Biofunctional polymer nanoparticles for intra-articular targeting and retention in cartilage

Rothenfluh, Dominique A.; Bermudez, Harry; O’Neil, Conlin P.; Hubbell, Jeffrey A.

doi:10.1038/nmat2116

Cited by 305 publications

(282 citation statements)

References 36 publications

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“…S11A, arrowhead). Normal joints are known for continual tissue remolding by MMP; however, targeting this area by systemic delivery is difficult due to the avascular nature of the cartilage and fast synovial fluid clearance (35). To study the CMP accumulation at the joints and other tissues specifically, we conducted further in vivo CMP targeting experiments using BALB/c mice.…”

Section: Resultsmentioning

confidence: 99%

Targeting collagen strands by photo-triggered triple-helix hybridization

Foss

Summerfield

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

167

244

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Collagen remodeling is an integral part of tissue development, maintenance, and regeneration, but excessive remodeling is associated with various pathologic conditions. The ability to target collagens undergoing remodeling could lead to new diagnostics and therapeutics as well as applications in regenerative medicine; however, such collagens are often degraded and denatured, making them difficult to target with conventional approaches. Here, we present caged collagen mimetic peptides (CMPs) that can be phototriggered to fold into triple helix and bind to collagens denatured by heat or by matrix metalloproteinase (MMP) digestion. Peptidebinding assays indicate that the binding is primarily driven by stereo-selective triple-helical hybridization between monomeric CMPs of high triple-helical propensity and denatured collagen strands. Photo-triggered hybridization allows specific staining of collagen chains in protein gels as well as photo-patterning of collagen and gelatin substrates. In vivo experiments demonstrate that systemically delivered CMPs can bind to collagens in bones, as well as prominently in articular cartilages and tumors characterized by high MMP activity. We further show that CMP-based probes can detect abnormal bone growth activity in a mouse model of Marfan syndrome. This is an entirely new way to target the microenvironment of abnormal tissues and could lead to new opportunities for management of numerous pathologic conditions associated with collagen remodeling and high MMP activity.A s the most abundant protein in mammals, collagens play a crucial role in tissue development and regeneration, and their structural or metabolic abnormalities are associated with debilitating genetic diseases and various pathologic conditions. Although collagen remodeling occurs during development and normal tissue maintenance, particularly for renewing tissues (e.g., bones), excess remodeling activity is commonly seen in tumors, arthritis, and many other chronic wounds. During collagen remodeling, large portions of collagens are degraded and denatured by proteolytic enzymes, which can be explored for diagnostic and therapeutic purposes. Since unstructured proteins are not ideal targets for rational drug design, library approaches have been employed to develop monoclonal antibody (1, 2) and peptide probes (3) that specifically bind to cryptic sites in collagen strands that become exposed when denatured. However, these probes suffer from poor pharmacokinetics (4), and/or low specificity, and binding affinity (5).We envisioned that triple helix, the hallmark structural feature of collagen, could provide a unique targeting mechanism for the denatured collagens. The triple helix is nearly exclusively seen in collagens except as small subdomains in a few noncollagen proteins (6). Considering its striking structural similarity to the DNA double helix in terms of multiplex formation by periodic interchain hydrogen bonds along the polymer backbone (6), we thought that a small peptide sequence with strong triple-helix prope...

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Section: Resultsmentioning

confidence: 99%

Targeting collagen strands by photo-triggered triple-helix hybridization

Foss

Summerfield

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

167

244

View full text Add to dashboard Cite

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“…[1][2][3][4][5] For example, Hubbell and coworkers have developed a drug delivery system with dual targeting moieties, which led up to a 72-fold increase in targeting to the extracellular compartment of articular cartilage in mice. 6 Although significant progress has been made in terms of identifying the targets and construction of targeting nanoparticles, the shape effect of the nanoparticle platform per se on cell binding and internalization through receptor-ligand interactions has not yet been investigated thoroughly. 7,8 Our interest here is to synthesize nanoparticles of different shapes and sizes and use a well-known receptor-ligand pair to study whether the shape effects exist, and if they do, which shape is more favorable for this particular receptor-ligand pair.…”

