Polyvalent dendrimer-methotrexate as a folate receptor-targeted cancer therapeutic.
Polyvalent dendrimer-methotrexate as a folate receptor-targeted cancer therapeutic.
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DOI：
10.1021/mp3002232
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发表时间：
2012-09-04
影响因子：
4.9
通讯作者：
Baker JR Jr
中科院分区：
文献类型：
--
作者：
Thomas TP;Huang B;Choi SK;Silpe JE;Kotlyar A;Desai AM;Zong H;Gam J;Joice M;Baker JR Jr
我们以前的研究已经证明，与叶酸（FA）和甲氨蝶呤（MTX）结合的第5代树枝状聚合物（G5）具有比单独MTX更高的化疗指数。尽管如此，与每个树枝状聚合物连接的FA和MTX分子数量的批次间不一致导致具有不同生物活性的缀合物批次，特别是当尝试放大合成时。由于MTX是通过酯键结合的，因此人们担心血清酯酶活性和靶向结合物的生物利用度差异也可能导致生物学不一致。为了解决这些问题，我们采取了一种新的方法来合成多价G5-MTX n共轭物通过点击化学，连接MTX的树枝状聚合物通过酯酶稳定的酰胺键。表面等离子体共振结合研究表明，以这种方式合成的G5-MTX 10缀合物通过多价相互作用与FA受体（FR）结合，显示出比游离MTX高4300倍的亲和力。该缀合物抑制二氢叶酸还原酶，并通过FR特异性细胞内化在表达FR的KB细胞中诱导细胞毒性。因此，树枝状聚合物上的多价MTX起到作为靶向分子以及化疗药物的双重作用。新合成的G5-MTXn缀合物可作为具有癌症治疗潜力的FR靶向化疗剂。
Our previous studies have demonstrated that a generation 5 dendrimer (G5) conjugated with both folic acid (FA) and methotrexate (MTX) has a higher chemotherapeutic index than MTX alone. Despite this, batch-to-batch inconsistencies in the number of FA and MTX molecules linked to each dendrimer led to conjugate batches with varying biological activity, especially when scaleup synthesis was attempted. Since the MTX is conjugated through an ester linkage, there were concerns that biological inconsistency could also result from serum esterase activity and differential bioavailability of the targeted conjugate. In order to resolve these problems, we undertook a novel approach to synthesize a polyvalent G5–MTXn conjugate through click chemistry, attaching the MTX to the dendrimer through an esterase-stable amide linkage. Surface plasmon resonance binding studies show that a G5–MTX10 conjugate synthesized in this manner binds to the FA receptor (FR) through polyvalent interaction showing 4300-fold higher affinity than free MTX. The conjugate inhibits dihydrofolate reductase, and induces cytotoxicity in FR-expressing KB cells through FR-specific cellular internalization. Thus, the polyvalent MTX on the dendrimer serves the dual role as a targeting molecule as well as a chemotherapeutic drug. The newly synthesized G5–MTXn conjugate may serve as a FR-targeted chemotherapeutic with potential for cancer therapy.
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影响因子：
17.1
作者：
Mullen DG;Fang M;Desai A;Baker JR;Orr BG;Banaszak Holl MM
通讯作者：
Banaszak Holl MM
影响因子：
7.3
作者：
Majoros, IJ;Thomas, TP;Baker, JR
通讯作者：
Baker, JR
影响因子：
15
作者：
Arranz-Plaza, E;Tracy, AS;Boons, GJ
通讯作者：
Boons, GJ
影响因子：
11.2
作者：
Kukowska-Latallo, JF;Candido, KA;Baker, JR
通讯作者：
Baker, JR
影响因子：
1.8
作者：
Huang, Baohua;Desai, Ankur;Zong, Hong;Tang, Shengzhuang;Leroueil, Pascale;Baker, James R., Jr.
通讯作者：
Baker, James R., Jr.