Polyvalent Dendrimer-Methotrexate as a Folate Receptor-Targeted Cancer Therapeutic
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- 作者：Thommey P. Thomas ; Baohua Huang ; Seok Ki Choi ; Justin E. Silpe ; Alina Kotlyar ; Ankur M. Desai ; Hong Zong ; Jeremy Gam ; Melvin Joice ; James R. Baker ; Jr.
- 刊名：Molecular Pharmaceutics
- 出版年：2012
- 出版时间：September 4, 2012
- 年：2012
- 卷：9
- 期：9
- 页码：2669-2676
- 全文大小：359K
- 年卷期：v.9,no.9(September 4, 2012)
- ISSN：1543-8392
文摘
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鈥揗TXn 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鈥揗TX10 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鈥揗TXn conjugate may serve as a FR-targeted chemotherapeutic with potential for cancer therapy.