title: Multi-small molecule conjugations as new targeted delivery carriers for tumor therapy.
abstract: In response to the challenges of cancer chemotherapeutics, including poor physicochemical properties, low tumor targeting ability, and harmful side effects, we developed a new tumor-targeted multi-small molecule drug delivery platform. Using paclitaxel (PTX) as a model therapeutic, we prepared two prodrugs, ie, folic acid-fluorescein-5(6)-isothiocyanate-arginine-paclitaxel (FA-FITC-Arg-PTX) and folic acid-5-aminofluorescein-glutamic-paclitaxel (FA-5AF-Glu-PTX), composed of folic acid (FA, target), amino acids (Arg or Glu, linker), and fluorescent dye (fluorescein in vitro or near-infrared fluorescent dye in vivo) in order to better understand the mechanism of PTX prodrug targeting. In vitro and acute toxicity studies demonstrated the low toxicity of the prodrug formulations compared with the free drug. In vitro and in vivo studies indicated that folate receptor-mediated uptake of PTX-conjugated multi-small molecule carriers induced high antitumor activity. Notably, compared with free PTX and with PTX-loaded macromolecular carriers from our previous study, this multi-small molecule-conjugated strategy improved the water solubility, loading rate, targeting ability, antitumor activity, and toxicity profile of PTX. These results support the use of multi-small molecules as tumor-targeting drug delivery systems.
authors.affiliation: Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People's Republic of China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Shan
authors.affiliation: Department of Biology, University of South Dakota, Vermillion, SD, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wu
authors.affiliation: Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Biomedical Engineering, School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Siwen
authors.initials: S
authors.lastname: Li
authors.affiliation: Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People's Republic of China.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Xu
authors.affiliation: Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People's Republic of China.
authors.forename: Wengen
authors.initials: W
authors.lastname: Cao
authors.affiliation: Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Suzhou University, Suzhou, People's Republic of China.
authors.forename: Guizhen
authors.initials: G
authors.lastname: Gao
authors.affiliation: Department of Biomedical Engineering, School of Life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Yueqing
authors.initials: Y
authors.lastname: Gu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry / Q000494:pharmacology; D005492:Folic Acid / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D023382:Toxicity Tests, Acute; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D011355:Prodrugs; C000610507:folic acid-5-aminofluorescein-glutamic-paclitaxel; C000610506:folic acid-fluorescein-5(6)-isothiocyanate-arginine-paclitaxel; D018698:Glutamic Acid; D005492:Folic Acid; D001120:Arginine; D016650:Fluorescein-5-isothiocyanate; D017239:Paclitaxel
keywords: multi-small molecules; paclitaxel; prodrugs; targeting; tumor therapy