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Advances in Nanotheranostics with Plasmonic and Magnetic Nanoparticles
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Sérgio R. S. Veloso, Paula M. T. Ferreira, J. A. Martins, Paulo J. G. Coutinho, Elisabete M. S. Castanheira
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.
High-grade Glioma
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Donald C. Macarthur, Christof M. Kramm, Matthias A. Karajannis
The integrins αvβ3 and αvβ5 regulate angiogenesis and invasiveness in glioma, possibly by modulating activation of the TGF-β pathway, and the integrin inhibitor cilengitide underwent advanced clinical development in glioblastoma based on promising preclinical data.124 Despite radiographic responses in patients with recurrent disease in early-phase clinical trials, the drug failed to meet predefined endpoints in subsequent phase II adult and pediatric trials for recurrent HGG,125,126 as well as two phase III studies for adults with newly diagnosed glioblastoma.127,128
Bacteria and Bioactive Peptides
Published in Prakash Srinivasan Timiri Shanmugam, Understanding Cancer Therapies, 2018
Ameer Khusro, Chirom Aarti, Paul Agastian
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.
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.
How not to discover a drug - integrins
Published in Expert Opinion on Drug Discovery, 2021
The most promising anti-integrin for cancer was cilengitide – a cyclic-RGD peptide that inhibits both αVβ3 and αVβ5 (see Figure 1). PII studies of cilengitide looked promising in glioblastoma [108], pancreatic cancer [109], melanoma [110], non-small cell lung cancer [111], squamous cell carcinoma of the head and neck [112] and prostate cancer [113] both as monotherapy and as part of combination therapy. However, PIII trials failed to show any benefit [114,115]. One of the complications with cilengitide, similar to that with GPIIb/IIIa antagonists, is agonist-like activity [116]. Thus, cilengitide at low concentrations stimulates angiogenesis [117] and enhances endothelial permeability [118], while the antagonist activity likely dominates at higher concentrations. So, while researchers are looking at other potential cancers to treat with cilengitide it fundamentally has the same problems as GPIb/IIIa antagonists – agonist-like activity and poor PK profile. If anything is to be learned from GPIIb/IIIa studies is that both these problems need to be addressed to develop a successful agent ie, a pure antagonist with once-daily dosing. Just as GPIIb/IIIa antagonists were discovered without agonist-like activity there are new small molecule αVβ3 antagonists without agonist-like activity [119].