Molecular Delivery of Cytotoxic Agents via Integrin Activation

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: active targeting; cancer; integrins; molecular delivery; receptor targeting; selective citotoxycity.

Figure 1

Linear (RGD) and cyclic peptides mostly used to target integrins; snapshot of the ligand-binding region of integrin α_vβ₃ with cRGDfK (structure 1L5G, PDB databank, α_v green chain, β₃ orange chain, cRGDfK violet).

Figure 2

Inhibition of proliferation by Cisplatin and RGD-Targeted Pt(IV). Compounds (A) and (B) in endothelial and tumor cells, data refer to IC₅₀ (μM).

Figure 3

Metallacage decorated with RGD peptides to target integrins and to entrap cisPlatin drug.

Figure 4

Tetrameric (A) and monomeric (B) RAFT-RGD systems as platinum (IV) complexes.

Figure 5

Platinum(IV) prodrug linked to a cyclic RGD–peptide and its guanosine 5-monophosphate adduct obtained by photoactivation.

Figure 6

Nitrogen mustard derivatives conjugated with cyclic RGD integrin ligand.

Figure 7

5-Fluorouracil conjugates with cRGDyK.

Figure 8

RGD peptide as integrin targeting carrier for methotrexate.

Figure 9

Dual-drug conjugate: doxorubicin and bortezomib on oxidized dextran with cRGD for integrin targeting.

Figure 10

Doxorubicin conjugated with carboxymethylcellulose decorated with arginine and the RGD peptide.

Figure 11

Doxorubicin conjugated with the integrin-targeting unit c[DKP-f 3-RGD] composed of the RGD tripeptide cyclized within a diketopiperazine and characterized by a high selectivity toward integrin α_vβ_3.

Figure 12

Daunorubicin conjugated by oxime linkage to a polypeptide with a NGR integrin ligand.

Figure 13

Doxorubicin conjugated with RGD peptide via sulfur link to succinimide.

Figure 14

Sunitinib is linked to a cyclic RGD portion that selectively directs the conjugates toward α_Vβ₃-integrin overexpressing cells.

Figure 15

Camptothecin conjugated with the cyclic peptide ALOS4 to bind integrin α_vβ₃.

Figure 16

Cyclopentapeptide to carry camptothecin with a short linker.

Figure 17

Camptothecin conjugated to a cyclopeptide with a multifunctional linker.

Figure 18

Structure of RGD-conjugates to Naproxen and Ibuprofen; inhibition of cell proliferation (%) by the compounds at 100 µM.

Figure 19

Structure of Ketoprofen-RGD-GGAG peptide, Naproxen-RGD-GGAG peptide and inhibitory % values of conjugates at 100 µM.

Figure 20

Molecular structures of cyclo(DKP-RGD)-NPV-PTX; IC₅₀ of biotinylated vitronectin binding to the α_vβ₃ receptor; antiproliferative activity of cyclo(DKP-RGD)-NPV-PTX in α_vβ₃-expressing human renal cell carcinoma 786-O cells in the presence of elastase from human leukocytes.

Figure 21

Conjugate c(RGDfK)-Val-Cit-Gly-Pro-Cry-55gly, antiproliferative activity against M21 and M21-L human melanoma cells.

Figure 22

Inhibition data of cyclo[DKP-RGD]-PEG4-ValAla-PABC-Cry-55gly in biotinylated vitronectin binding to human integrin α_vβ₃ assays, and antiproliferative activity of against M21 and M21-L cell lines.

Figure 23

RAFT-c(RGDfk)₄-Cry-55gly and antiproliferative activity against U87 human glioblastoma, M21 and M21-L human melanoma cell lines.

Figure 24

Molecular structures of auristatins MMAE and MMAF.

Figure 25

MMAE conjugates: cyclo[DKP-isoDGR]-VA-MMAE and cyclo[DKP-isoDGR]-Unc-MMAE; inhibition of biotinylated vitronectin binding to the isolated α_vβ₃ receptor; antiproliferative activity of cyclo[DKP-isoDGR]-VA-MMAE and cyclo[DKP-isoDGR]-Unc-MMAE against U87 and M21 cancer cell lines.

Figure 26

Structure of α_vβ₃ integrin conjugates cyclo(DKP-RGD)-A-Gluc-MMAE (A) and cyclo(DKP-RGD)-B-Gluc-MMAE (B); inhibition of biotinylated vitronectin binding to the α_vβ₃ receptor.

Figure 27

Structure of BG-P-TAT and inhibition potency.