Design of an Inflammation-Sensitive Polyelectrolyte-Based Topical Drug Delivery System for Arthritis

Abstract

Abstract. The most successful treatment strategy for arthritis is intra-articular injections that are costly and have reduced patient compliance. The purpose of the current study was to develop an inflammationsensitive system for topical drug administration. Multi-macromolecular alginate-hyaluronic acid-chitosan (A-H-C) polyelectrolyte complex nanoparticles, loaded with indomethacin were developed employing pre-gel and post-gel techniques in the presence of dodecyl-L-pyroglutamate (DLP). In addition to in vitro studies, in silico simulations were performed to affirm and associate the molecular interactions inherent to the formulation of core all-natural multi-component biopolymeric architectures composed of an anionic (alginate), a cationic (chitosan), and an amphi-ionic polyelectrolytic (hyaluronic acid) macromolecule. The results demonstrated that DLP significantly influenced the size of the synthesized nanoparticles. Drug-content analysis revealed higher encapsulation efficiency (77.3%) in the presence of DLP, irrespective of the techniques used. Moreover, in vitro drug release studies showed that indomethacin release from the nanosystem was significantly improved (98%) in Fenton's reagent. Drug permeation across a cellulose membrane using a Franz diffusion cell system showed an initial surge flux (0.125 mg/cm −2 /h), followed by sustained release of indomethacin for the post-gel nanoparticles revealing its effective skin permeation efficiency. In conclusion, the study presents novel nanoparticles which could effectively encapsulate and deliver hydrophobic drugs to the target site, particularly for arthritis.

In silico analytico‐mathematical interpretation of biopolymeric assemblies: Quantification of energy surfaces and molecular attributes via atomistic simulations

“…The MMER analysis provided an excellent insight into the composition of the nanostructured system wherein the alginate chains carried the drug molecule, hyaluronic acid provided proposed inflammation sensitive coating over the carrier molecule, and finally chitosan acted as the bridging agent to congeal the anionic molecules together—forming a stable and functional TPIQ architecture. Interestingly, HYA (being amphi‐ionic) provided the much needed ionic balance within the TPIQ and hence the formation of a well‐connected 3D architecture supported by extensive H‐bonding among the bimolecular (ALG:CHT, CHT‐HYA, and HYA:ALG) and trimolecular (ALG‐CHT‐HYA) regions and involved –COOH/‐COOH, –OH/–OH, –NH/–OH, –OCO–OH, –COOH–OH, and –COOH/–NH functional groups (Figure ) . The above discussion clearly confirms the important role played by amphi‐ionic or amphoteric systems in generation of effective polyelectrolyte complexes for biomedical applications.…”

“…Color codes for elements in (a): carbon (cyan), hydrogen (white), nitrogen (blue), and oxygen (red). Color codes for structures in (b): alginate (red), chitosan (blue), and hyaluronic acid (yellow) (Reference ; reproduced with permission from springer nature © 2015)…”

Inflammation-Responsive Polymers

“…One of the pioneered inflammation-responsive polymeric drug delivery systems described were biodegradable hydrogels of cross-linked hyaluronic acid (HA), which specifically degrades in the presence of hydroxyl radicals (Nobuhiko et al, 1992). Since then, different architectures based on HA have been used with this aim (Nobuhiko et al, 1993;Bijukumar et al, 2016). More recently, other redox-responsive polymers have also been exploited for targeting inflammatory areas or for treating inflammation-related diseases reducing local oxidative stress.…”

“…These inflammation-sensitive polymeric systems have been designed for different applications such as drug delivery systems (Mountziaris et al, 2011;Zhang et al, 2015b;Lee et al, 2015;Li et al, 2017;Nobuhiko et al, 1993;Bijukumar et al, 2016) for the treatment of inflammation-related diseases such as atherosclerosis, ischemia, rheumatoid arthritis, coronary artery disease, IBD, or, the most studied one, cancer. Moreover, bioactive films based on these kinds of polymers have been used as implant coatings to reduce the so-called foreign body reaction to implanted biomaterials (Kim et al, 2011;Wu et al, 2015;Mercanzini et al, 2010).…”

“…This redox microenvironment defines the difference between healthy and inflamed tissue and, hence, can be exploited as marker of inflammation-related diseases for detection, diagnosis, and therapy. In particular, different ROS-responsive polymers including polymer-drug conjugates that self-assemble into nanoparticles (Clond et al, 2013;Wilson et al, 2010;Jager et al, 2016), microparticles (Nobuhiko et al, 1993), cross-linked hydrogels (Nobuhiko et al, 1992;Ito et al, 2007), bioactive coating (Kim et al, 2011), and scaffolds (Martin et al, 2014) have been widely investigated in the last decades because of their potential as drug delivery systems to sites of inflammation (Wilson et al, 2010;Bijukumar et al, 2016) or as tools for the early diagnosis and monitorization of inflammatory-related diseases (Sowers et al, 2014;Seo et al, 2016).…”