title: Lyophilized Cheliensisin A submicron emulsion for intravenous injection: characterization, in vitro and in vivo antitumor effect.
abstract: Growing attentions have been focused on natural antitumor drugs. Recently, a novel and potent antitumor drug Cheliensisin A (GC-51) with broad-spectrum efficiency has been developed. However, due to its poor water solubility and chemical instability, choosing the appropriate dosage form is of great significance. This study aimed at developing a lyophilized submicron emulsion for GC-51 and further improving the therapeutic index of the drug. The resultant lyophilized GC-51 submicron emulsion was much more stable than its solution, which can be stored for years without significant change on physicochemical properties. And its solubility was increased from 6.74+/-0.14 to 2.00+/-0.10 mg mL(-1). The 50% inhibitory concentration IC50 values were calculated from growth curves by MTT assay on various tumor cell lines. Compared with the IC50 of GC-51 crude drug, that of lyophilized GC-51 submicron emulsion decreased from 24.04+/-1.97 to 8.23+/-1.84 microg mL(-1) on HepG2, and from 31.08+/-2.56 to 10.85+/-2.09 microg mL(-1) on CT-26, from 17.90+/-1.83 to 7.49+/-1.87 microg mL(-1) on HeLa and from 16.38+/-2.41 to 10.13+/-2.12 microg mL(-1) on A549, respectively. In the time-dependent assay of tumor cell viability, lyophilized GC-51 submicron emulsion exhibited significantly lower inhibition rate in the initial action times, but increased gradually afterwards. That means lyophilized submicron emulsion as the vector for GC-51 had some protective and delayed release effect. Further, the in vivo therapeutic efficacy was measured in pulmonary metastasis of colon cancer-bearing BALB/c mice model. An obvious enhanced antitumor activity was observed after administration of lyophilized GC-51 submicron emulsion (P<0.05), which increased from 22.78+/-3.5 to 41.42+/-4.2% compared with GC-51 injection. And the life span of tumor-bearing mice in lyophilized GC-51 submicron emulsion group was significantly longer than that of the mice in GC-51 injection and normal saline groups. Compared with crude drug, the lyophilized GC-51 submicron emulsion showed a significantly higher antitumor efficiency both in vivo and in vitro, suggesting a potential application in tumor chemotherapy.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education West China School of Pharmacy, Sichuan University, Southern Renmin Road, No. 17, Section 3, Chengdu 610041, PR China.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhao
authors.forename: Tao
authors.initials: T
authors.lastname: Gong
authors.forename: Yao
authors.initials: Y
authors.lastname: Fu
authors.forename: Yu
authors.initials: Y
authors.lastname: Nie
authors.forename: Li-Li
authors.initials: LL
authors.lastname: He
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003110:Colonic Neoplasms / Q000473:pathology; D004355:Drug Stability; D004563:Electrochemistry; D004655:Emulsions; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D005612:Freeze Drying; D006367:HeLa Cells; D006801:Humans; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D010316:Particle Size; D011753:Pyrones / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D016019:Survival Analysis
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004655:Emulsions; D004852:Epoxy Compounds; D011753:Pyrones; C504861:cheliensisin A