Chemical design of a radiolabeled gelatinase inhibitor peptide for the imaging of gelatinase activity in tumors

Hanaoka, Hirofumi; Mukai, Takahiro; Habashita, Sayo; Asano, Daigo; Ogawa, Kenji; Kuroda, Yoshihiro; Akizawa, Hiromichi; Iida, Yasuhiko; Endo, Keigo; Saga, Tsuneo; Saji, Hideo

doi:10.1016/j.nucmedbio.2007.04.002

Cited by 30 publications

(28 citation statements)

References 34 publications

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“…Our previously designed compound, 111 In-labeled diethylenetriaminepentaacetic acid (DTPA)-conjugated cCTT, showed a good correlation between its tumor accumulation and MMP-2 activity in the tumor, but the accumulations in MMP-2-expressing tumors were relatively low. 11) Oligomers of b-amino acids, b-peptides, have emerged as a promissing class of peptidomimetics. [13][14][15] It is recognized that one of their important characteristics is to form stable secondary structures with as few as four b-amino acid residues.…”

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confidence: 99%

Synthesis of a .BETA.-Tetrapeptide Analog as a Mother Compound for the Development of Matrix Metalloproteinase-2-Imaging Agents

Mukai

Suganuma

Soejima

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Matrix metalloproteinases (MMPs) comprise a family of enzymes that degrade the basement membrane and extracellular matrix, thus contributing to tissue remodeling and cell migration. 1,2) Numerous studies have demonstrated the various roles of MMPs in pathological processes associated with cancer and atherosclerosis, making MMPs potential targets for diagnosis using noninvasive imaging.3,4) Among MMPs, MMP-2, which degrades a major component of the basement membrane, has been studied extensively and shown to be involved in tumor invasion and metastasis, 5,6) and atherosclerotic plaque rupture. 7,8) For in vivo imaging of MMP-2 activity, we and others used a cyclic decapeptide, cCTTH-WGFTLC (cCTT), as the mother compound because of the clinical and radiopharmaceutical utility of peptide radiopharmaceuticals.9-11) The cyclic decapeptide cCTT was screened as a selective gelatinase (especially MMP-2) inhibitor using phage display technology. Koivunen et al. showed that cyclic decapeptides containing the amino acid sequence His-TrpGly-Phe (HWGF) exhibited selective inhibition toward MMP-2 and MMP-9 activities while a liner peptide containing the HWGF sequence had little inhibitory activity. 10) In tumor-bearing mice, however, both radiolabeled cCTTs exhibited low accumulation in MMP-2-positive tumors. They considered the poor stabilities of these peptides in vivo as one of the causes of low tumor accumulations. Our previously designed compound, 111In-labeled diethylenetriaminepentaacetic acid (DTPA)-conjugated cCTT, showed a good correlation between its tumor accumulation and MMP-2 activity in the tumor, but the accumulations in MMP-2-expressing tumors were relatively low. 11)Oligomers of b-amino acids, b-peptides, have emerged as a promissing class of peptidomimetics. [13][14][15] It is recognized that one of their important characteristics is to form stable secondary structures with as few as four b-amino acid residues. Furthermore, they are entirely stable against proteolytic degradation in vivo. Gademann et al. synthesized a linear b-tetrapeptide analog, Ac-b 3 -HThr-b 2 -HLys-b 3 -HTrp-b 3 -HPhe-NH 2 , to mimic a somatostatin (cyclic 14-mer) in its binding to the human somatostatin receptors, which is known to rest upon a turn containing the amino acid sequence PheTrp-Lys-Thr.16) The turn of the linear b-tetrapeptide analog which has the retro-sequence, is comparable to that of the cyclic a-peptide both in size and orientation of the side chains, although the amide bonds are reversed. These findings led to the design of a linear b-tetrapeptide analog, H-b-His-OH (1), as a downsized derivative to mimic cCTT. In the present study, b-tetrapeptide (1) was prepared by solution-phase synthesis techniques and its inhibitory effect on MMP-2 activity was compared with that of cCTT. To investigate the validity of the drug design, the linear a-tetrapeptides, H-His-Trp-Gly-Phe-OH (2) and H-PheGly-Trp-His-OH (3), were also prepared for comparison (Fig. 1). Results and DiscussionIn general, the preparation of b-amino acids ca...

