Advances in Nanotheranostics with Plasmonic and Magnetic Nanoparticles
Carla Vitorino, Andreia Jorge, Alberto Pais in Nanoparticles for Brain Drug Delivery, 2021
Apart from the active targeting agents towards tumour cells previously described, other less explored ligands have been combined with magnetic nanoparticles, such as anti-Hsp70 specific antibody [68], which explores the Hsp70 large expression on high-grade glioma cell membranes owing to tumour-specific lipids which anchor this protein on the cell surface [67]. Other alternative ligand is the Cilengitide (a cyclic RGD peptide) which targets the integrins αVβ3 and αVβ5 overexpressed in glioblastoma cells, where the combination with ultrasound-targeted microbubble destruction has been shown to strongly increase the nanoparticle uptake [69]. Nevertheless, other recent strategies used in specific targeting with magnetic nanoparticles and their combination with MRI in glioma therapy are shown in Table 10.1.
Bacteria and Bioactive Peptides
Prakash Srinivasan Timiri Shanmugam in Understanding Cancer Therapies, 2018
Peptides comprise a few amino acids to about 40 or more amino acids coupled through amide and/or disulfide bonds, providing varied-size molecules. In the last few years, Leuprorelin, Octreotide, and Goserelin have been used against prostate cancer and breast cancer. Carfilzomib, a protease inhibitor, is used for multiple myeloma (Kaspar and Reichert 2013). The administration of peptides can be oral, subcutaneous, intravenous, or via inhalation. In spite of limited anticancer peptides, peptide therapy may have significant potential in tumor treatment. A synthetic six amino acid peptide of αC-ß4 loop region of EGFR has been known to inhibit the dimerization and signaling activity of EGFR in the presence of its ligand (Ahsan et al. 2013). Additionally, this peptide promotes EGFR interaction with the heat shock protein Hsp90, thereby catalyzing the degradation of EGFR (Ahsan et al. 2013). At present, anticancer peptides such as Cilengitide, Trebananib, NGR-hTNF, Tyroserleutide, etc., are undergoing phase III clinical trials against glioblastoma, ovarian, mesothelioma, or liver cancers (Kaspar and Reichert 2013). The lack of targeting intracellular proteins is the major limitation of currently available anticancer peptides, thereby limiting their effectiveness (Milletti 2012). Thus, an ideal anticancer peptide involves the development of cell-penetrating peptides (CPPs) that can cross the cellular membrane to modulate key intracellular proteins involved in cancer growth regulation.
Imaging Angiogenesis
Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman in Molecular Imaging in Oncology, 2008
Integrins are cell surface receptors that play an important role in cell-cell and cell-matrix interactions. The integrins αvβ3 and αvβ5 are especially well examined and are expressed on angiogenic endothelial cells and on some metastatic tumor cells, but not on quiescent endothelium. Disruption of the αvβ3 integrin by monoclonal antibodies or cyclic peptides leads to activation of p53 and endothelial cell apoptosis. Examples of drugs in clinical trial include Vitaxin® (humanized antibody to αvβ3 LM609) and EMD121974 (Cilengitide®), a cyclic pentapeptide with highly specific binding to αvβ3 and αvβ5. These agents are currently evaluated in phase I to III trials comprising patients with glioblastoma in combination with temozolomide, patients with irinotecan refractory colorectal cancer, and patients with Kaposi’s sarcoma.
Improving therapeutic resistance: beginning with targeting the tumor microenvironment
Published in Journal of Chemotherapy, 2022
Xiao-ying Guan, Xiao-li Guan, Zuo-yi Jiao
Cilengitide is a novel anti-angiogenic drug that targets integrin in vascular endothelial cells. In preclinical studies, cilengitide inhibited tumor angiogenesis by inhibiting the FAK/Src/AKT signalling pathway, targeting the binding of RGD to integrins on endothelial cells [79]. Cilengitide is the most promising integrin inhibitor found thus far by clinical research. However, cilengitide as a standard treatment for GBM had poor efficacy in phase III clinical trials [123]. Compared with cilengitide, GLPG0187 is a broad-spectrum and effective integrin receptor antagonist that can improve e anti-tumor efficacy. However, a phase I clinical trial in adult patients with advanced malignancies to study the tolerability and safety of intravenous GLPG0187 in patients with end-stage cancer, showed that GLPG0187 failed to show monotherapeutic efficacy [80].
Dual integrin αvβ3 and αvβ5 blockade attenuates cardiac dysfunction by reducing fibrosis in a rat model of doxorubicin-induced cardiomyopathy
Published in Scandinavian Cardiovascular Journal, 2021
Integrin-mediated TGF-β1 activation is a pharmacological target and its efficacy has been confirmed in fibrotic diseases of several organs [13–16]. Cilengitide (CGT) is an effective αvβ3 and αvβ5 integrin inhibitor, which was initially developed as an antitumor drug for patients with newly diagnosed glioblastoma [17] and then was tested further in experimental fibrotic diseases [15,16]. In vitro integrin inhibition by CGT, strongly diminished cardiac fibroblast differentiation into detrimental MFBs in spontaneously hypertensive rats [18]. However, the in vivo effect of CGT on myocardial fibrosis and cardiac dysfunction has not been investigated. Therefore, the present study aimed to establish a rat model of long-term cardiomyopathy manifested as fibrosis, consistent with clinical presentation, and to test whether CGT administration, by inhibiting αvβ3 and αvβ5 integrin, can produce a preventive strategy to mitigate myocardial fibrosis and rescue cardiac function.
The evolving role of antiangiogenic therapies in glioblastoma multiforme: current clinical significance and future potential
Published in Expert Opinion on Investigational Drugs, 2019
Casey Anthony, Nikol Mladkova-Suchy, David Cory Adamson
Integrins mediate endothelial cell adhesion and migration in angiogenesis, as well as cell attachment to the extracellular matrix of cells during tumor cell invasion. Cilengitide is an αVβ3 and αVβ5 integrin inhibitor, which enhances neoplastic apoptosis and simultaneously blocks integrin-mediated angiogenesis and tumor migration [39]. In recurrent GBM, a phase II study resulted in PFS-6 of 15% and a median OS of 9.9 months with minimal toxicity [40]. Further study in 30 patients showed similar median PFS (8 weeks), and PFS-6 of 12% of patients [41]. A phase II study in newly diagnosed GBM showed an OS of 19.7 months, as well as a higher OS (30 months) in patients with O6-methylguanine-DNA methyltransferase (MGMT) methylation [42], significant improvement over traditional TMZ and radiation treatment. However, these results should be interpreted with caution since the comparison was with historical controls and not within a clinical trial. Another phase II study in newly diagnosed GBM demonstrated improvement in patients with a median PFS of 8 months, PFS-6 of 69%, and OS of 16.1 months [43], with higher OS in patients with MGMT promoter methylation. Unfortunately, the following phase III CENTRIC trial in patients with methylated MGMT showed no improvement in PFS or OS [44], warranting no further clinical trials as a primary therapy for GBM.
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