PURPOSE: 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.
PURPOSE: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: Roger Stupp; Warren P Mason; Martin J van den Bent; Michael Weller; Barbara Fisher; Martin J B Taphoorn; Karl Belanger; Alba A Brandes; Christine Marosi; Ulrich Bogdahn; Jürgen Curschmann; Robert C Janzer; Samuel K Ludwin; Thierry Gorlia; Anouk Allgeier; Denis Lacombe; J Gregory Cairncross; Elizabeth Eisenhauer; René O Mirimanoff Journal: N Engl J Med Date: 2005-03-10 Impact factor: 91.245
Authors: Bong-Seop Lee; Manabu Fujita; Natalya M Khazenzon; Kolja A Wawrowsky; Sebastian Wachsmann-Hogiu; Daniel L Farkas; Keith L Black; Julia Y Ljubimova; Eggehard Holler Journal: Bioconjug Chem Date: 2006 Mar-Apr Impact factor: 4.774
Authors: Manabu Fujita; Bong-Seop Lee; Natalya M Khazenzon; Manuel L Penichet; Kolja A Wawrowsky; Rameshwar Patil; Hui Ding; Eggehard Holler; Keith L Black; Julia Y Ljubimova Journal: J Control Release Date: 2007-06-05 Impact factor: 9.776
Authors: David N Louis; Hiroko Ohgaki; Otmar D Wiestler; Webster K Cavenee; Peter C Burger; Anne Jouvet; Bernd W Scheithauer; Paul Kleihues Journal: Acta Neuropathol Date: 2007-07-06 Impact factor: 17.088
Authors: Hui Ding; Jose Portilla-Arias; Rameshwar Patil; Keith L Black; Julia Y Ljubimova; Eggehard Holler Journal: Biomaterials Date: 2011-04-22 Impact factor: 12.479
Authors: Hui Ding; Irving Fox; Rameshwar Patil; Anna Galstyan; Keith L Black; Julia Y Ljubimova; Eggehard Holler Journal: J Nanomater Date: 2017-05-21 Impact factor: 2.986
Authors: Rameshwar Patil; Pallavi R Gangalum; Shawn Wagner; Jose Portilla-Arias; Hui Ding; Arthur Rekechenetskiy; Bindu Konda; Satoshi Inoue; Keith L Black; Julia Y Ljubimova; Eggehard Holler Journal: Macromol Biosci Date: 2015-06-02 Impact factor: 4.979
Authors: Qingxin Mu; Mike Jeon; Meng-Hsuan Hsiao; Victoria K Patton; Kui Wang; Oliver W Press; Miqin Zhang Journal: Adv Healthc Mater Date: 2015-03-11 Impact factor: 9.933
Authors: Chen Fang; Kui Wang; Zachary R Stephen; Qingxin Mu; Forrest M Kievit; Daniel T Chiu; Oliver W Press; Miqin Zhang Journal: ACS Appl Mater Interfaces Date: 2015-03-18 Impact factor: 9.229