Integrin-Targeted Peptide- and Peptidomimetic-Drug Conjugates for the Treatment of Tumors.
BACKGROUND
Integrins are heterodimeric cell surface receptors that mediate cell-cell and cell-extracellular matrix adhesion. These molecules play a role in processes such as cell growth and proliferation, differentiation, migration, cell trafficking, besides contributing to angiogenesis and tumor development. Given their biological role, integrins have been proposed as amenable targets in medicinal chemistry. In particular, αvβ3, αvβ5, αvβ6 and α5β1, integrins involved in tumor angiogenesis and metastasis, have been the subject of studies aimed at the discovery of novel cancer therapeutics. A large number of peptides and peptidomimetics based on the RGD (Arg-Gly-Asp) recognition sequence were developed in the past two decades as integrin ligands. Though such ligands have not been satisfactory as anti-angiogenic agents, their use as tools to achieve selective tumor targeting of anticancer drugs has been explored.


OBJECTIVE
In this review, we summarize recent literature and patent applications in which integrin peptidic and peptidomimetic ligands were conjugated to chemotherapeutic agents both with stable or cleavable bonds to achieve tumor targeted drug delivery.


METHODS
Relevant recent patents and literature in this field have been considered spanning the search from 2000 to 2016. Literature and patents were examined according to the different classes of cytotoxic drug targeted to integrins.


CONCLUSIONS
In spite of the promising features of the conjugates, none of them has entered clinical trials. New efforts are focused on innovative approaches in the field such as the synthesis of new integrin ligands able to target a single integrin type or the employment of nanoparticles based drug delivery systems.
Consiglio Nazionale delle Ricerche, Istituto di Scienze e Tecnologie Molecolari, Via Golgi 19, I-20133 Milano. Italy.
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Arosio
Consiglio Nazionale delle Ricerche, Istituto di Scienze e Tecnologie Molecolari, Via Golgi 19, I-20133 Milano. Italy.
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Manzoni
Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milan. Italy.
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Corno
Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milan. Italy.
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Perego
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D053758:Nanoparticles; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010330:Patents as Topic; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry; D057786:Peptidomimetics / Q000008:administration & dosage / Q000737:chemistry
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016023:Integrins; D010455:Peptides; D057786:Peptidomimetics
Cancer; drug delivery; drug-conjugates; integrins; peptidomimetics; tumor targeting