title: Polymeric tubulysin-peptide nanoparticles with potent antitumor activity.
abstract: OBJECTIVE
  Tubulysins are naturally occurring tetrapeptides with potent antiproliferative activity against multiple cancer cell lines. However, they are also highly toxic in animal models. In order to improve the therapeutic index of this class of compounds, a nanoparticle prodrug of tubulysin A (TubA) was synthesized and evaluated in vitro and in vivo.
  
  
  METHODS
  A thiol derivative of TubA was covalently attached to a linear, beta-cyclodextrin based polymer through a disulfide linker (CDP-TubA). The polymer conjugate assembled into stable nanoparticles. Inhibition of tubulin polymerization and antiproliferative activity of the polymer conjugate were evaluated in vitro. The preclinical efficacy of CDP-TubA administered i.v. was evaluated in nude mice bearing s.c. implanted human HT29 colorectal and H460 non-small cell lung carcinoma tumors.
  
  
  RESULTS
  The IC(50) of CDP-TubA (in Tub A equivalents) was 24, 5, and 10 nmol/L versus 3, 1, and 2 nmol/L for Tub A in NCI-H1299 (lung), HT-29 (colon), and A2780 (ovarian) cell lines, respectively. Tub A and the active thiol derivative were potent inhibitors of tubulin polymerization, whereas CDP-TubA showed minimal inhibition, indicating that target inhibition requires release of the peptide drug from the nanoparticles. The maximum tolerated dose of CDP-TubA was 6 mg/kg (in TubA equivalents) versus 0.05 mg/kg for TubA in nude mice. In vivo, a single treatment cycle of three weekly doses of CDP-TubA showed a potent antitumor effect and significantly prolonged survival compared with TubA alone.
  
  
  CONCLUSIONS
  Cyclodextrin polymerized nanoparticles are an enabling technology for the safe and effective delivery of tubulysins for the treatment of cancer.
authors.affiliation: Insert Therapeutics, Pasadena, California, USA. tschluep@calandopharma.com
authors.forename: Thomas
authors.initials: T
authors.lastname: Schluep
authors.forename: Paula
authors.initials: P
authors.lastname: Gunawan
authors.forename: Ling
authors.initials: L
authors.lastname: Ma
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Jensen
authors.forename: Julienne
authors.initials: J
authors.lastname: Duringer
authors.forename: Steven
authors.initials: S
authors.lastname: Hinton
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Richter
authors.forename: Jungyeong
authors.initials: J
authors.lastname: Hwang
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy*; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D009842:Oligopeptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011108:Polymers; D011355:Prodrugs / Q000494:pharmacology; D012995:Solubility; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D009842:Oligopeptides; D011108:Polymers; D011355:Prodrugs; D014404:Tubulin; D047392:beta-Cyclodextrins; C510756:tubulysin A; C031215:betadex