title: Preparation of intravenous injection nanoformulation of VESylated gemcitabine by co-assembly with TPGS and its anti-tumor activity in pancreatic tumor-bearing mice.
abstract: Our recent publication showed that VES-dFdC nanocapsules in pure water could be obtained via the self-assembling of VES-dFdC prodrug synthesized by coupling gemcitabine (dFdC) with vitamin E succinate (VES). To prepare the intravenous injection nanoformulation, we present here a novel strategy to improve the stability and drug concentration of VES-dFdC nanoformulation in PBS or isotonic solution. Particularly, D-α-tocopheryl polyethylene glycol succinate (TPGS), usually used as drug solubilizer and coincidentally contains the same VES moiety as VES-dFdC prodrug and PEG chain, is selected to co-assemble with VES-dFdC prodrug. The zeta potentials of all the TPGS/VES-dFdC co-assemblies were close to 0 mV, and their particle size measured by dynamic light scattering (DLS) decreased from 113 to 36 nm with increasing TPGS/VES-dFdC molar ratios from 0.15 to 1.5. Stable colloidal suspensions were obtained without aggregates in PBS at 4 °C in one month or isotonic solution at 37 °C in one week, and the weight concentration of VES-dFdC prodrug increased from 7 to 17 mg/mL when the molar ratios of TPGS/VES-dFdC ranged from 0.5/1 to 1.5/1. The concentration of VES-dFdC prodrug was high enough to be used as intravenous injection nanoformulation in nude mice. Interestingly, along with the increase of TPGS/VES-dFdC molar ratios from 0.3/1 to 1.5/1, the morphology of TPGS/VES-dFdC co-assemblies changed from loose nanocapsule to compact micelle revealed by transmission electron microscope (TEM). Finally, the co-assembly of TPGS/VES-dFdC (TPGS/VES-dFdC: 1/1) was selected as intravenous injection nanoformulation to evaluate the antitumor activity. Compared with native dFdC, TPGS/VES-dFdC nanoformulation with 0.2mmol/kg of dosage showed similar low toxicity in vivo, but 4.7 times high of tumor inhibition rate in nude mice with pre-established BxPC-3 tumors.
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China; Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw 01-224, Poland.
authors.forename: Haijing
authors.initials: H
authors.lastname: Meng
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China; Institute of Chemistry and Biochemistry, Free University Berlin, Berlin, Takustr. 3 14195, Germany.
authors.forename: Fang
authors.initials: F
authors.lastname: Du
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Diagnostic Imaging, ChangZheng Hospital, Shanghai 200003, PR China.
authors.forename: Shiyuan
authors.initials: S
authors.lastname: Liu
authors.affiliation: College of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan 430070, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China. Electronic address: jhyu@sist.ecnu.edu.cn.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Yu
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry; D004355:Drug Stability; D004356:Drug Storage; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs; D014810:Vitamin E / Q000031:analogs & derivatives / Q000737:chemistry; D024502:alpha-Tocopherol / Q000737:chemistry; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D011355:Prodrugs; D003841:Deoxycytidine; D014810:Vitamin E; D011092:Polyethylene Glycols; D024502:alpha-Tocopherol; C014225:tocophersolan; D000093542:Gemcitabine
keywords: Antitumor activity; Chemical compounds studied in this article 2,2’-difluorodeoxycytidine (PubChem CID:60750); Co-assembly; Intravenous injection nanoformulation; Methyl thiazolyl tetrazolium (PubChem CID:64965); TPGS; VES-dFdC; Vitamin E succinate (PubChem CID:20353); d-α-Tocopheryl polyethylene glycol succinate (PubChem CID:71406)