Recent Advances in Targeting the Urokinase Plasminogen Activator with Nanotherapeutics

Abstract

The aberrant proteolytic landscape of the tumor microenvironment is a key contributor of cancer progression. Overexpression of urokinase plasminogen activator (uPA) and/or its associated cell-surface receptor (uPAR) in tumor versus normal tissue is significantly associated with worse clinicopathological features and poorer patient survival across multiple cancer types. This is linked to mechanisms that facilitate tumor cell invasion and migration, via direct and downstream activation of various proteolytic processes that degrade the extracellular matrix�ultimately leading to metastasis. Targeting uPA has thus long been considered an attractive anticancer strategy. However, poor bioavailability of several uPA-selective smallmolecule inhibitors has limited early clinical progress. Nanodelivery systems have emerged as an exciting method to enhance the pharmacokinetic (PK) profile of existing chemotherapeutics, allowing increased circulation time, improved bioavailability, and targeted delivery to tumor tissue. Combining uPA inhibitors with nanoparticle-based delivery systems thus offers a remarkable opportunity to overcome existing PK challenges associated with conventional uPA inhibitors, while leveraging potent candidates into novel targeted nanotherapeutics for an improved anticancer response in uPA positive tumors.

Targeted imaging of uPAR expression in vivo with cyclic AE105 variants

“…The lack of severe overt phenotypes in uPAR-deficient mice combined with low uPAR-expression levels in homeostatic and non-inflamed tissues, prompted a change in strategies for in vivo uPAR-targeting from being primarily focused on function-inhibition approaches 20 , 21 to rely more on targeted-cytotoxic approaches to eradicate uPAR-expressing cells 22 – 29 . Parallel to those new attempts to design cytotoxic uPAR-targeted therapies, others developed several non-invasive imaging approaches to visualize uPAR expression in vivo—thus completing a possible theranostic pipeline for uPAR in clinical oncology 30 – 36 . The virtue of these uPAR-specific imaging platforms is that they (i) can aid patient stratification, (ii) can follow treatment responses using positron emission tomography (PET) scanning 31 , 37 – 40 , and (iii) can potentially be used to increase cancer surgery precision by fluorescence-guided intraoperative imaging 33 , 34 , 41 , 42 .…”