Molecular Delivery of Cytotoxic Agents Via Integrin Activation
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cancers Review Molecular Delivery of Cytotoxic Agents via Integrin Activation Martina Cirillo and Daria Giacomini * Department of Chemistry “Giacomo Ciamician”, Alma Mater Studiorum University of Bologna, Via Selmi 2, 40126 Bologna, Italy; [email protected] * Correspondence: [email protected] Simple Summary: Chemotherapy constituted a cornerstone in cancer treatment, but it suffers from non-selective drug cytotoxicity; an active drug targeting exerted by covalent conjugates between antitumor agents and some integrin ligands should have a more selective antitumor efficacy and could be an effective answer to reduce intolerable side-effects of current therapies. In this review we focused on those cytotoxic agents that were covalently inserted in molecular cargos characterized by specific integrin ligands. It was demonstrated that the integrin recognizing fragments were able to switch on an active and selective targeting against tumor cells. Abstract: Integrins are cell adhesion receptors overexpressed in tumor cells. A direct inhibition of integrins was investigated, but the best inhibitors performed poorly in clinical trials. A gained attention towards these receptors arouse because they could be target for a selective transport of cytotoxic agents. Several active-targeting systems have been developed to use integrins as a selective cell entrance for some antitumor agents. The aim of this review paper is to report on the most recent results on covalent conjugates between integrin ligands and antitumor drugs. Cytotoxic drugs thus conjugated through specific linker to integrin ligands, mainly RGD peptides, demonstrated that the covalent conjugates were more selective against tumor cells and hopefully with fewer side effects than the free drugs. Keywords: integrins; active targeting; molecular delivery; receptor targeting; cancer; selective citotoxycity Citation: Cirillo, M.; Giacomini, D. Molecular Delivery of Cytotoxic Agents via Integrin Activation. 1. Introduction Cancers 2021, 13, 299. https:// doi.org/10.3390/cancers13020299 Great efforts have been devoted to find innovative therapies for cancer [1–3]. Chemother- apy constituted a cornerstone in cancer treatment but it suffers from several limitations, among Received: 23 December 2020 others, it presents several intolerable side-effects due to non-specific targeting, and the appear- Accepted: 12 January 2021 ance of multiple drug resistance [4]. To get over these difficulties, a preferential localization of Published: 15 January 2021 the anticancer agents has been chosen as target strategy. Thus, specialized delivery systems and targeting approaches to get selective, effective therapeutic and diagnostic modalities Publisher’s Note: MDPI stays neu- have been studied [5,6]. Extensive efforts have been made to design and realize focused tral with regard to jurisdictional clai- therapeutics in response to specific biomarkers, receptors, and tumor microenvironments for a ms in published maps and institutio- precise therapy of cancer. These strategies are referred to as “active targeting” complementary nal affiliations. to a passive targeting that was referred to specific pathophysiological characteristics of tumor tissues [7]. Tumor cells overexpress some receptors, and this could be used to functionalize nanotherapeutics to recognize the receptors on the tumor surface (active targeting) leading to a preferential accumulation within the tumor via receptor-mediated endocytosis [7–9]. Copyright: © 2021 by the authors. Li- Among targets, folate receptors were the most commonly selected cancer targets, censee MDPI, Basel, Switzerland. particularly for ovarian cancers [10,11]; the riboflavin receptor, instead, emerged in recent This article is an open access article distributed under the terms and con- years because carrier protein of vitamin B2, and three riboflavin transporters were found ditions of the Creative Commons At- overexpressed in several cancers and could be chosen for tumor targeted drug delivery tribution (CC BY) license (https:// systems [12]. CD44, a cell surface adhesion receptor for hyaluronic acid (HA), is highly creativecommons.org/licenses/by/ expressed in many cancers and regulates metastasis via recruitment to cell surface; therefore, 4.0/). various HA-based drug delivery systems have been developed for a CD44-mediated tumor Cancers 2021, 13, 299. https://doi.org/10.3390/cancers13020299 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 299 2 of 25 targeting [13,14]. Enhanced expression of CD133, a cell surface antigen able to detect and isolate cancer stem cells, correlated with shorter patient lifespan and more aggressive disease, then monoclonal antibodies carrying drugs or toxins