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

Abstract

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.

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

“…These nanocarriers are nanosized three-dimensional networks of chemically or physically crosslinked hydrophilic polymers [13,14,15,16,17,18,19]. It should be pointed out, that in some cases physically crosslinked nanogels can be chemically crosslinked, in a second step, to improve their long-term stability when circulating in the bloodstream [20].…”

“…Various amine-functionalized polymers have been grafted onto HA through the carboxylic acid group. Moreover, it can also be used to add new functional groups like maleimide [20,42,43] or amines [39,44,45,46]. Functionalization with a maleimide is useful for grafting thiol-containing polymers.…”

“…By varying the copolymer composition and molar mass, the CAT of the HA-copolymer derivative can be precisely tuned to obtain nanogels at the body temperature. Based on this, the group of Auzely-Velty et al has synthesized a large variety of thermoresponsive HA based-nanogels [20,42,43,48,49].…”

Recent Advances in Crosslinked Nanogel for Multimodal Imaging and Cancer Therapy

“…Compared with micelles or liposomes, a crosslinked structure can stabilize the nanogels, leading to the non-dissociable nanostructure [ 39 , 40 , 41 , 42 ]. Such structure makes nanogels keep intact in the circulation, thus resulting in improved biodistribution and better tumor accumulation [ 43 , 44 ].…”

Extracellular Matrix Mimics Using Hyaluronan-Based Biomaterials

“…(E) 3D hydrogels for cell encapsulation, with tuned mechanical properties (varying the HA M w , the crosslinking degree, and/or the HA blended with other biocompatible materials)[58]. All the images were used and adapted, with permission, from[58,[97][98][99]. Abbreviations: LYVE, Lymphatic vessel endothelial receptor for hyaluronan; RHAMM, receptor for hyaluronan-mediated motility; TLR, toll-like receptor.…”