Self-Titrating Anticoagulant Nanocomplexes That Restore Homeostatic Regulation of the Coagulation Cascade

Lin, Kevin Y.; Lo, Justin H.; Consul, Nikita; Kwong, Gabriel A.; Bhatia, Sangeeta N.

doi:10.1021/nn501129q

Cited by 36 publications

(30 citation statements)

References 66 publications

(109 reference statements)

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“…One example of the use of this is the incorporation of an MMP-cleavable peptide (GGRMSMPV) into a hyaluronic acid hydrogel that was used to deliver a recombinant tissue inhibitor of MMPs in a porcine model of myocardial infarction 113 . In addition to MMP-responsive hydrogels, there exist other cleavage systems that respond to biomolecules present in the body, such as glucose-responsive hydrogels for insulin delivery 114,115 and thrombin-responsive hydrogels to regulate blood coagulation 116,117 . Degradation can also be triggered in real time with externally provided cues.…”

Section: Mesh Size Controls Diffusion and Releasementioning

confidence: 99%

Designing hydrogels for controlled drug delivery

2016

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Hydrogel delivery systems can leverage therapeutically beneficial outcomes of drug delivery and have found clinical use. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including small-molecule drugs, macromolecular drugs and cells. Owing to their tunable physical properties, controllable degradability and capability to protect labile drugs from degradation, hydrogels serve as a platform in which various physiochemical interactions with the encapsulated drugs control their release. In this Review, we cover multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on physical and chemical properties of the hydrogel network and the hydrogel–drug interactions across the network, mesh, and molecular (or atomistic) scales. We discuss how different mechanisms interact and can be integrated to exert fine control in time and space over the drug presentation. We also collect experimental release data from the literature, review clinical translation to date of these systems, and present quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems.

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Section: Mesh Size Controls Diffusion and Releasementioning

confidence: 99%

Designing hydrogels for controlled drug delivery

2016

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“…For each of the three PEGylated compounds, we used a 5 kDa PEG chain, a length widely used in the literature 22 and successfully applied to several nanoparticle systems in our group. 23, 24 We were also interested in determining whether it is beneficial to display the targeting moiety on the distal end of the PEG chain, as such a modification could potentially improve cell-targeting functionality.…”

Section: Resultsmentioning

confidence: 99%

Comparison of Modular PEG Incorporation Strategies for Stabilization of Peptide–siRNA Nanocomplexes

Kwon

Zhang

et al. 2016

Bioconjugate Chem.

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Nanoparticulate systems have shown great promise in overcoming the considerable trafficking barriers associated with systemic nucleic acid delivery, which must be addressed in order to unlock the full potential of technologies such as RNAi and gene editing in vivo. In addition to mediating the cytoplasmic delivery of nucleic cargo and shielding it from nuclease degradation and immunostimulation, nucleic acid-containing nanomaterials delivered intravenously must also be stable in the bloodstream after administration in order to avoid toxicity and off-target delivery. To this end, the hydrophilic molecule polyethylene glycol (PEG) has been deployed in many different nanoparticle systems to prevent aggregation and recognition by the reticuloendothelial system. However, the optimal strategy for incorporating PEG into self-assembled nucleic acid delivery systems to obtain nanoparticle stability while retaining important functions such as receptor targeting and cargo activity remains unclear. In this work, we develop substantially improved formulations of tumor-penetrating nanocomplexes (TPNs), targeted self-assembled nanoparticles formulated with peptides and siRNA that have been shown to mitigate tumor burden in an orthotopic model of ovarian cancer. We specifically sought to tailor TPNs for intravenous delivery by systematically comparing formulations with three different classes of modular PEG incorporation, namely PEG graft polymers, PEG lipids, and PEGylated peptide – each synthesized using straightforward bioconjugation techniques. We found that addition of PEG lipids or PEGylated peptide carriers led to formation of small and stable nanoparticles, but only nanoparticles formulated with PEGylated peptide carriers retained substantial activity in a gene silencing assay. In vivo, this formulation significantly decreased accumulation in off-target organs and improved initial availability in circulation, compared to the original non-PEGylated particles. Thus, from amongst a set of candidate strategies, we identified TPNs with admixed PEGylated peptide carriers as the optimal formulation for systemic administration of siRNA, based on their performance in a battery of physicochemical and biological assays. Moreover, this optimized formulation confers pharmacologic advantages that may enable further translational development of tumor-penetrating nanocomplexes, highlighting the preclinical value of comparing formulation strategies, and the relevance of this systematic approach for the development of other self-assembled nanomaterials.

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“…Such triggering can be from internal stimuli such as pH, enzyme action, temperature, and shear forces or external stimuli such as focused ultrasound, NIR irradiation, and magnetic impulses. 135,136,201,202,219,[316][317][318][319][320][321][322][323][324][325][326][327][328] These unique "triggered release" approaches continue to add exciting refinements and attributes in the area of vascular nanomedicine, which can be leveraged to enhance delivery efficiency and release kinetics and therapeutic effects site selectively in various vascular pathologies.…”

Section: Current State-of-the-art In Vascular Nanomedicine Systems Anmentioning

confidence: 99%

Vascular Nanomedicine: Current Status, Opportunities, and Challenges

Sun

Gupta

2019

Semin Thromb Hemost

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The term “nanotechnology” was coined by Norio Taniguchi in the 1970s to describe the manipulation of materials at the nano (10−9) scale, and the term “nanomedicine” was put forward by Eric Drexler and Robert Freitas Jr. in the 1990s to signify the application of nanotechnology in medicine. Nanomedicine encompasses a variety of systems including nanoparticles, nanofibers, surface nano-patterning, nanoporous matrices, and nanoscale coatings. Of these, nanoparticle-based applications in drug formulations and delivery have emerged as the most utilized nanomedicine system. This review aims to present a comprehensive assessment of nanomedicine approaches in vascular diseases, emphasizing particle designs, therapeutic effects, and current state-of-the-art. The expected advantages of utilizing nanoparticles for drug delivery stem from the particle's ability to (1) protect the drug from plasma-induced deactivation; (2) optimize drug pharmacokinetics and biodistribution; (3) enhance drug delivery to the disease site via passive and active mechanisms; (4) modulate drug release mechanisms via diffusion, degradation, and other unique stimuli-triggered processes; and (5) biodegrade or get eliminated safely from the body. Several nanoparticle systems encapsulating a variety of payloads have shown these advantages in vascular drug delivery applications in preclinical evaluation. At the same time, new challenges have emerged regarding discrepancy between expected and actual fate of nanoparticles in vivo, manufacturing barriers of complex nanoparticle designs, and issues of toxicity and immune response, which have limited successful clinical translation of vascular nanomedicine systems. In this context, this review will discuss challenges and opportunities to advance the field of vascular nanomedicine.

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Self-Titrating Anticoagulant Nanocomplexes That Restore Homeostatic Regulation of the Coagulation Cascade

Cited by 36 publications

References 66 publications

Designing hydrogels for controlled drug delivery

Designing hydrogels for controlled drug delivery

Comparison of Modular PEG Incorporation Strategies for Stabilization of Peptide–siRNA Nanocomplexes

Vascular Nanomedicine: Current Status, Opportunities, and Challenges

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