Conjugates of Cell Adhesion Peptides for Therapeutics and Diagnostics Against Cancer and Autoimmune Diseases

Abstract

Overexpressed cell-surface receptors are hallmarks of many disease states and are often used as markers for targeting diseased cells over healthy counterparts. Cell adhesion peptides, which are often derived from interacting regions of these receptor-ligand proteins, mimic surfaces of intact proteins and, thus, have been studied as targeting agents for various payloads to certain cell targets for cancers and autoimmune diseases. Because many cytotoxic agents in the free form are often harmful to healthy cells, the use of cell adhesion peptides in targeting their delivery to diseased cells has been studied to potentially reduce required effective doses and associated harmful side-effects. In this review, multiple cell adhesion peptides from extracellular matrix and ICAM proteins were used to selectively direct drug payloads, signal-inhibitor peptides, and diagnostic molecules, to diseased cells over normal counterparts. RGD constructs have been used to improve the selectivity and efficacy of diagnostic and drug-peptide conjugates against cancer cells. From this precedent, novel conjugates of antigenic and cell adhesion peptides, called bifunctional peptide inhibitors (BPIs), have been designed to selectively regulate immune cells and suppress harmful inflammatory responses in autoimmune diseases. Similar peptide conjugations with imaging agents have delivered promising diagnostic methods in animal models of rheumatoid arthritis. BPIs have also been shown to generate immune tolerance and suppress autoimmune diseases in animal models of type-1 diabetes, rheumatoid arthritis, and multiple sclerosis. Collectively, these studies show the potential of cell adhesion peptides in improving the delivery of drugs and diagnostic agents to diseased cells in clinical settings.

Naturally occurring cell adhesion inhibitors

“…Commercially available cell adhesion inhibitors are almost all developed based on peptide [ 83 , 84 ]. But naturally occurring inhibitors such as MSs A–D ( 40 – 43 ) were not only first isolated in the culture of Microsphaeropsis sp.…”

Are Integrins Still Practicable Targets for Anti-Cancer Therapy?

“…Integrin αVβ3, α5β1, and αVβ6 have been explored for non-invasive tumor imaging purposes, using magnetic resonance imaging (MRI), positron emission tomography (PET), computer tomography (CT), and optical and ultrasound-based imaging techniques [9,196,197]. Their targeting is of great potential relevance for the early diagnosis, staging of disease, patient’s stratification, and therapeutic monitoring [198].…”

“…PET technology has been preferred for use in animal models and in humans because of its high intrinsic sensitivity. The level of expression of αVβ3 detected by PET correlated with the level of αVβ3 determined by immunohistochemistry, suggesting that this approach is a good surrogate of integrin expression in vivo [197,199,200]. Tracers targeted by anti-αV integrin antibodies or peptides showed high levels of specific tumor accumulation by PET, Single Photon Emission Computed Tomography (SPECT), or optical imaging in different cancer models [201,202,203,204,205].…”

The Role of the Innate Immune System in Cancer Dormancy and Relapse

“…Endogenous antagonists of Integrin α5β1, such as endostatin, represent an alternative strategy for controlling the reactivation of dormant tumor cells and are currently under study for the treatment of NSCLC [ 102 ]. A similar approach, whether with monoclonal antibodies or endostatins, has been proposed for imaging purposes to diagnose and localize micro-metastases [ 103 ].…”