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Avidin grafted dextran nanostructure enables a month-long intra-discal retention.

ABSTRACT: Low back pain is often the direct result of degeneration of the intervertebral disc. A wide range of therapeutics including anti-catabolic, pro-anabolic factors and chemo-attractants that can stimulate resident cells and recruit endogenous progenitors are under consideration. The avascular nature and the dense matrix of this tissue make it challenging for systemically administered drugs to reach their target cells inside the nucleus pulposus (NP), the central gelatinous region of the intervertebral disc (IVD). Therefore, local intra-discal injection of therapeutic drugs directly into the NP is a clinically relevant delivery approach, however, suffers from rapid and wide diffusion outside the injection site resulting in short lived benefits while causing systemic toxicity. NP has a high negative fixed charge density due to the presence of negatively charged aggrecan glycosaminoglycans that provide swelling pressures, compressive stiffness and hydration to the tissue. This negative fixed charge density can also be used for enhancing intra-NP residence time of therapeutic drugs. Here we design positively charged Avidin grafted branched Dextran nanostructures that utilize long-range binding effects of electrostatic interactions to bind with the intra-NP negatively charged groups. The binding is strong enough to enable a month-long retention of cationic nanostructures within the NP following intra-discal administration, yet weak and reversible to allow movement to reach cells dispersed throughout the tissue. The branched carrier has multiple sites for drug conjugation and can reduce the need for multiple injections of high drug doses and minimize associated side-effects, paving the way for effective clinical translation of potential therapeutics for treatment of low back pain and disc degeneration.

SUBMITTER: Wagner EK

PROVIDER: S-EPMC7374582 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Avidin grafted dextran nanostructure enables a month-long intra-discal retention.

Wagner Erica K EK Vedadghavami Armin A Jacobsen Timothy D TD Goel Shakti A SA Chahine Nadeen O NO Bajpayee Ambika G AG

Scientific reports 20200721 1

Low back pain is often the direct result of degeneration of the intervertebral disc. A wide range of therapeutics including anti-catabolic, pro-anabolic factors and chemo-attractants that can stimulate resident cells and recruit endogenous progenitors are under consideration. The avascular nature and the dense matrix of this tissue make it challenging for systemically administered drugs to reach their target cells inside the nucleus pulposus (NP), the central gelatinous region of the interverteb ...[more]

PMID: 32694557

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Project description:Targeted drug delivery to joint tissues like cartilage remains a challenge that has prevented clinical translation of promising osteoarthritis (OA) drugs. Local intra-articular (IA) injections of drugs suffer from rapid clearance from the joint space and slow diffusive transport through the dense, avascular cartilage matrix comprised of negatively charged glycosaminoglycans (GAGs). Here we apply drug carriers that leverage electrostatic interactions with the tissue's high negative fixed charge density (FCD) for delivering small molecule drugs to cartilage cell and matrix sites. We demonstrate that a multi-arm cationic nano-construct of Avidin (mAv) with 28 sites for covalent drug conjugation can rapidly penetrate through the full thickness of cartilage in high concentration and have long intra-cartilage residence time in both healthy and arthritic cartilage via weak-reversible binding with negatively charged aggrecans. mAv's intra-cartilage mean uptake was found to be 112× and 33× the equilibration bath concentration in healthy and arthritic (50% GAG depleted) cartilage, respectively. mAv was conjugated with Dexamethasone (mAv-Dex), a broad-spectrum glucocorticoid, using a combination of hydrolysable ester linkers derived from succinic anhydride (SA), 3,3-dimethylglutaric anhydride (GA) and phthalic anhydride (PA) in 2:1:1 M ratio that enabled 50% drug release within 38.5 h followed by sustained release in therapeutic doses over 2 weeks. A single 10 μM low dose of controlled release mAv-Dex (2:1:1) effectively suppressed IL-1α-induced GAG loss, cell death and inflammatory response significantly better than unmodified Dex over 2 weeks in cartilage explant culture models of OA. With this multi-arm design, <1 μM Avidin was needed - a concentration which has been shown to be safe, preventing further GAG loss and cytotoxicity. A charge-based cartilage homing drug delivery platform like this can elicit disease modifying effects as well as facilitate long-term symptomatic pain and inflammation relief by enhancing tissue specificity and prolonging intra-cartilage residence time of OA drugs. This nano-construct thus has high translational potential for enabling intra-cartilage delivery of a broad array of small molecule OA drugs and their combinations to chondrocytes, enabling OA treatment with a single injection of low drug doses and eliminating toxicity issues associated with multiple high dose injections.

Dataset Information

Avidin grafted dextran nanostructure enables a month-long intra-discal retention.

Publications

Avidin grafted dextran nanostructure enables a month-long intra-discal retention.

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