Recent Advances in Targeting the Urokinase Plasminogen Activator with Nanotherapeutics
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 small-molecule 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.
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