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

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.

SUBMITTER: Simon-Gracia L

PROVIDER: S-EPMC8708492 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Integrin alpha(5)beta(1) is expressed on several types of cancer cells, including colon cancer, and plays an important role in tumor growth and metastasis. The ability to target the integrin alpha(5)beta(1) using an appropriate drug delivery nano-vector can significantly help in inhibiting tumor growth, reducing tumor metastasis, and decreasing deleterious side effects associated with different cancer therapies. Liposomes are nano-sized phospholipid bilayer vesicles that have been extensively studied as drug delivery carriers. The goal of this study is to design stealth liposomes (liposomes covered with polyethylene glycol (PEG)) that will target colon cancer cells that express the integrin alpha(5)beta(1). The PEG provides a steric barrier allowing the liposomes to circulate in the blood and the functionalizing moiety, PR_b peptide, will specifically recognize and bind to alpha(5)beta(1) expressing cells. PR_b is a novel peptide sequence that mimics the cell adhesion domain of fibronectin, and includes four building blocks, RGDSP (the primary recognition site for alpha(5)beta(1)), PHSRN (the synergy site for alpha(5)beta(1)), a (SG)(5) linker, and a KSS spacer. In this study we have demonstrated that by varying the amount of PEG (PEG750 or PEG2000) and PR_b on the liposomal interface we can engineer nano-vectors that bind to CT26.WT, HCT116, and RKO colon cancer cells in a specific manner and are internalized through most likely alpha(5)beta(1)-mediated endocytosis. GRGDSP-targeted stealth liposomes bind to colon cancer cells and internalize, but they have much lesser efficiency than PR_b-targeted stealth liposomes, and more importantly they are not as specific since many integrins bind to RGD peptides. PR_b-targeted stealth liposomes are as cytotoxic as free 5-Fluorouracil (5-FU) and exert the highest cytotoxicity on CT26.WT cells compared to GRGDSP-targeted stealth liposomes and non-targeted stealth liposomes. Thus, the proposed targeted delivery system has the great potential to deliver a therapeutic load directly to colon cancer cells, in an efficient and specific manner.

Project description:PurposeEndometriosis is a chronic condition characterized by high fibrotic content and affecting about 10% of women during their reproductive years. Yet, no clinically approved agents are available for non-invasive endometriosis detection. The purpose of this study was to investigate the utility of a gadolinium-based collagen type I targeting probe (EP-3533) to non-invasively detect endometriotic lesions using magnetic resonance imaging (MRI). Previously, this probe has been used for detection and staging of fibrotic lesions in the liver, lung, heart, and cancer. In this study we evaluate the potential of EP-3533 for detecting endometriosis in two murine models and compare it with a non-binding isomer (EP-3612).ProceduresFor imaging, we utilized two GFP-expressing murine models of endometriosis (suture model and injection model) injected intravenously with EP3533 or EP-33612. Mice were imaged before and after bolus injection of the probes. The dynamic signal enhancement of MR T1 FLASH images was analyzed, normalized, and quantified, and the relative location of lesions was validated through ex vivo fluorescence imaging. Subsequently, the harvested lesions were stained for collagen, and their gadolinium content was quantified by inductively coupled plasma optical emission spectrometry (ICP-OES).ResultsWe showed that EP-3533 probe increased the signal intensity in T1-weighted images of endometriotic lesions in both models of endometriosis. Such enhancement was not detected in the muscles of the same groups or in endometriotic lesions of mice injected with EP-3612 probe. Consequentially, control tissues had significantly lower gadolinium content, compared to the lesions in experimental groups. Probe accumulation was similar in endometriotic lesions of either model.ConclusionsThis study provides evidence for feasibility of targeting collagen type I in the endometriotic lesions using EP3533 probe. Our future work includes investigation of the utility of this probe for therapeutic delivery in endometriosis to inhibit signaling pathways that cause the disease.

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

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