Receptor‐Targeted Drug Delivery and the (Many) Problems We Know of: The Case of CD44 and Hyaluronic Acid

Abstract

CD44 is best known for being the most common receptor of hyaluronic acid (HA). It is also a heterogeneous molecule: while its standard isoform (CD44s) is ubiquitously expressed, there are also a range of variants (CD44v), and both CD44s and CD44v undergo a variety of post‐translational modifications. The signaling roles and frequent overexpression of both CD44s and CD44v in cancer (e.g., in cancer initiating cells/cancer stem cells) has raised interest in them for diagnostic applications, but also—and most importantly for this review—as possible molecular targets in tumor therapy, with their endocytic character being a clear advantage for the intracellular release of payloads. In this area, the most popular approach employs HA‐based carriers. However, their rational design and therefore the success of HA‐based therapies are hampered by the rather limited understanding of not only the identity, but also the dynamic properties of CD44. In this review, the reader is exposed to the full breadth of the challenges that HA carriers currently face, which start at the CD44 post‐transcriptional and post‐translational heterogeneity, and also include the understanding of receptor clustering phenomena (influencing also HA avidity), as well as the evaluation of off‐target effects.

Functional ligands for improving anticancer drug therapy: current status and applications to drug delivery systems

“…Due to its tumorigenic functions and level of expression often associated with tumor-initiating cells/cancer stem cells, CD44 is considered an early indicator for cancer cell proliferation (Basakran, 2015 ; Rios De La Rosa et al., 2018 ). This establishes CD44 as a biomarker in cancer diagnosis, particularly for breast, colorectal, head and neck, pancreas, bowel and prostate cancers (Rios De La Rosa et al., 2018 ). CD44 has a high affinity for HA, and all isoforms of CD44 contain an HA-specific binding domain near the N terminus (Lintuluoto et al., 2021 ).…”

Nano‐Oncologicals: A Tortoise Trail Reaching New Avenues

“…As a consequence, the targeting capacity of HA is rather unspecific. [94,95] Despite this, several works have shown that HA-based nanosystems tend to accumulate in the tumor tissue, which could be also caused by its stealth properties, or a combined effect of these active and passive mechanisms. [93] The first report in this line showed that HA-coated liposomes encapsulating mitomycin C were more efficacious than the un-coated carriers, in different murine cancer models (colon, melanoma, and lung metastasis).…”

Regulation of Hedgehog Signaling by miRNAs and Nanoformulations: A Possible Therapeutic Solution for Colorectal Cancer

“…CD44 is a surface protein responsible for interaction between cells and also plays vital role in the adhesion and migration of the cells ( 137 ). The CD44 has a specific binding site for hyaluronic acid which facilitates interaction with selectin, osteopontin, fibronectin, laminin, and collagen in the extracellular matrix ( 138 ). The binding of hyaluronic acid with CD44 results in the activation of epidermal growth factor receptor family kinases such as the MAPK and PI3/AkT that in turn promotes growth and proliferation in various cancers ( 138 ).…”

“…The CD44 has a specific binding site for hyaluronic acid which facilitates interaction with selectin, osteopontin, fibronectin, laminin, and collagen in the extracellular matrix ( 138 ). The binding of hyaluronic acid with CD44 results in the activation of epidermal growth factor receptor family kinases such as the MAPK and PI3/AkT that in turn promotes growth and proliferation in various cancers ( 138 ). Majority of CSCs population have CD44 surface markers along with other cell surface markers that increase invasiveness and stemness ( 139 ).…”