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.|Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, West China Hospital, West China Medical School, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Jiang
J
Liu
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Ning
N
Ji
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Fangman
F
Chen
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Xiaobo
X
Luo
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Yu
Y
Zhou
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Hongxia
H
Dan
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Xin
X
Zeng
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Jing
J
Li
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Congkui
C
Sun
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Jinyu
J
Meng
School of Chemical Engineering, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Xiaojie
X
Ju
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Min
M
Zhou
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Hanshuo
H
Yang
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Longjiang
L
Li
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Xinhua
X
Liang
School of Chemical Engineering, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Liangyin
L
Chu
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Lu
L
Jiang
Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, West China Hospital, West China Medical School, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Yang
Y
He
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University , Chengdu, Sichuan 610041, P. R. China.
Qianming
Q
Chen
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009055:Mouth / Q000187:drug effects / Q000473:pathology; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D011741:Pyrimidine Nucleosides / Q000737:chemistry*
D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D011741:Pyrimidine Nucleosides; D005472:Fluorouracil
5-FU; J-TA ribonucleoside nanoparticles; cancer therapy; drug delivery systems; self-assembled