Hyaluronic Acid–Based Activatable Nanomaterials for Stimuli‐Responsive Imaging and Therapeutics: Beyond CD44‐Mediated Drug Delivery

Abstract

There is a rapidly increasing interest in developing stimuli-responsive nanomaterials for treating a variety of diseases. By enabling the activation of function locally at the sites of interest, it is possible to increase therapeutic efficacy significantly while simultaneously reducing adverse side effects. While there are many sophisticated nanomaterials available, they are often highly complex and not easily transferrable to industrial scales and clinical settings. However, nanomaterials based on hyaluronic acid offer a compelling strategy for reducing their complexity while retaining several desirable benefits such as active targeting and stimuli-responsive degradation. Herein, the basic properties of hyaluronic acid, its binding partners, and natural routes for degradation by hyaluronidases-hyaluronic-aciddegrading enzymes-and oxidative stresses are discussed. Recent advances in designing hyaluronic acid-based, actively targeted, hyaluronidase-or reactive-oxygen-species-responsive nanomaterials for both diagnostic imaging and therapeutic delivery, which go beyond merely the classical targeting of CD44, are summarized.

Reversing tumor stemness via orally targeted nanoparticles achieves efficient colon cancer treatment

“…Extensive clinical evidence has demonstrated that CD44 and CD168 are overexpressed in several malignant tumors and can be utilized for targeted drug design 25,26 . Hyaluronic acid (HA), a natural polysaccharide composed of N-acetyl-D-glucosamine and D-glucuronic acid, has been rigorously validated as a target of CD44 and CD168 27 .…”

Design of Soft Nanocarriers Combining Hyaluronic Acid with Another Functional Polymer for Cancer Therapy and Other Biomedical Applications

“…In the past decade, several reviews have described the advantages and properties of polymeric nanocarriers [5,7,9,32,62,65,81] as well as HA-based nanosystems [6,79,82,83,84,85,86]. Nonetheless, to the best of our knowledge, none of them have focused on polymeric nanocarriers combining HA and custom-made polymers as major components, as done in this review.…”

“…In addition to application in antitumor therapy, nanocarriers based on HA-polymer conjugates or complexes can also be used for several other applications, like rheumatoid arthritis (RA) therapy, delivery of drugs through the brain-blood barrier (BBB), siRNA delivery, sensing bacterial enzymes, imaging, among others [79]. However, as described in this review, only few examples of such applications have been investigated using HA-based polymeric nanocarriers, leaving a large field for future exploration.…”

Tumor Microenvironment-Responsive Nanomaterials as Targeted Delivery Carriers for Photodynamic Anticancer Therapy

“…HA has good biocompatibility and can target the CD44 receptor overexpressed in many types of cancer cells (Toole, 1990 ). When reaching the tumor tissues, hyaluronidase within tumor tissues can degrade HA (Choi et al, 2019 ). Shi et al ( 2016 ) used diiodo-styryl-BODIPY as a PS, and then conjugated HA to prepare hyaluronidas-responsive nanoparticles (named DBHA) as activatable photodynamic theranostics for treating cancer.…”