Systemically Administered Hemostatic Nanoparticles for Identification and Treatment of Internal Bleeding

Abstract

Internal bleeding is an injury that can be difficult to localize and effectively treat without invasive surgeries. Injectable polymeric nanoparticles have been developed that can reduce clotting times and blood loss, but they have yet to incorporate sufficient diagnostic capabilities to assist in identifying bleeding sources. Herein, polymeric nanoparticles were developed to simultaneously treat internal bleeding while incorporating tracers for visualization of the nanoparticles by standard clinical imaging modalities. Addition of 1,1′-dioctadecyl-3,3,3′,3′tetramethylindodicarbocyanine perchlorate (DiD; a fluorescent dye), biotin functionality, and gold nanoparticles to hemostatic polymeric nanoparticles resulted in nanoparticles amenable to imaging with near-infrared (NIR) imaging, immunohistochemistry, and X-ray computed tomography (CT), respectively. Following a lethal liver resection injury, visualization of accumulated nanoparticles by multiple imaging methods was achieved in rodents, with the highest accumulation observed at the liver injury site, resulting in improved survival rates. Tracer addition to therapeutic nanoparticles allows for an expansion of their applicability, during stabilization by first responders to diagnosis and identification of unknown internal bleeding sites by clinicians using standard clinical imaging modalities.

Nanophosphor-Based Contrast Agents for Spectral X-ray Imaging

“…This is of paramount importance, since it could allow for estimations of the amount of contrast agent required per area of interest (cm 3 ), such as the size of the tumor. In addition, approximations can be made for the detection of smaller tumor sizes, when our material is attached, allowing for potential detection of early cancers, tracking of cancer metastases (secondary cancers), and quantification of therapeutic responses [3,51,52,53,56].…”

Synthetic Blood Substitutes

“…Instead of coating particles with Fg, resent designs have also utilized Fg-relevant small molecular weight peptides for particle surface decoration. Most of these approaches have utilized linear small RGD peptides, e.g., CGRGD or GRGDS, that have binding capability to platelet surface integrin GPIIb-IIIa [216,217]. Two potential issues with using these peptides are (i) their ubiquitous nature to bind to many different integrins on other cells (i.e., lack of platelet specificity) and (ii) their reported ability to trigger activation of resting platelets (i.e., systemic prothrombotic risk) [218][219][220].…”

“…Two potential issues with using these peptides are (i) their ubiquitous nature to bind to many different integrins on other cells (i.e., lack of platelet specificity) and (ii) their reported ability to trigger activation of resting platelets (i.e., systemic prothrombotic risk) [218][219][220]. Nonetheless, from a feasibility standpoint, decoration of micro-and nanoparticles with these RGD peptides has resulted in platelet-mimetic constructs with promising hemostatic ability in vitro and in vivo [216,217,221]. The issue of platelet specificity can be potentially resolved by utilizing peptides that have higher selectivity to the active platelet GPIIb-IIIa.…”

Bioinspired artificial platelets for transfusion applications in traumatic hemorrhage

“…Therefore, strategies have evolved toward using small peptides to render PLT‐mimetic functionalities. Examples of these are seen in designs involving surface decoration of RBCs or synthetic polymeric particles with fibrinogen‐mimetic arginine‐glycine‐aspartic acid (RGD) and alanine‐glycine‐aspartic acid (AGD) peptides that can bind to active PLT integrin GPIIb‐IIIa . These designs essentially recapitulate only the fibrinogen‐mediated aggregation mechanism of active PLTs, and they have shown promising hemostatic capacity in animal models.…”

“…An important aspect to consider for successful clinical translation of these approaches is the binding specificity of the peptides. For example, the RGD peptides used in some designs are highly ubiquitous, and this may pose cross‐reactivity challenges in vivo. Also, ubiquitous RGD peptides are known to trigger activation of resting circulating PLTs; this may pose systemic prothrombotic risks in vivo.…”