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

The rapid advancement in medicine requires the search for new drugs, but also for new carrier systems for more efficient and targeted delivery of the bioactive molecules. Among the latter, polymeric nanocarriers have an increasingly growing potential for clinical applications due to their unique physical and chemical characteristics. In this regard, nanosystems based on hyaluronic acid (HA), a polysaccharide which is ubiquitous in the body, have attracted particular interest because of the biocompatibility, biodegradability and nonimmunogenic property provided by HA. Furthermore, the fact that hyaluronic acid can be recognized by cell surface receptors in tumor cells, makes it an ideal candidate for the targeted delivery of anticancer drugs. In this review, we compile a comprehensive overview of the different types of soft nanocarriers based on HA conjugated or complexed with another polymer: micelles, nanoparticles, nanogels and polymersomes. Emphasis is made on the properties of the polymers used as well as the synthetic approaches for obtaining the different HA-polymer systems. Fabrication, characterization and potential biomedical applications of the nanocarriers will also be described.

Heparosan as a potential alternative to hyaluronic acid for the design of biopolymer-based nanovectors for anticancer therapy.

Glycosaminoglycans (GAGs) are important components of the extracellular matrix that have attracted great interest for drug delivery and pharmaceutical applications due to their diverse biological functions. Among GAGs, heparosan (Hep), a biosynthetic precursor of heparin, has recently emerged as a promising building block for the design of nanoparticles with stealth properties. Though this non-sulfated polysaccharide has a chemical structure very close to that of hyaluronic acid (HA), it distinguishes from HA in that it is biologically inert in the extracellular spaces in the body. In this study, we designed Hep- and HA-based nanogels (NGs) that differ only in the chemical nature of the hydrophilic shell. The nanogels were prepared in a very straightforward way from Hep and HA modified with a thermoresponsive copolymer properly designed to induce self-assembly below room temperature. This versatile synthetic approach also enabled further shell-crosslinking allowing an increase in the colloidal stability. After careful characterization of the un-crosslinked and crosslinked Hep and HA NGs in terms of size (Z-average diameters of un-crosslinked and crosslinked NGs ∼110 and 150 nm) and morphology, they were injected intravenously into tumor-bearing mice for biodistribution experiments. Interestingly, these show that the liver uptake of Hep nanogels is remarkably reduced and tumor accumulation significantly improved as compared to HA nanogels (intensity ratios of tumor-to-liver of 2.2 and 1.4 for the un-crosslinked and crosslinked Hep NGs versus 0.11 for the un-crosslinked and crosslinked HA ones). These results highlight the key role played by the shell-forming GAGs on the in vivo fate of nanogels, which correlates with the specific biological properties of Hep and HA.

A versatile method for the selective core-crosslinking of hyaluronic acid nanogels via ketone-hydrazide chemistry: from chemical characterization to in vivo biodistribution.

The development of biopolymer-based nanogels has gained particular interest to achieve successful delivery of therapeutics for the treatment of various diseases, such as cancer, infection and diabetes. Herein, we report a new and simple methodology for the covalent stabilization of self-assembled gel nanoparticles based on hyaluronic acid (HA) modified with a thermoresponsive ketone-functional copolymer. This relies on the selective formation of hydrazone crosslinks with bishydrazides within the globular domains of the copolymer chains formed above the cloud point temperature. This approach allows tuning of the crosslinking density by varying the dihydrazide crosslinker to ketone molar ratio. The size distributions and morphology of the nanogels were assessed using dynamic light scattering (DLS), cryo-transmission and scanning electron microscopy. In vitro cellular uptake in several cancer cells and in vivo biodistribution of the nanogels in different mouse tumor models were then explored to assess the effectiveness of this crosslinking strategy. The data from these experiments show prolonged blood circulation, longer than 24 hours, for the crosslinked nanogels and high tumor accumulation.