Sustained intra-cartilage delivery of interleukin-1 receptor antagonist using cationic peptide and protein-based carriers

Mehta, Shikhar; Boyer, Timothy L.; Akhtar, Sumayyah; He, Tengfei; Zhang, Chenzhen; Vedadghavami, Armin; Bajpayee, Ambika G.

doi:10.1016/j.joca.2023.01.573

Cited by 13 publications

(12 citation statements)

References 41 publications

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“…46 These principles of optimal net charge design based on the negative fixed charge density of tissues were confirmed and successfully applied to the development of cartilage targeting carriers in our previous work. [47][48][49][50][51] Remarkably, mExo-AP and mExo-BP demonstrated enhanced uptake in Caco-2 cells compared to other formulations, with improvements of 1.5-fold and 2.5-fold compared to native mExo, respectively (Fig. 4B).…”

Section: Biomaterials Science Papermentioning

confidence: 88%

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Milk exosomes anchored with hydrophilic and zwitterionic motifs enhance mucus permeability for applications in oral gene delivery

Zhang,

Millán Cotto

et al. 2024

Biomater. Sci.

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Section: Biomaterials Science Papermentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Milk exosomes anchored with hydrophilic and zwitterionic motifs enhance mucus permeability for applications in oral gene delivery

Zhang,

Millán Cotto

et al. 2024

Biomater. Sci.

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“…Both mAv and CPC at 2× higher working concentrations were safe to use as no changes in cell viability, metabolism, or effects on relative GAG loss and nitrite release from cartilage explants were observed compared to saline control. While mAv has been successfully used for delivery of small molecule drugs to cartilage in low doses, ,,,, CT imaging requires many folds higher IOX doses compared to drugs. This may require mAv’s use at concentrations higher than 100 μM that have been shown to be safe .…”

Section: Discussionmentioning

confidence: 99%

“…This can be helpful especially in monitoring patients with traumatic joint injuries who are at a high risk of developing OA in future . Our laboratory has designed cartilage targeting optimally charged cationic carriers that possess sufficient electrical driving force to rapidly carry the conjugated cargo through the full thickness of cartilage tissue in high concentrations following their intra-articular administration in the synovial joint. − Here we use an arginine rich cationic peptide carrier with net charge of +8 (CPC, (RRAAAA) 3 RR) and a cationic multi-arm PEGylated Avidin (mAv) nanoconstruct ,, for intra-cartilage delivery of IOX as both carriers can rapidly penetrate through the full thickness of healthy and OA cartilage resulting in about 100× higher uptake than uncharged carriers. These carriers are designed to possess optimal cationic charge based on cartilage tissue’s negative fixed charge density (FCD) that enables high Donnan partitioning ( K CPC = 7.6; K mAv = 6) at the synovial fluid–cartilage interface resulting in steep intra-tissue concentration gradients and thus facilitating rapid transport and high uptake. − Too high of a cationic charge on the carrier can result in strong binding with cartilage GAGs in the superficial zone, preventing their penetration (Figure B).…”

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confidence: 99%

Cationic Carrier Mediated Delivery of Anionic Contrast Agents in Low Doses Enable Enhanced Computed Tomography Imaging of Cartilage for Early Osteoarthritis Diagnosis

Zhang

Vedadghavami

et al. 2023

ACS Nano

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Cartilage tissue exhibits early degenerative changes with onset of osteoarthritis (OA). Early diagnosis is critical as there is only a narrow time window during which therapeutic intervention can reverse disease progression. Computed tomography (CT) has been considered for cartilage imaging as a tool for early OA diagnosis by introducing radio-opaque contrast agents like ioxaglate (IOX) into the joint. IOX, however, is anionic and thus repelled by negatively charged cartilage glycosaminoglycans (GAGs) that hinders its intra-tissue penetration and partitioning, resulting in poor CT attenuation. This is further complicated by its short intra-tissue residence time owing to rapid clearance from joints, which necessitates high doses causing toxicity concerns. Here we engineer optimally charged cationic contrast agents based on cartilage negative fixed charge density by conjugating cartilage targeting a cationic peptide carrier (CPC) and multi-arm avidin nanoconstruct (mAv) to IOX, such that they can penetrate through the full thickness of cartilage within 6 h using electrostatic interactions and elicit similar CT signal with about 40× lower dose compared to anionic IOX. Their partitioning and distribution correlate strongly with spatial GAG distribution within healthy and early- to late-stage arthritic bovine cartilage tissues at 50–100× lower doses than other cationic contrast agents used in the current literature. The use of contrast agents at low concentrations also allowed for delineation of cartilage from subchondral bone as well as other soft tissues in rat tibial joints. These contrast agents are safe to use at current doses, making CT a viable imaging modality for early detection of OA and staging of its severity.

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“…Cationic nanocarriers that form weak electrostatic interactions with the anionic cartilage ECM can be an effective approach to overcome the electrostatic barrier 12–18 . For an effective therapeutic outcome, the nanocarriers first need to adhere to the cartilage tissue, and then penetrate and be retained throughout the full‐thickness cartilage 19 .…”

Section: Introductionmentioning

confidence: 99%

Branched poly‐l‐lysine for cartilage penetrating carriers

Gonzales,

Hoque,

Gilpin

et al. 2023

Bioengineering & Transla Med

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Joint diseases, such as osteoarthritis, often require delivery of drugs to chondrocytes residing within the cartilage. However, intra‐articular delivery of drugs to cartilage remains a challenge due to their rapid clearance within the joint. This problem is further exacerbated by the dense and negatively charged cartilage extracellular matrix (ECM). Cationic nanocarriers that form reversible electrostatic interactions with the anionic ECM can be an effective approach to overcome the electrostatic barrier presented by cartilage tissue. For an effective therapeutic outcome, the nanocarriers need to penetrate, accumulate, and be retained within the cartilage tissue. Nanocarriers that adhere quickly to cartilage tissue after intra‐articular administration, transport through cartilage, and remain within its full thickness are crucial to the therapeutic outcome. To this end, we used ring‐opening polymerization to synthesize branched poly(l‐lysine) (BPL) cationic nanocarriers with varying numbers of poly(lysine) branches, surface charge, and functional groups, while maintaining similar hydrodynamic diameters. Our results show that the multivalent BPL molecules, including those that are highly branched (i.e., generation two), can readily adhere and transport through the full thickness of cartilage, healthy and degenerated, with prolonged intra‐cartilage retention. Intra‐articular injection of the BPL molecules in mouse knee joint explants and rat knee joints showed their localization and retention. In summary, this study describes an approach to design nanocarriers with varying charge and abundant functional groups while maintaining similar hydrodynamic diameters to aid the delivery of macromolecules to negatively charged tissues.

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Sustained intra-cartilage delivery of interleukin-1 receptor antagonist using cationic peptide and protein-based carriers

Cited by 13 publications

References 41 publications

Milk exosomes anchored with hydrophilic and zwitterionic motifs enhance mucus permeability for applications in oral gene delivery

Milk exosomes anchored with hydrophilic and zwitterionic motifs enhance mucus permeability for applications in oral gene delivery

Cationic Carrier Mediated Delivery of Anionic Contrast Agents in Low Doses Enable Enhanced Computed Tomography Imaging of Cartilage for Early Osteoarthritis Diagnosis

Branched poly‐l‐lysine for cartilage penetrating carriers

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