are used in targeting CD133 to enhance the immune response towards the disease [15]. The epidermal growth factor (EGF) receptor family is highly involved in triggering an uncontrolled signal transduction [16]. EphA2 receptor has much potential due to a possible correlation with tumor progression and metastatic spread through inhibition of receptor oligomerization and activation [17]. Integrins are heterodimeric transmembrane receptors constituted by two protein chains, α and β, and particularly attractive as pharmacological targets [18,19]. These cell adhesion glycoproteins have a fundamental role in increasing invasion, migration, and proliferation; moreover, they have been linked to tumor angiogenesis, which is an essential process for tumor growth and metastasis [20–23]. Changes in the expression of integrins in immune and stromal cells were described to support aggressive tumoral phenotypes [24]. The most studied integrins in oncology are the RGD-integrins such as αvβ3/β5 and α5β1 integrins [25]. These integrins recognize the tripeptide arginine–glycine–aspartic acid (RGD) as the minimal sequence in extracellular matrix (ECM) proteins. Among non- natural ligands, particular attention was ascribed to cyclic peptides containing the RGD sequence into the cycle (cRGDs, Figure1). Since the earliest studies, cRGDs showed higher potency than linear RGD sequences in the inhibition of integrin receptor [26]. This result could be ascribed to a lower flexibility due to conformational constrains by the cyclic structure and thus a higher directionality of the non-covalent interactions engaged by the cyclic molecules in the integrin-binding site. In a snapshot of the ligand-binding region of integrin αvβ3 with cRGDfK (X-ray structure 1L5G, PDB data bank) [27] the ligand interactions with protein residues are highlighted. FigureFigure 1. Linear (RGD) (RGD) and and cyclic cyclic peptides peptides mostly mostly used used to target to target integrins integrins;; snapshot snapshot of of the ligand- bindingthe ligand region-binding of region integrin of integrinαvβ3 with αvβ3 cRGDfK with cRGDfK (structure (structure 1L5G, 1L5G, PDB PDB databank, databank,α v green chain, αv green chain, β3 orange chain, cRGDfK violet). β3 orange chain, cRGDfK violet). Cancers 2021, 13, x 3 of 27 Cancers 2021, 13, 299 3 of 25 The peptide inserts into a crevice on the integrin head: the ligand binding site. The arginine residue of the ligand inserts into a narrow groove of the αv chain and engages salt bridges with aspartates 150 and 218, whereas the aspartate of the ligand coordinates the Mn2+ at the metalThe ion peptide-dependent inserts adhesion into a crevice site (MIDAS) on the integrinof the β3head: chain. the Interrupting ligand binding site. The the interactionsarginine between residue integrins of the and ligand extracellular inserts into ECM a narrow through groove RGD- oflike the compoundsαv chain and engages salt as inhibitors appearedbridges witha valuable aspartates strategy 150 and to 218,trigger whereas tumor the cell aspartate apoptosis. of the The ligand failure coordinates of the Mn2+ Cilengitide, a cyclicat the RGD metal pe ion-dependentptide inhibitor, adhesion in phase site II/III (MIDAS) clinical of thetrialsβ3 chain.may be Interrupting due to the the interactions complexity of integrinsbetween integrinsbiology; andthe extracellularinterest for these ECM throughreceptors RGD-like was lower. compounds However, as inhibitors re- appeared cent literature pointeda valuable out strategy to reconsider to trigger these tumor important cell apoptosis. receptors The [25 failure–30] as oftarget Cilengitide, in the a cyclic RGD cancer research.peptide inhibitor, in phase II/III clinical trials may be due to the complexity of integrins biology; In the last thefew interest years, foramong these the receptors various was developed lower. However, delivery recent systems, literature peptides pointed have out to reconsider been widely appliedthese importantas carriers receptors for receptor [25– 30recognition] as target inand the active cancer-targeting research. of cytotoxic drugs to cancer cellsIn [31,32 the last]. In fewparticular, years, amongon targeting the various integrin developed receptors, delivery linear and systems, cyclic peptides have RGD peptide motifsbeen widely(Figure applied1) have been as carriers employed for receptor as delivery recognition agents for and small active-targeting molecular of cytotoxic weight drugs, peptides,drugs to cancerand proteins cells [31 to,32 tumor]. In particular, endothelial on cells targeting [33–37 integrin]. receptors, linear and cyclic The aim ofRGD this review peptide was motifs to consider (Figure1 )the have most been recent employed papers as focusing delivery on agents molecular for small molecular delivery systemsweight for specific