Temozolomide delivery to tumor cells by a multifunctional nano vehicle based on poly(β-L-malic acid).
Temozolomide delivery to tumor cells by a multifunctional nano vehicle based on poly(β-L-malic acid).
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DOI：
10.1007/s11095-010-0091-0
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发表时间：
2010-11
影响因子：
3.7
通讯作者：
Ljubimova, Julia Y.
中科院分区：
文献类型：
--
作者：
Patil, Rameshwar;Portilla-Arias, Jose;Ding, Hui;Inoue, Satoshi;Konda, Bindu;Hu, Jinwei;Wawrowsky, Kolja A.;Shin, Paul K.;Black, Keith L.;Holler, Eggehard;Ljubimova, Julia Y.
关键词：
替莫唑胺（TMZ）是一种释放DNA烷基化剂的前体药物，与放射联合使用时是治疗神经胶质肿瘤的最有效药物。TMZ是有毒的，治疗剂量受到严重副作用的限制。因此，需要靶向递送以提高效率并降低非肿瘤组织毒性。利用聚（β-L-苹果酸）平台合成了多功能靶向TMZ酰肼纳米缀合物，该缀合物含有转铁蛋白受体（TfR）的靶向单克隆抗体三亮氨酸（LLL），用于pH依赖性内体膜破坏，PEG用于保护。水溶性TMZ纳米缀合物的流体动力学直径在6.5至14.8 nm的范围内，微扰电位在−6.3至−17.7 mV的范围内。在37°C下40小时内观察到人血浆中50%的降解。与聚合物缀合的TMZ的半衰期为5-7小时，而游离TMZ的半衰期为1.8小时。通过含有LLL和抗TfR抗体的TMZ纳米缀合物的形式获得了人脑和乳腺癌细胞活力的最强降低。TMZ抗性癌细胞系对TMZ纳米缀合物治疗敏感。TMZ-聚合物纳米缀合物通过受体介导的内吞作用进入肿瘤细胞，有效地降低癌细胞活力，并且可以潜在地用于靶向肿瘤治疗。
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. 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. 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. 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.
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影响因子：
10.8
作者：
Fujita, Manabu;Lee, Bong-Seop;Ljubimova, Julia Y.
通讯作者：
Ljubimova, Julia Y.
影响因子：
15.9
作者：
Kitange, Gaspar J.;Carlson, Brett L.;Sarkaria, Jann N.
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Sarkaria, Jann N.
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作者：
Kabanov, AV;Batrakova, EV;Alakov, VY
通讯作者：
Alakov, VY
影响因子：
4.1
作者：
Lacroix, M;Abi-Said, D;Sawaya, R
通讯作者：
Sawaya, R
影响因子：
3
作者：
Brem, Sarah;Tyler, Betty;Brem, Henry
通讯作者：
Brem, Henry