Homing Peptide-Based Targeting of Tenascin-C and Fibronectin in Endometriosis.

Lorena Simón-Gracia,Allan Tobi,Kristina Kiisholts,Maire Peters,Vilma Petrikaitė,Prakash Lingasamy,Merli Saare,Tambet Teesalu,Andres Salumets

doi:10.3390/nano11123257

Abstract

The current diagnostic and therapeutic strategies for endometriosis are limited. Although endometriosis is a benign condition, some of its traits, such as increased cell invasion, migration, tissue inflammation, and angiogenesis are similar to cancer. Here we explored the application of homing peptides for precision delivery of diagnostic and therapeutic compounds to endometriotic lesions. First, we audited a panel of peptide phages for the binding to the cultured immortalized endometriotic epithelial 12Z and eutopic stromal HESC cell lines. The bacteriophages displaying PL1 peptide that engages with angiogenic extracellular matrix overexpressed in solid tumors showed the strongest binding to both cell lines. The receptors of PL1 peptide, tenascin C domain C (TNC-C) and fibronectin Extra Domain-B (Fn-EDB), were expressed in both cells. Silver nanoparticles functionalized with synthetic PL1 peptide showed specific internalization in 12Z and HESC cells. Treatment with PL1-nanoparticles loaded with the potent antimitotic drug monomethyl auristatin E decreased the viability of endometriotic cells in 2D and 3D cultures. Finally, PL1-nanoparticless bound to the cryosections of clinical peritoneal endometriotic lesions in the areas positive for TNC-C and Fn-EDB immunoreactivities and not to sections of normal endometrium. Our findings suggest potential applications for PL1-guided nanoparticles in precision diagnosis and therapy of endometriosis.

Highlights

IntroductionThe endometrial glandular epithelial and stromal cells establish outgrowths outside the uterine tissue throughout the abdominal–pelvic peritoneum and visceral organs [1]
To map the landscape of homing peptides potentially useful for targeting endometriotic lesions, we first studied the binding of a panel of T7 phages displaying different tumor homing peptides to two cultured human cell lines which are commonly used as models of endometriotic cells: 12Z and HESC cells [31,32]
These cell lines were chosen to represent the stromal and the glandular epithelial compartments of the endometrium, both known to play a role in the pathogenesis of endometriosis

Summary

Introduction

The endometrial glandular epithelial and stromal cells establish outgrowths outside the uterine tissue throughout the abdominal–pelvic peritoneum and visceral organs [1]. Endometriosis affects ~5–10% of women in reproductive age, and it is a frequent source of infertility and chronic pelvic pain [2]. Available treatments (painkillers, laparoscopic resection of endometriotic lesions, and hormonal treatments such as contraceptives, gonadotropin releasing hormone agonists (GnRHa), and antagonists) only alleviate the symptoms of the disease and/or are associated with serious side effects [3]. Hormonal treatments are effective in pain reduction but cause frequent

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Results

Conclusion