Bisphosphonate-functionalized hyaluronic acid showing selective affinity for osteoclasts as a potential treatment for osteoporosis

Abstract

Current treatments for osteoporosis involve the administration of high doses of bisphosphonates (BPs) over a number of years. However, the efficiency of the absorption of these drugs and specificity towards targeted osteoclastic cells is still suboptimal. In this study, we have exploited the natural affinity of high (H) and low (L) molecular-weight hyaluronic acid (HA) towards a cluster of differentiation 44 (CD44) receptors on osteoclasts to use it as a biodegradable targeting vehicle. We covalently bonded BP to functionalised HA (HA-BP) and found that HA-BP conjugates were highly specific to osteoclastic cells and reduced mature osteoclast numbers significantly more than free BP. To study the uptake of HA-BP, we fluorescently derivatised the polymer-drug with fluorescein B isothiocyanate (FITC) and found that L-HA-BP could seamlessly enter osteoclastic cells. Alternatively, we tested polyvinyl alcohol (PVA) as a synthetic polymer delivery vehicle using similar chemistry to link BP and found that osteoclast numbers did not reduce in the same way. These findings could pave the way for biodegradable polymers to be used as vehicles for targeted delivery of anti-osteoporotic drugs.

Self‐Healing Polymeric Hydrogel Formed by Metal–Ligand Coordination Assembly: Design, Fabrication, and Biomedical Applications

“…In this review, we describe methods of conjugation of different ligands including bisphosphonate (BP), catechol, histidine (His), pyridine (Py), etc., to polymer backbones ( Figure ) followed by a discussion on hydrogel formation. The presented chelating ligands have been conjugated to biocompatible polymers including HA and poly(ethylene glycol) (PEG) using “click”‐type reaction or amide coupling reaction.…”

“…For this purpose, we selected HA, an abundant polysaccharide in human body, and modified it with BP groups by using different conjugation strategies including thiol‐ene addition reaction, thiol‐disulfide exchange reaction, as well as Michael addition reaction . Notably, a facile method to obtain BP modified HA derivative (HA‐BP) from its thiolated precursor (HA‐SH) using UV‐mediated thiol‐ene radical addition of acrylamide‐functionalized BP was developed . This method resulted in a brush‐like conjugate containing few BP moieties per thiol group on the HA backbone.…”

Moldable Hyaluronan Hydrogel Enabled by Dynamic Metal–Bisphosphonate Coordination Chemistry for Wound Healing

“…The formed hydrogels possess self‐healing properties and can be injected or printed, which is a very attractive property in noninvasive tissue engineering applications. According to our previous reports, HA‐BP derivative was obtained from HA modified with thiol (SH) groups (HA‐SH) by UV–light initiated radical thiol–ene addition reaction to BP‐acrylamide derivative . Despite of high conjugation yields of the thiol–ene reaction, reproducibility of this synthesis was poor due to numerous side crosslinking reactions involving highly reactive radicals.…”

Feasibility of polymer-drug conjugates for non-cancer applications

“…However, the L-HA conjugate was more toxic against the cells than the H-HA and the free drug. Interestingly, the L-HA conjugate could localise inside osteoclast like cells, while H-HA conjugate adhered to the cell surface and did not exhibit any cellular uptake over 12 h [174].…”