title: Targeted Delivery of Cabazitaxel by Conjugation to Albumin-PEG-folate Nanoparticles Using a Cysteine-acrylate Linker and Simple Synthesis Conditions.
abstract: BACKGROUND
  Cabazitaxel (CBZ) is a new taxane approved by FDA for treatment of castration- resistant prostate cancer not responding to docetaxel. However, CBZ is not a suitable substrate for p-glycoprotein 60, an efflux pump which transports anticancer drugs out of malignant cells and is therefore a promising drug for treatment of multidrug resistant tumors. Similar to other taxanes, the presence of Tween 80 in the CBZ formulation shows that it is insoluble in water.
  
  
  METHODS
  In order to increase the solubility and circulation time of this drug, CBZ-human serum albumin (HSA) conjugate was synthesized. The designed linker was composed of methacrylic acid and N-acetyl cysteine to increase the solubility of CBZ and to increase the efficiency of conjugation. Targeting was performed by poly(ethylene glycol)-folic acid amide bound formation with carboxyl groups of HSA during in the step of nanoparticle formation. Cytotoxicity of nanoparticles was evaluated in vitro on HT-29, as a folate negative cell line, and MDA-MB-231, as a folate positive cell line.
  
  
  RESULTS
  H-NMR, Gel Permeation Chromatography, High Pressure Liquid Chromatography and UV spectrophotometry analysis confirmed the composition of conjugates. The resulting nanoparticles had a spherical shape, narrow size distribution and mean diameter of 138 nm. The efficiency of conjugation was 41.6 %. The IC50 of CBZ in targeted nanoparticles was 10.1 and 17.4% lower than that of the free CBZ for HT-29 and MDA-MB-231 cells, respectively.
  
  
  CONCLUSIONS
  This designed drug delivery system was more water-soluble and had enhanced in vitro characteristics and higher cytotoxic activity on cancer cells.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran. Iran.
authors.forename: Mohammad Kazem
authors.initials: MK
authors.lastname: Khoeeniha
authors.affiliation: Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran. Iran.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Esfandyari-Manesh
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran. Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Behrouz
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran. Iran.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Amini
authors.affiliation: Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran. Iran.
authors.forename: Behrang Shiri
authors.initials: BS
authors.lastname: Varnamkhasti
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran. Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Atyabi
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran. Iran.
authors.forename: Rassoul
authors.initials: R
authors.lastname: Dinarvand
mesh_terms: D000179:Acrylates / Q000737:chemistry; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000737:chemistry; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D005492:Folic Acid / Q000737:chemistry*; D019073:HT29 Cells; D006801:Humans; D008968:Molecular Conformation; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D012709:Serum Albumin / Q000737:chemistry*; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000179:Acrylates; D000970:Antineoplastic Agents; D012709:Serum Albumin; D043823:Taxoids; D011092:Polyethylene Glycols; C552428:cabazitaxel; D005492:Folic Acid; C036658:acrylic acid; D003545:Cysteine
keywords: Cabazitaxel; conjugate; gel permeation chromatography; human serum albumin; nanoparticle; targeting