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confidence: 99%

Synthesis of a .BETA.-Tetrapeptide Analog as a Mother Compound for the Development of Matrix Metalloproteinase-2-Imaging Agents

Mukai

Suganuma

Soejima

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…111 In-radiolabeled CTT was used to measure MPP-2 and MMP-9 expression levels and showed a significant correlation between signal and both normal and tumor tissue MPP activity [133]. However, CTT imaging is currently limited by relatively poor tumor uptake and peptide stability [134].…”

Section: Molecular Imaging Methodsmentioning

confidence: 99%

Molecular imaging in cancer treatment

Michalski

Chen

2010

Eur J Nucl Med Mol Imaging

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The success of cancer therapy can be difficult to predict, as its efficacy is often predicated upon characteristics of the cancer, treatment, and individual that are not fully understood or are difficult to ascertain. Monitoring the response of disease to treatment is therefore essential and has traditionally been characterized by changes in tumor volume. However, in many instances, this singular measure is insufficient for predicting treatment effects on patient survival. Molecular imaging allows repeated in vivo measurement of many critical molecular features of neoplasm, such as metabolism, proliferation, angiogenesis, hypoxia, and apoptosis, which can be employed for monitoring therapeutic response. In this review, we examine the current methods for evaluating response to treatment and provide an overview of emerging PET molecular imaging methods that will help guide future cancer therapies.

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“…Importantly, synthetic and recombinant CTT peptides showed nearly identical inhibitory activities against MMP-2 and MMP-9 (25,(30)(31)(32)(33). In our previous study, we found recombinant CTT peptide, when fused with kringle 5, could inhibit MMP-9 caseinolytic activity in a concentration-dependent manner (25).…”

Section: Characterization and Preparation Of Aarpa And Aarpbmentioning

confidence: 99%

Therapeutic Targeting of Angiogenesis with a Recombinant CTT Peptide–Endostatin Mimic–Kringle 5 Protein

Wang

Yang

2014

Molecular Cancer Therapeutics

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Angiogenesis is required for tumor growth and metastasis, and targeting angiogenesis is a novel anticancer strategy. However, cancer development is a complex multistep process, and single antiangiogenic agents have limited therapeutic efficacy. Here, we report a triple fusion protein, namely CTT peptideendostatin mimic-kringle 5 (AARP), consisting of MMP-2/9-selective inhibitory peptide (CTT peptide) and well-known endogenous antiangiogenic agents (endostatin mimic and kringle 5), which can simultaneously target matrix metalloproteinases (MMP) and endothelial cells, blocking their actions. AARP was bacterially expressed, and biologic activity of purified AARP was assessed. AARP could significantly inhibit the enzymatic activity of MMP-2/9, proliferation, migration, and tube formation of endothelial cells in vitro. The antitumor activity of AARP was shown in a concentration-dependent manner when injected i.p. into immunodeficient mice bearing multidrug-resistant human epidermoid carcinomas (KB), and AARP is superior to clinical grade endostatin in inhibiting KB xenograft growth. In mouse models of Lewis lung carcinoma (LLC) and hepatoma H22, when given as a single dose, AARP is highly effective for reducing tumor growth, angiogenesis, and metastasis, and increasing survival time. AARP possessed significantly greater antiangiogenic activity than endostatin mimic, CTT peptide-kringle 5 (RK5) both in vitro and in vivo. Compared with conventional chemotherapeutic agents (cyclophosphamide and paclitaxel), AARP is also effective. More importantly, AARP is cytocompatible and no tissue toxicity could be observed after large dose administration. Taken together, our findings suggest AARP is a highly effective, safe, and more potent antiangiogenic agent for blocking tumor angiogenesis and metastasis, and warrants further testing for clinical applications.

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Chemical design of a radiolabeled gelatinase inhibitor peptide for the imaging of gelatinase activity in tumors

Cited by 30 publications

References 34 publications

Synthesis of a .BETA.-Tetrapeptide Analog as a Mother Compound for the Development of Matrix Metalloproteinase-2-Imaging Agents

Synthesis of a .BETA.-Tetrapeptide Analog as a Mother Compound for the Development of Matrix Metalloproteinase-2-Imaging Agents

Molecular imaging in cancer treatment

Therapeutic Targeting of Angiogenesis with a Recombinant CTT Peptide–Endostatin Mimic–Kringle 5 Protein

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