Temozolomide delivery to tumor cells by a multifunctional nano vehicle based on poly(β-L-malic acid).
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.
Patil
Rameshwar
R
Department of Neurosurgery, Cedars-Sinai Medical Center, 8631 W. Third Street, Suite 800E, Los Angeles, California 90048, USA.
Portilla-Arias
José
J
Ding
Hui
H
Inoue
Satoshi
S
Konda
Bindu
B
Hu
Jinwei
J
Wawrowsky
Kolja A
KA
Shin
Paul K
PK
Black
Keith L
KL
Holler
Eggehard
E
Ljubimova
Julia Y
JY
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
D000970:Antineoplastic Agents; D008081:Liposomes; D008293:Malates; D011108:Polymers; C074640:poly(malate); D003606:Dacarbazine; D000077204:Temozolomide
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