Enhanced cellular uptake and intracellular drug controlled release of VESylated gemcitabine prodrug nanocapsules.
Gemcitabine, 2',2'-difluoro-2'-deoxycytidine (dFdC), is the first-line antitumor agent in the treatment of pancreatic tumors. However, it possesses certain drawbacks, such as poor biological half-life resulted from rapid metabolism and the induction of resistance, leading to its restricted therapeutic potential. With the purpose of overcoming the above drawbacks, we developed a novel VESylated gemcitabine (VES-dFdC) prodrug by coupling the N4-amino group of the pyrimidine ring of dFdC to the carboxylic group of vitamin E succinate (VES). The resulting amphiphilic compound could protect the N4-amino group of the pyrimidine ring of dFdC from being degraded by cytidine deaminase. What is more, the prodrug was able to form nanocapsules in aqueous media (similar to the structure of cytomembrane), confirmed by transmission electron microscope (TEM). Their average particle size is about 107 nm with zeta potential of -33.4 mV measured by dynamic light scattering (DLS). VES-dFdC nanocapsules showed accelerated accumulative drug release profile in simulated lysosome environment (sodium acetate buffer pH 5+cathepsin B, an enzyme in lysosome), due to the easily hydrolyzed property of amide bond by cathepsin B, while rather stable in PBS (pH 7.4) or sodium acetate buffer (pH 5.0) without cathepsin B, indicating their enhanced intracellular drug controlled release manner. Besides, VES-dFdC prodrug nanocapsules showed enhanced cellular uptake ability, and the amount of cellular uptake of the nanocapsules by the pancreatic cancer cell line BxPC-3 is seventy times higher than that of native gemcitabine in the first 1.5 h. Compared with free gemcitabine, VES-dFdC nanocapsules showed essentially increased growth inhibition activity against BxPC-3 cells, indicating its great potential as prodrug for pancreatic tumor therapy with improved antitumor activity.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
Yanfen
Y
Fang
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China; Institute of Chemistry and Biochemistry, Free University Berlin, Takustr 3, 14195 Berlin, Germany.
Fang
F
Du
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
Yanyun
Y
Xu
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College 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.
Haijing
H
Meng
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China; College of Chemical Engineering, Wuhan University of Technology, Wuhan 430070, PR China.
Jin
J
Huang
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
Xiongwen
X
Zhang
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
Wei
W
Lu
Department of Diagnostic Imaging, ChangZheng Hospital, Shanghai 200003, PR China.
Shiyuan
S
Liu
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, College of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China. Electronic address: jhyu@sist.ecnu.edu.cn.
Jiahui
J
Yu
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001692:Biological Transport; D002021:Buffers; D002401:Cathepsin B / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003564:Cytidine Deaminase / Q000737:chemistry; D003692:Delayed-Action Preparations; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D065546:Drug Liberation; D004355:Drug Stability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000737:chemistry; D046529:Microscopy, Electron, Transmission; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D010316:Particle Size; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D024505:Tocopherols / Q000737:chemistry*; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D002021:Buffers; D003692:Delayed-Action Preparations; D053769:Nanocapsules; D011355:Prodrugs; D003841:Deoxycytidine; D002401:Cathepsin B; D003564:Cytidine Deaminase; D024505:Tocopherols; D000093542:Gemcitabine
Enhanced cellular uptake; Intracellular drug controlled release; Nanocapsules; VESylated gemcitabine