RGD Peptidomimetic MMAE‐Conjugate Addressing Integrin αVβ3‐Expressing Cells with High Targeting Index**

Abstract

Small molecule‐drug conjugates (SMDCs) mimicking the RGD sequence (‐Arg‐Gly‐Asp‐) with a non‐peptide moiety require a pharmacophore‐independent attachment site. A library of 36 sulfonamide‐modified RGD mimetics with nM to pM affinity for integrin αVβ3 was synthesized and analysed via DAD mapping. The best structure of the conjugable RGD mimetic was used and a linker was attached to an aromatic ring by Negishi cross‐coupling. The product retained high affinity and selectivity for integrin αVβ3. The conjugable RGD mimetic was then attached to an enzymatically cleavable GKGEVA linker equipped with a self‐immolative PABC and the antimitotic drug monomethyl auristatin E (MMAE). The resulting SMDC preferred binding to integrin αVβ3 over α5β1 in a ratio of 1 : 4519 (ELISA) and showed selectivity for αVβ3‐positive WM115 cells over αVβ3‐negative M21‐L cells in the in vitro cell adhesion assay as well as in cell viability assays with a targeting index of 134 (M21‐L/WM115).

Multimodal Imaging-Guided Synergistic Photodynamic Therapy Using Carbonized Zn/Co Metal-Organic Framework Loaded with Cytotoxin Against Liver Cancer

“…RGD, a distinctive peptide sequence, exhibits an affinity for tumor cell surfaces that overexpress αvβ3 integrins. 26 , 27 Given the elevated expression of these integrins in HepG2 cells, RPZC, via RGD, binds to the cell’s αvβ3 integrin surface, achieving targeted action. In contrast, regular liver cells, having a diminished αvβ3 integrin expression, do not facilitate stable binding with RPZC, hence the absence of significant red fluorescence in THLE-2 cells.…”

Small molecule– and peptide–drug conjugates addressing integrins: A story of targeted cancer treatment

“…Receptor Family Integrin Alternative name Natural ligand [147] Peptide or small-molecule ligands cytotactin/tenascin-C, disintegrins, HIV Tat protein, laminin, MMP-2, osteopontin, prothrombin, thrombospondin, vWf c(DKP-RGD) [198] , c(CGisoDGRG) [199] , c(AmpRGD) [200] , c(CSSAGSLFC) (ALOS-4) [201] ) Peptides: RGD, GRGDS [175] Small molecules: (Tyrosine based) RGD mimetics [177,[202][203][204][205] , isoxazolines [184] ,IPS-02001 [206] , benzenesulfonic amids [20] ,AV-38/398 [207] Other: RNA aptamers [186] , RGD-knotting peptides [187,188] α V β 5 Vitronectin, bone sialoprotein, fibronectin, HIV Tat protein Cyclic peptides (e.g. Cilengitide ® [193,194] , c(RGDXX) [195,196,208] ) [209] , small molecules (e.g.…”

“…[204] A second generation of related conjugates was developed, whereby the small molecule ligand was improved by a modified conjugation strategy for the small molecule ligand and a sulfonamide instead of a carboxylic amide (Table 4.1, entry 8; Figure 4.4). [205] Additionally, the peptide linker was prolongated with the tripeptide Gly-Lys-Gly to investigate the was also reported that the introduction of the PEG 2000 only slightly improved the selectivity against the α V -negative cells but reduced the overall cytotoxicity which might be a shielding effect of the polyethylene glycol unit. [205] One approach to overcome the drawback of non-receptor mediated uptake is the use of cell-penetrating peptides (CPP) in combination with tumour targeting homing devices.…”

“…[205] Additionally, the peptide linker was prolongated with the tripeptide Gly-Lys-Gly to investigate the was also reported that the introduction of the PEG 2000 only slightly improved the selectivity against the α V -negative cells but reduced the overall cytotoxicity which might be a shielding effect of the polyethylene glycol unit. [205] One approach to overcome the drawback of non-receptor mediated uptake is the use of cell-penetrating peptides (CPP) in combination with tumour targeting homing devices. Feni et al [267] reported conjugates of c(DKP-RGD) and daunorubicin linked by an sC18 CPP and, in some cases, a GFLG-cleavage sequence (cathepsin) (Table 4.1, entry 5).…”

“…However, this decreased cytotoxicity can also be explained by the absence of integrin α V β 3 on KB cells, which was later determined. [205] Nevertheless, even the introduction of a non-cleavable linker without attaching a homing device resulted in the same activity-decreasing effect. [43] Zanella et al [303] developed a dual action ligand/PDC which consisted of a c(DKP-RGD) targeting unit and a ligand for vascular endothelial growth factor receptors (VEGFRs) (Table 4.5, entry 2;…”