PSMA-Targeted Stably Linked 鈥淒endrimer-Glutamate Urea-Methotrexate鈥?as a Prostate Cancer Therapeutic

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• 作者：Baohua Huang ; James Otis ; Melvin Joice ; Alina Kotlyar ; Thommey P. Thomas
• 刊名：Biomacromolecules
• 出版年：2014
• 出版时间：March 10, 2014
• 年：2014
• 卷：15
• 期：3
• 页码：915-923
• 全文大小：429K
• 年卷期：v.15,no.3(March 10, 2014)
• ISSN：1526-4602

文摘

One of the important criteria for achieving efficient nanoparticle-based targeted drug delivery is that the drug is not prematurely released at off-target sites. Here we report the preclinical evaluation of a serum-stable dendrimer-based drug conjugate capable of actively targeting into prostate cancer (PC) cells, delivered through the prostate-specific membrane antigen (PSMA). Multiple molecules of PSMA-binding small molecule glutamate urea (GLA; targeting agent) and the drug methotrexate (MTX) were conjugated to generation 5 PAMAM dendrimer (G5) through Cu-free 鈥渃lick鈥?chemistry. The GLA was conjugated through a stable amide bond, and the MTX was conjugated either through ester (Es)- or amide (Am)-coupling, to generate G5-GLA_m-(Es)MTX_n and G5-GLA_m-(Am)MTX_n, respectively. In serum-containing medium, free MTX was slowly released from 鈥淕5-GLA_m-(Es)MTX_n鈥? with 8% MTX released from the dendrimer in 72 h, whereas the MTX on G5-GLA_m-(Am)MTX_n was completely stable. The G5-GLA_m-(Am)MTX_n bound and internalized into PSMA-expressing LNCaP cells, but not into PSMA-negative PC3 cells. The conjugate-inhibited recombinant dihydrofolate reductase and induced potent cytotoxicity in the LNCaP cells, but not in the PC3 cells. Similar to the action of free GLA, stable amide-linked dendrimer-GLA was capable of inhibiting the enzyme N-acetylated 伪-linked acidic dipeptidase (NAALADase) activity of PSMA. The G5-GLA_m-MTX_n may serve as a serum-stable nanoparticle conjugate to specifically and effectively target and treat PSMA-overexpressing prostate tumors.