Sustained intra-cartilage delivery of low dose dexamethasone using a cationic carrier for treatment of post traumatic osteoarthritis

Bajpayee, Ambika G.; Vega, Rodolfo E. De la; Scheu, Maximiliano; Varady, Nathan H.; Yannatos, Isabel; Brown, L A; Krishnan, Yamini; Fitzsimons, TJ; Bhattacharya, Pallab; Frank, Eliot H.; Grodzinsky, Alan J.; Porter, Ryan M.

doi:10.22203/ecm.v034a21

Cited by 74 publications

(67 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although significant systemic side effects were noted in the animals that received repeated injections of DEX, these studies have all demonstrated a protective capacity of DEX in the preservation of joint tissues in the short term. Others have also described successes in the treatment of PTOA using IA DEX in ACL deficient rabbit models, as well as using triamcinolone acetonide in the knees of ACL transected Yorkshire pigs . A clinical study is currently underway to investigate the efficacy of IA DEX in the management of distal radius fractures to prevent PTOA of the wrist …”

mentioning

confidence: 99%

Molecular Response of Rabbit Menisci to Surgically Induced Hemarthrosis and a Single Intra‐Articular Dexamethasone Treatment

Heard

Barton

Agbojo

et al. 2019

Journal Orthopaedic Research

View full text Add to dashboard Cite

Anterior cruciate ligament reconstructive surgery can restore biomechanical stability, however, such surgery cannot reliably prevent the onset of post-traumatic osteoarthritis. The aim of this study was to elucidate the molecular response that occurs within the menisci following a surgical injury that allows bleeding into the joint space, and then to investigate the effect of dexamethasone (DEX) on this molecular response. Cell viability studies following acute controlled exposure to blood and blood plus DEX were also conducted. Forty-eight New Zealand white rabbits were randomly allocated into control, sham, surgical, and surgical + DEX groups (each group n = 6). Animals were sacrificed at 48 h and 9 weeks, and menisci were harvested. The messenger RNA (mRNA) expression levels for key inflammatory, and degradative proteins, as well as mRNA levels for autophagy pathway molecules were quantified, and statistically significant changes were described. Meniscal cell viability was calculated by incubating groups of medial and lateral menisci in autologous blood, or autologous blood plus DEX for 48 h (each group n = 4; total of eight medial and eight lateral menisci), and then conducting a histological live/dead assay. Results indicated a significant reduction in only medial meniscal cell viability when the tissue was exposed to blood in combination with DEX. A single administration of DEX following surgery significantly suppresses the elevated molecular expression for key inflammatory and degradative markers within menisci at 48 h and 9 weeks post-surgery. In vitro, autologous blood did not affect cell viability, but addition of DEX uniquely impacted the medial menisci.

show abstract

mentioning

confidence: 99%

Molecular Response of Rabbit Menisci to Surgically Induced Hemarthrosis and a Single Intra‐Articular Dexamethasone Treatment

Heard

Barton

Agbojo

et al. 2019

Journal Orthopaedic Research

View full text Add to dashboard Cite

show abstract

“…[42] This interesting result is however mitigated by the detrimental influence of Avidin itself on GAGs, hypothesized by the authors. [30] In comparison, chitosan is a much stronger binder due to its significantly higher net charge and partitioning coefficient. Consequently, the retention time and efficacy of chitosan-dex are expected to be significantly higher, while having high biocompatibility and low cell toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…[23,29] Improved infiltration, suppression of injury-induced joint swelling and catabolic gene expression could be shown when injecting Avidin-dex intra-articularly in a posttraumatic OA rabbit model. [30] Although providing strong binding, electrostatic interactions are rather unspecific and could lead to off-target delivery. In parallel, we focused on developing a more specific approach by using a collagen type II-binding peptide.…”

Section: Introductionmentioning

confidence: 99%

Cartilage-targeting dexamethasone prodrugs increase the efficacy of dexamethasone

Formica

Barreto

Zenobi‐Wong

2019

Journal of Controlled Release

View full text Add to dashboard Cite

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 charge 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 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.

show abstract

“…This gradient allows continued diffusion and further transport of the P4-phage into the tumor tissue than observed with the control-phage. The difference in concentration gradients resulting in improved tissue uptake has been observed in cartilage explants [80][81][82] and mucus hydrogels 63 . Data represents mean ± SD (n=3).…”

Section: Effect Of Surface Chargementioning

confidence: 94%

Identification of peptide coatings that enhance diffusive transport of nanoparticles through the tumor microenvironment

Mohanty

Liu

Kim

et al. 2019

Preprint

View full text Add to dashboard Cite

In solid tumors, increasing drug penetration promotes their regression and improves the therapeutic index of compounds. However, the heterogeneous extracellular matrix (ECM) acts a steric and interaction barrier that hinders effective transport of therapeutics, including nanomedicines. Specifically, the interactions between the ECM and surface physicochemical properties of nanomedicines (e.g. charge, hydrophobicity) impedes their diffusion and penetration.To address the challenges using existing surface chemistries, we used peptide-presenting phage libraries as a high-throughput approach to screen and identify peptides as coatings with desired physicochemical properties that improve diffusive transport through the tumor microenvironment.Through iterative screening against the ECM and identification by next-generation DNA sequencing and analysis, we selected individual clones and measured their transport by diffusion assays. Here, we identified a net-neutral charge, hydrophilic peptide P4 that facilitates All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. . https://doi.org/10.1101/659524 doi: bioRxiv preprint significantly higher diffusive transport of phage than negative control through in vitro tumor ECM.Through alanine mutagenesis, we confirmed that the hydrophilicity, charge, and their spatial ordering impact diffusive transport. P4 phage clone exhibited almost 200-fold improved uptake in ex vivo pancreatic tumor xenografts compared to the negative control. Nanoparticles coated with P4 exhibited ~40-fold improvement in diffusivity in pancreatic tumor tissues, and P4-coated particles demonstrated less hindered diffusivity through the ECM compared to particles functionalized with gold standard poly(ethylene) glycol or iRGD peptide ligand. By leveraging the power of molecular diversity using phage display, we can greatly expand the chemical space of surface chemistries that can improve the transport of nanomedicines through the complex tumor microenvironment to ultimately improve their efficacy. Quantification Amplification Phage libraryScreening of phage-presenting peptide library through a tumor ECM model Identification and selection of potential peptide using nextgeneration sequencingSelection of a faster diffusing clone through in vitro validation using Transwell and multichannel diffusion assay Ex vivo uptake validation of the selected clone followed by comparison of diffusivity of peptide-coated nanoparticle with gold standards using multiple particle tracking All rights reserved. No reuse allowed without permission.

show abstract

Sustained intra-cartilage delivery of low dose dexamethasone using a cationic carrier for treatment of post traumatic osteoarthritis

Cited by 74 publications

References 74 publications

Molecular Response of Rabbit Menisci to Surgically Induced Hemarthrosis and a Single Intra‐Articular Dexamethasone Treatment

Molecular Response of Rabbit Menisci to Surgically Induced Hemarthrosis and a Single Intra‐Articular Dexamethasone Treatment

Cartilage-targeting dexamethasone prodrugs increase the efficacy of dexamethasone

Identification of peptide coatings that enhance diffusive transport of nanoparticles through the tumor microenvironment

Contact Info

Product

Resources

About