title: Temozolomide delivery to tumor cells by a multifunctional nano vehicle based on poly(β-L-malic acid).
abstract: OBJECTIVE
  Temozolomide (TMZ) is a pro-drug releasing a DNA alkylating agent that is the most effective drug to treat glial tumors when combined with radiation. TMZ is toxic, and therapeutic dosages are limited by severe side effects. Targeted delivery is thus needed to improve efficiency and reduce non-tumor tissue toxicity.
  
  
  METHODS
  Multifunctional targetable nanoconjugates of TMZ hydrazide were synthesized using poly(β-L-malic acid) platform, which contained a targeting monoclonal antibody to transferrin receptor (TfR), trileucine (LLL), for pH-dependent endosomal membrane disruption, and PEG for protection.
  
  
  RESULTS
  The water-soluble TMZ nanoconjugates had hydrodynamic diameters in the range of 6.5 to 14.8 nm and ζ potentials in the range of -6.3 to -17.7 mV. Fifty percent degradation in human plasma was observed in 40 h at 37°C. TMZ conjugated with polymer had a half-life of 5-7 h, compared with 1.8 h for free TMZ. The strongest reduction of human brain and breast cancer cell viability was obtained by versions of TMZ nanoconjugates containing LLL and anti-TfR antibody. TMZ-resistant cancer cell lines were sensitive to TMZ nanoconjugate treatment.
  
  
  CONCLUSIONS
  TMZ-polymer nanoconjugates entered the tumor cells by receptor-mediated endocytosis, effectively reduced cancer cell viability, and can potentially be used for targeted tumor treatment.
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, 8631 W. Third Street, Suite 800E, Los Angeles, California 90048, USA.
authors.forename: Rameshwar
authors.initials: R
authors.lastname: Patil
authors.forename: José
authors.initials: J
authors.lastname: Portilla-Arias
authors.forename: Hui
authors.initials: H
authors.lastname: Ding
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Bindu
authors.initials: B
authors.lastname: Konda
authors.forename: Jinwei
authors.initials: J
authors.lastname: Hu
authors.forename: Kolja A
authors.initials: KA
authors.lastname: Wawrowsky
authors.forename: Paul K
authors.initials: PK
authors.lastname: Shin
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.forename: Eggehard
authors.initials: E
authors.lastname: Holler
authors.forename: Julia Y
authors.initials: JY
authors.lastname: Ljubimova
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D008081:Liposomes; D008293:Malates / Q000737:chemistry*; D008970:Molecular Weight; D053758:Nanoparticles; D011108:Polymers / Q000737:chemistry*; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D008293:Malates; D011108:Polymers; C074640:poly(malate); D003606:Dacarbazine; D000077204:Temozolomide
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