In vivo visualization of osteoarthritic hypertrophic lesions

Hu, Hai; Lim, Ngee Han; Juretschke, Hans Paul; Ding‐Pfennigdorff, Danping; Florian, Peter; Kohlmann, Markus; Kandira, Abdullah; Kries, Jens Peter von; Saas, Joachim; Rudolphi, Karl Asmund; Wendt, K. Ulrich; Nagase, Hideaki; Plettenburg, Oliver; Nazaré, Marc; Schultz, Carsten

doi:10.1039/c5sc01301a

Cited by 21 publications

(15 citation statements)

References 41 publications

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“…Previous studies have shown that small (<15 nm) cationic nanocarriers can overcome the biological barriers of the joint by binding and penetrating anionic cartilage tissue faster than the carriers can be cleared from the joint space (10)(11)(12)(13)(14)(15)(16). It is vital for clinical translation of these cartilage-penetrating nanocarriers to identify an optimal nanocarrier surface charge that is both safe and efficacious.…”

Section: Introductionmentioning

confidence: 99%

Cartilage-penetrating nanocarriers improve delivery and efficacy of growth factor treatment of osteoarthritis

et al. 2018

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Osteoarthritis is a debilitating joint disease affecting nearly 30 million people for which there are no disease-modifying therapies. Several drugs that have failed clinical trials have shown inefficient and inadequate delivery to target cells. Anabolic growth factors are one class of such drugs that could be disease-modifying if delivered directly to chondrocytes, which reside deep within dense, anionic cartilage tissue. To overcome this biological barrier, we conjugated a growth factor to a cationic nanocarrier for targeted delivery to chondrocytes and retention within joint cartilage after direct intra-articular injection. The nanocarrier uses reversible electrostatic interactions with anionic cartilage tissue to improve tissue binding, penetration, and residence time. Amine terminal polyamidoamine (PAMAM) dendrimers were end functionalized with variable molar ratios of poly(ethylene glycol) (PEG) to control surface charge. From this small family of variably PEGylated dendrimers, an optimal formulation showing 70% uptake into cartilage tissue and 100% cell viability was selected. When conjugated to insulin-like growth factor 1 (IGF-1), the dendrimer penetrated bovine cartilage of human thickness within 2 days and enhanced therapeutic IGF-1 joint residence time in rat knees by 10-fold for up to 30 days. In a surgical model of rat osteoarthritis, a single injection of dendrimer–IGF-1 rescued cartilage and bone more effectively than free IGF-1. Dendrimer–IGF-1 reduced width of cartilage degeneration by 60% and volumetric osteophyte burden by 80% relative to untreated rats at 4 weeks after surgery. These results suggest that PEGylated PAMAM dendrimer nanocarriers could improve pharmacokinetics and efficacy of disease-modifying osteoarthritis drugs in the clinic.

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Section: Introductionmentioning

confidence: 99%

Cartilage-penetrating nanocarriers improve delivery and efficacy of growth factor treatment of osteoarthritis

et al. 2018

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“…Functionalization of poly(propylene sulphide nanoparticles and subsequent IA injection in mice knees resulted in a 72‐fold increase in cartilage‐targeting ability compared to nanoparticles functionalized with the scrambled control 103 . In contrast to other reported peptides, this sequence has been successfully used in preclinical models for diagnostics and drug delivery applications 12,91,103‐106 . In fact, the conjugation of this peptide to magnetic resonance imaging (MRI) contrast agents has allowed in vivo localization of cartilage hypertrophic changes in a rat model of OA 104 .…”

Section: Targeting For Ia Drug Deliverymentioning

confidence: 99%

Biomaterial strategies for improved intra‐articular drug delivery

Castro

Garcı́a

Guldberg

2020

J Biomedical Materials Res

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Osteoarthritis (OA) is a joint degenerative disease that has become one of the leading causes of disability in the world. It is estimated that OA affects 50 million adults in the United States. Currently, there are no FDA‐approved treatments that slow OA progression and its treatment is limited to pain management strategies and life style changes. Despite the discovery of several disease‐modifying OA drugs (DMOADs) and promising results in preclinical studies, their clinical translation has been significantly limited because of poor intra‐articular (IA) bioavailability and challenges in delivering these compounds to tissues of interest within the joint. Here, we review current OA treatments and their effectiveness at reducing joint pain, as well as novel targets for OA treatment and the challenges related to their clinical translation. Moreover, we discuss intra‐articular (IA) drug delivery as a promising route of administration, describe its inherent challenges, and review recent advances in biomaterial‐based IA drug delivery for OA treatment. Finally, we highlight the potential of tissue targeting in the development of effective IA drug delivery systems.

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“…In a more predictive mode, studies would be performed in intervention mode, dosing would thus be initiated after reaching first defined milestones of developing early osteoarthritis. We recently demonstrated that this is possible in principle; by applying cartilage targeted MRI contrast agents intra‐articularly, we could detect a defined stage of early onset of osteoarthritis, which could represent an ideal time point to initiate drug treatment. In such kind of alternatively designed study, animals could be grouped differently and treatment could be started upon showing this particular phenotype, thus reducing variability from the start and showing a clearer picture of the real impact of the examined drug candidates on developing pathology.…”

Section: Impact Of Chemical Biologymentioning

confidence: 99%