N-Alkylisatin-Loaded Liposomes Target the Urokinase Plasminogen Activator System in Breast Cancer

Lisa Belfiore,Darren N Saunders,Kara L Vine,Marie Ranson

doi:10.3390/pharmaceutics12070641

Lisa Belfiore, Darren N Saunders + Show 2 more

Open Access

https://doi.org/10.3390/pharmaceutics12070641

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Abstract

The urokinase plasminogen activator and its receptor (uPA/uPAR) are biomarkers for metastasis, especially in triple-negative breast cancer. We prepared anti-mitotic N-alkylisatin (N-AI)-loaded liposomes functionalized with the uPA/uPAR targeting ligand, plasminogen activator inhibitor type 2 (PAI-2/SerpinB2), and assessed liposome uptake in vitro and in vivo. Receptor-dependent uptake of PAI-2-functionalized liposomes was significantly higher in the uPA/uPAR overexpressing MDA-MB-231 breast cancer cell line relative to the low uPAR/uPAR expressing MCF-7 breast cancer cell line. Furthermore, N-AI cytotoxicity was enhanced in a receptor-dependent manner. In vivo, PAI-2 N-AI liposomes had a plasma half-life of 5.82 h and showed an increased accumulation at the primary tumor site in an orthotopic MDA-MB-231 BALB/c-Fox1nu/Ausb xenograft mouse model, relative to the non-functionalized liposomes, up to 6 h post-injection. These findings support the further development of N-AI-loaded PAI-2-functionalized liposomes for uPA/uPAR-positive breast cancer, especially against triple-negative breast cancer, for which the prognosis is poor and treatment is limited.

Highlights

Breast cancer is the most common invasive cancer in women worldwide and remains a leading cause of cancer-related morbidity and mortality [1]
This work aimed to improve upon the solubility and delivery of the potent N-alkylisatin (N-AI) cytotoxin to uPA/uPAR positive breast cancer cells, through the conjugation of plasminogen activator inhibitor type 2 (PAI-2) to the surface of PEGylated N-AI-loaded liposomes
This work supports the rationale for targeting uPAR-positive breast cancer cells, using N-AI-loaded PAI-2-functionalized liposomes, and provides a basis for the further development of liposomes that can target heterogeneous tumor cells within the triple-negative breast cancer (TNBC) subtype, in which uPAR was shown to play a key role in driving metastasis

Summary

Introduction

Breast cancer is the most common invasive cancer in women worldwide and remains a leading cause of cancer-related morbidity and mortality [1]. Numerous studies and clinical evidence indicate that the urokinase plasminogen activator system (uPAS) play a key role in breast cancer metastasis [3,4]. In this system uPA, secreted as a zymogen, is activated upon binding to its specific cell surface receptor uPAR. Progression-free survival is inversely correlated with uPA and uPAR expression [6,7]. Patients with high uPA mRNA levels are more likely to suffer from metastatic disease [8], and overexpression of uPAR by tumor cells or stromal cells is associated with a poor prognosis for metastatic breast cancer [9]

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