Cartilage-targeting dexamethasone prodrugs increase the efficacy of dexamethasone

Florian A Formica, Goncalo Barreto, Marcy Zenobi-Wong

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

Intra-articular administration of glucocorticoids such as dexamethasone is a common treatment for osteoarthritic inflammation and pain. Despite its potent anti-inflammatory properties, multiple barriers hinder the drug's effectiveness in the articular space. In particular, the high turnover rate of the synovial fluid and the dense cartilage extracellular matrix (ECM) lead to poor drug penetration into cartilage. In order to increase the infiltration and retention time, two dexamethasone prodrugs were developed. Firstly, dexamethasone was conjugated to polycationic chitosan, which led to deep and sustained infiltration of the drug into full thickness cartilage, due to its strong electrostatic interactions with the high negative fixed charges of the cartilage ECM. Secondly, dexamethasone was conjugated to a collagen type II-binding peptide, WYRGRL, and this prodrug was shown to be retained in the deep zones of cartilage through specific interactions with cartilage-specific collagen type II bundles. In both cases, active dexamethasone was released from the carrier by ester linkage hydrolysis. Complexing dexamethasone with either chitosan or collagen type II-affinity carriers increased its binding and therapeutic efficacy inside cartilage, compared to the free drug. Both dexamethasone conjugates significantly reduced levels of inflammatory markers and slowed the loss of glycosaminoglycans in an ex vivo model. A single dose of a cartilage-targeting dexamethasone prodrug represents a promising alternative to the repetitive glucocorticoid injections needed to compensate for its rapid clearance from the joint cavity.
Alkuperäiskielienglanti
LehtiJournal of Controlled Release
Vuosikerta295
Sivut118-129
Sivumäärä12
ISSN1873-4995
DOI - pysyväislinkit
TilaJulkaistu - 10 helmikuuta 2019
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

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