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Imaging Angiogenesis
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Ambros J. Beer, Markus Schwaiger
Inhibition of MMPs activity interferes with both endothelial and tumor cell invasion into the extracellular matrix at primary and metastatic sites. The family of MMPs consists of at least 20 distinct enzymes, of which the gelatinases MMP-2 and MMP-9 are closely associated with angiogenesis. Selective and nonselective MMP inhibitors are in advanced clinical trial. Examples of these agents include marimastat, AG3340 (prinomastat), Col-3, neovastat, and BMS275291. Marimastat demonstrated a survival benefit in patients with metastatic gastric cancer and in patients with glioblastoma treated in combination with temozolomid. However, it is also one of the first antiangiogenic agents, which demonstrated dose-limiting side effects, mostly severe inflammatory polyarthritis (45).
Imaging Matrix Metalloproteinase Expression: Applications for Cardiovascular Imaging
Published in Robert J. Gropler, David K. Glover, Albert J. Sinusas, Heinrich Taegtmeyer, Cardiovascular Molecular Imaging, 2007
In a more successful approach, Bremer et al. reported on a biocompatible near-infrared fluorogenic MMP substrate that is used as an activatable reporter probe to sense MMP activity (19). The rationale for this study is based on the quenching of closely positioned fluorochromes that occurs when the enzyme is cleaved by MMP-2 in vivo. Images of tumors in nude mice were clearly visualized using this near infrared fluorescence (NIRF) imaging agent, while negative control rats that were injected with 150 mg/kg of the MMP-2 inhibitor prinomastat twice a day for two days showed significantly lower tumor uptake.
Polymeric Conjugates for Angiogenesis-Targeted Tumor Imaging and Therapy
Published in Mansoor M. Amiji, Nanotechnology for Cancer Therapy, 2006
Amitava Mitra, Anjan Nan, Bruce R. Line, Hamidreza Ghandehari
Optical imaging methods to assess MMP activity has been achieved using a NIR fluorescence probe attached to a MMP-2 substrate.94–96 The MMP-2 imaging probe consists of three elements: a quenched NIR fluorochrome (Cy5.5), a MMP-2 peptide substrate (GPLGVRGK), and a PEG-poly-L-lysine (PEG–PLL) graft copolymer.94 The conjugate is designed such that the peptides are cleaved by MMP-2 at the tumor site, resulting in several hundred percent increases in the NIR fluorescence, allowing visualization of the MMP-2 in human fibrosarcoma tumor. Next MMP-2 inhibition was imaged after treatment with prinomastat where the treated tumor showed significantly lower NIR signal as compared to the untreated tumors.94 A similar NIR fluorescence-based probe has been designed for MMP-7 that is over expressed in colon, breast, and pancreatic cancer.97 In tumor extract containing MMP-7 in vitro, the fluorescence signal from the probe was enhanced 7-fold after enzymatic degradation. This probe could also be used to image tumor-associated enzyme activity and also inhibition of MMP-7 in vivo.
Vascular and extracellular matrix remodeling by physical approaches to improve drug delivery at the tumor site
Published in Expert Opinion on Drug Delivery, 2020
Sara Gouarderes, Anne-Françoise Mingotaud, Patricia Vicendo, Laure Gibot
Matrix remodeling is one of the most valuable approaches to improve the delivery of therapeutic agents as evidenced in vivo with single or chronic injections of pharmacological agents able to degrade tumor ECM proteins. Among them, let’s cite hormones like relaxin [21], enzymes like collagenases [22], angiotensin inhibitor called losartan [23], the antibody simtuzumab to inhibit the lysyl oxidase-like 2 (LOXL2) [24]. Unfortunately, metalloproteinases (MMP) inhibitors (such as marimastat and prinomastat) have not been clinically proven to be effective against cancer, due to their lack of specificity and poor tolerability [25]. One of the flagship studies combining pharmacological ECM matrix remodeling and concomitant treatment with anticancer nanoparticles was published in 2010 by Jain’s team. The authors showed that the repetitive injection of losartan decreased collagen amounts in several mouse tumor models, which in turn favor a higher penetration of doxorubicin-loaded liposomes (Doxil) into the tumor, particularly in the interstitial space, thus improving its therapeutic efficacy [26].
Low molecular mass natural and synthetic inhibitors of snake venom metalloproteinases
Published in Toxin Reviews, 2018
Lina María Preciado, Jaime Andrés Pereañez
The effectiveness of matrix metalloproteinases inhibitors (MMPIs) such as Marimastat (Figure 2A), AG-3340 (Prinomastat) (Figure 2B), Bay-12 9566 (Tanomastat) (Figure 2C) and CGS-270 23A (Figure 2D) in abrogating the hemorrhagic and proteolytic activities of whole E. ocellatus venom and EoVMP2 (a hemorrhagic P-III metalloproteinase) was demonstrated (Howes et al., 2007). The MMPIs Marimastat and CGS-270 23A are both hydroxamic acid derivatives that are designed to exert broad-range MMP inhibition by mimicking the cleavage site of MMP (collagen) substrate. On the other hand, AG-3340 and Bay-12 9566 are both designed to be selective inhibitors of the gelatinases MMP-2 and MMP-9 (Heath & Grochow, 2000; Hidalgo & Eckhardt, 2001; Yip et al., 1999). These compounds were effective in neutralizing the hemorrhagic activity of EoVMP2 in murine assays, but only AG-3340 successfully inhibited the hemorrhagic activity of whole E. ocellatus venom.
Gelatinase inhibitors: a patent review (2011-2017)
Published in Expert Opinion on Therapeutic Patents, 2018
The research of MMPIs begun in the late 1970s and flourished in early 1990s. As the gradual revelation of MMPs in tumorigenesis processes, early intensive research and development mainly focused on oncology area. This has propelled an array of first-generation MMPIs into the preclinical phase, and several of them quickly made their way to clinic testing, represented by batimastat, marimastat, CGS27023A, prinomastat, etc., as exhibited in Figure 5. However, the antitumor evaluation on these pan-MMP inhibitors was eventually disappointed, with the vast majority of them had to be terminated early or even pitifully cancelled in the late stage of clinical development, as poor efficacy and dose-limiting side effects such as tissue toxicity, poorly tolerated musculoskeletal pain (commonly known as MSS), and inflammation were frequently occurred of prolonged treatment with pan-MMPIs.