Differentiating Co-Delivery of Bisphosphonate and Simvastatin by Self-Healing Hyaluronan Hydrogel Formed by Orthogonal "Clicks": An In-Vitro Assessment.

Dmitri A Ossipov,Mads Lüchow,Michael Malkoch

doi:10.3390/polym13132106

Dmitri A Ossipov, Mads Lüchow + Show 1 more

Open Access

https://doi.org/10.3390/polym13132106

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Abstract

Due to its unique properties resembling living tissues, hydrogels are attractive carriers for the localized and targeted delivery of various drugs. Drug release kinetics from hydrogels are commonly controlled by network properties and the drug-network interactions. However, and simultaneously, the programmable delivery of multiple drugs with opposing properties (hydrophilicity, molecular weight, etc.) from hydrogels with determined network properties is still challenging. Herein, we describe the preparation of injectable self-healing hyaluronic acid (HA) hydrogels that release hydrophobic simvastatin and hydrophilic aminobisphosphonate (BP) drugs independently in response to acidic and thiol-containing microenvironments, respectively. We apply a prodrug strategy to BP by conjugating it to HA via a self-immolative disulfide linker that is stable in the blood plasma and is cleavable in the cytoplasm. Moreover, we utilize HA-linked BP ligands to reversibly bind Ca2+ ions and form coordination hydrogels. Hydrazone coupling of hydrophobic ligands to HA permits the encapsulation of simvastatin molecules in the resulting amphiphilic HA derivative and the subsequent acid-triggered release of the drug. The conjugation of BP and hydrophobic ligands to HA enables preparation of both bulk self-healing hydrogels and nanogels. Moreover, the developed hydrogel system is shown to be multi-responsive by applying orthogonally cleavable linkers. The presented hydrogel is a potential candidate for the combination treatment of osteoporosis and bone cancers as well as for bone tissue regeneration since it can deliver bone anabolic and anti-catabolic agents in response to bone diseases microenvironments.

Highlights

In the treatment of bone diseases, it is desirable to provide both bone anabolic and anti-catabolic treatments
We prepared hyaluronan (HA) derivatives in which aminobisphosphonates were permanently attached to hyaluronic acid (HA) backbone through stable chemical bonds, thereby excluding possibility for the release of aminobisphosphonates as intact drugs [29,30]
It was demonstrated that these HA-BP derivatives formed shear-thinning and self-healing hydrogels upon interaction with either hydrated metal ions such as Ca2+ [31], Mg2+ [32], Ag+ [33], or nanoparticles of inorganic salts such as calcium phosphate [30], magnesium silicate [32], calcium sodium phosphosilicate [34], and clay [35]

Summary

Introduction

In the treatment of bone diseases, it is desirable to provide both bone anabolic and anti-catabolic treatments. Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme reductase, were reported in several studies to induce an increase of bone mineral density (BMD) [13,14] through inhibiting the expression of matrix metalloproteases and promoting osteoblast differentiation [15] This bone anabolic effect of statins, was not shown in some other in vivo studies, which was explained by poor aqueous solubility of statins and their low concentration at the bone site [16]. To address unmet needs in nanotechnology-based drug delivery vehicles for bone diseases, we sought to make aminobisphosphonates acting simultaneously for three important purposes: (i) to act as bone targeting groups; (ii) to be released intact and act as anti-osteoclastic/anti-cancer drugs; and (iii) to enable immobilization of anabolic bone agents into localized hydrogel biomaterials for their subsequent sustained release at the bone resorbing sites. T1h. eTnhaenonmanedoimcineedpiclaintfeorpmlabtafsoerdmonbtahseesdelof-nastsheme bsleylfo-fahsysaelmurbolnyicoafcihdycaolnujurgoantiecdatocibdiscpohnojsupghoanteadtestoand hbydisrpophhoosbpichloignaantdesstharnodughhyodrtrhoopghonoablilyc rleigleaansadbsletlhinrkoeurgs.hHoyrdtrhoophgoobnicalelnycarpesluealastaiobnleoflbinokneerasn.aHboylidc raogpenhtsobociccurs deunricnagpthsue lsaeltfi-oansseomf bbloynaendapnraobvoidleicnaagnoepnatrstioclcecsuwristhdaudruinagl mthodeesoeflfb-iaosascteivmitby.ly and provide nanoparticles with a dual mode of bioactivity

Materials and Methods

Synthesis of Releasable 2-Pyridyldithio Derivative of Pamidronate 4

Synthesis of Aldehyde-Modified DN Derivative 6

Results and Discussion