Leung Kam
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Integrin receptors are a family of cell-surface heterodimeric glycoproteins that mediate diverse biological events (e.g., cell adhesion, migration, differentiation, proliferation, and apoptosis) involving cell–cell and cell–matrix interactions (1, 2). They consist of an α and a β subunit. They are important for cell adhesion and signal transduction. On the other hand, integrins affect tumor growth, tumor invasiveness, and metastasis (3, 4). The αβ integrin binds mainly to collagen type I, laminins, E-cadherin, and matrix metalloproteinase 1 (5). The αβ integrin is strongly expressed on tumor cells and has been implicated in tumor progression and metastasis (6, 7). In particular, prostate cancer cells and prostate cancer stem cells express high levels of αβ integrin (8, 9). A tetrapeptide sequence consisting of Asp-Gly-Glu-Ala (DGEA) has been identified as a recognition motif used by the type I collagen to bind to αβ integrin (10). DGEA was conjugated with Cy5.5 to study biodistribution of the tracer in prostate tumor-bearing mice (11). Cy5.5-DGEA exhibited high accumulation in the αβ-positive PC-3 human prostate tumor cells and kidneys in nude mice. Optical and positron emission tomography imaging with various DGEA peptides showed high kidney accumulation and high tumor washout rates (11-13). To induce high tumor retention, multiple Arg molecules have been added to DGEA to help cell penetration (14). A small linker (Gly-Lys-OH) was added to the C-terminal Ala of DGEA to reduce kidney accumulation (15). The Gly-Lys bond is cleaved by the kidney brush border Lys-specific carboxypeptidase before entering the proximal tubule cells for kidney clearance. Huang et al. (16) prepared Cy5.5-Asp-Gly-Glu-Ala-Gly-Lys-(Arg)-OH (Cy5.5-DGEAGK(R8)-OH) for optical imaging in mice bearing αβ-positive PC-3 prostate tumors with lower kidney accumulation and better tumor retention than Cy5.5-DGEAGK(R4)-OH and R4-DGEAGK(Cy5.5)-OH.
整合素受体是一类细胞表面异二聚体糖蛋白，介导涉及细胞 - 细胞和细胞 - 基质相互作用的多种生物学事件（如细胞粘附、迁移、分化、增殖和凋亡）(1, 2)。它们由一个α亚基和一个β亚基组成。它们对细胞粘附和信号转导很重要。另一方面，整合素影响肿瘤生长、肿瘤侵袭和转移(3, 4)。αβ整合素主要与I型胶原、层粘连蛋白、E - 钙粘蛋白和基质金属蛋白酶1结合(5)。αβ整合素在肿瘤细胞上强烈表达，并与肿瘤进展和转移有关(6, 7)。特别是，前列腺癌细胞和前列腺癌干细胞高水平表达αβ整合素(8, 9)。由天冬氨酸 - 甘氨酸 - 谷氨酸 - 丙氨酸（DGEA）组成的四肽序列已被确定为I型胶原用于与αβ整合素结合的识别基序(10)。DGEA与Cy5.5偶联，以研究该示踪剂在荷前列腺肿瘤小鼠中的生物分布(11)。Cy5.5 - DGEA在裸鼠的αβ阳性PC - 3人前列腺肿瘤细胞和肾脏中表现出高蓄积。用各种DGEA肽进行光学和正电子发射断层扫描成像显示肾脏高蓄积和高肿瘤洗脱率(11 - 13)。为了诱导高肿瘤滞留，已将多个精氨酸分子添加到DGEA中以帮助细胞穿透(14)。一个小的连接子（甘氨酸 - 赖氨酸 - OH）被添加到DGEA的C末端丙氨酸上以减少肾脏蓄积(15)。甘氨酸 - 赖氨酸键在进入近端小管细胞进行肾脏清除之前被肾刷状缘赖氨酸特异性羧肽酶切割。黄等人(16)制备了Cy5.5 - 天冬氨酸 - 甘氨酸 - 谷氨酸 - 丙氨酸 - 甘氨酸 - 赖氨酸 -（精氨酸）- OH（Cy5.5 - DGEAGK(R8)-OH），用于在荷αβ阳性PC - 前列腺肿瘤的小鼠中进行光学成像，与Cy5.5 - DGEAGK(R4)-OH和R4 - DGEAGK(Cy5.5)-OH相比，其肾脏蓄积更低，肿瘤滞留更好。