Section: Introductionmentioning

confidence: 99%

Folate‐mediated cell uptake of shell‐crosslinked spheres and cylinders

Zhang

Rossin

Hagooly

et al. 2008

J. Polym. Sci. A Polym. Chem.

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“…Larger particles tend to have slower in vitro release profiles, but when systemically delivered may be more readily detected and cleared from circulation, resulting in a lack of efficacy (29). For vascular targeting, because small particles show improved vessel adhesion and retention (16,(30)(31)(32), integrating slow-eluting conjugates into the nanoburr design allows for (i) improved drug loading; (ii) sub-100-nm NPs for vascular targeting; and (iii) sustained drug release over 2 weeks.…”

Section: Synthesis and Characterization Of The Nanoburr Drug Deliverymentioning

confidence: 99%

“…Conventional molecular targeting of relevant cell-based targets can be confounded by inter-and intrapatient heterogeneity in cell surface antigen expression (13,14). More recently, investigators have explored abundant noncellular targets such as the coagulation cascade (15), intraarticular cartilage (16), and extracellular matrix (17). Many human diseases are associated with compromised vasculature and increased vascular permeability (18,19).…”

mentioning

confidence: 99%

Spatiotemporal controlled delivery of nanoparticles to injured vasculature

Chan

Zhang

Tong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

231

181

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There are a number of challenges associated with designing nanoparticles for medical applications. We define two challenges here: (i) conventional targeting against up-regulated cell surface antigens is limited by heterogeneity in expression, and (ii) previous studies suggest that the optimal size of nanoparticles designed for systemic delivery is approximately 50-150 nm, yet this size range confers a high surface area-to-volume ratio, which results in fast diffusive drug release. Here, we achieve spatial control by biopanning a phage library to discover materials that target abundant vascular antigens exposed in disease. Next, we achieve temporal control by designing 60-nm hybrid nanoparticles with a lipid shell interface surrounding a polymer core, which is loaded with slow-eluting conjugates of paclitaxel for controlled ester hydrolysis and drug release over approximately 12 days. The nanoparticles inhibited human aortic smooth muscle cell proliferation in vitro and showed greater in vivo vascular retention during percutaneous angioplasty over nontargeted controls. This nanoparticle technology may potentially be used toward the treatment of injured vasculature, a clinical problem of primary importance.T he field of nanotechnology has crossed significant milestones from the systemic delivery of nanomedicines (1-5). However, the ability to achieve spatiotemporal control may be essential to many medical applications.In this study, we engineer a nanoparticle (NP) system that fundamentally changes the way we control spatiotemporal delivery of therapeutic agents. We designed approximately 60-nm core-shell hybrid NPs (6, 7) consisting of a polymeric core, a lipid interface, and a poly(ethylene glycol) (PEG) corona. For temporal control, we achieved the capacity for slow drug elution over 2 weeks using poly(lactic acid) (PLA) conjugates of paclitaxel as a model therapeutic agent (8), made by a modified drug-alkoxide ring-opening strategy (9, 10). These conjugates allow for controlled drug release by gradual ester hydrolysis despite the large surface area and short diffusion distances of sub-100-nm particles. For spatial control, we functionalized our NPs with ligands (11, 12) that target across a range of diseases in a consistent and reproducible manner. Conventional molecular targeting of relevant cell-based targets can be confounded by inter-and intrapatient heterogeneity in cell surface antigen expression (13,14). More recently, investigators have explored abundant noncellular targets such as the coagulation cascade (15), intraarticular cartilage (16), and extracellular matrix (17). Many human diseases are associated with compromised vasculature and increased vascular permeability (18,19). Therefore, we exploit these vascular breaches by targeting the underlying basement membrane. Toward this goal, we screened for heptapeptide ligands by biopanning a phage library against collagen IV (20), which represents 50% of the vascular basement membrane (21), and characterized specific ligands for targeting affinity against...

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Biofunctional polymer nanoparticles for intra-articular targeting and retention in cartilage

Cited by 305 publications

References 36 publications

Targeting collagen strands by photo-triggered triple-helix hybridization

Targeting collagen strands by photo-triggered triple-helix hybridization

Folate‐mediated cell uptake of shell‐crosslinked spheres and cylinders

Spatiotemporal controlled delivery of nanoparticles to injured vasculature

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