Platelet-like Nanoparticles: Mimicking Shape, Flexibility, and Surface Biology of Platelets To Target Vascular Injuries

Abstract

Targeted delivery of therapeutic and imaging agents in the vascular compartment represents a significant hurdle in using nanomedicine for treating hemorrhage, thrombosis, and atherosclerosis. While several types of nanoparticles have been developed to meet this goal, their utility is limited by poor circulation, limited margination, and minimal targeting. Platelets have an innate ability to marginate to the vascular wall and specifically interact with vascular injury sites. These platelet functions are mediated by their shape, flexibility, and complex surface interactions. Inspired by this, we report the design and evaluation of nanoparticles that exhibit platelet-like functions including vascular injury site-directed margination, site-specific adhesion, and amplification of injury site-specific aggregation. Our nanoparticles mimic four key attributes of platelets, (i) discoidal morphology, (ii) mechanical flexibility, (iii) biophysically and biochemically mediated aggregation, and (iv) heteromultivalent presentation of ligands that mediate adhesion to both von Willebrand Factor and collagen, as well as specific clustering to activated platelets. Platelet-like nanoparticles (PLNs) exhibit enhanced surface-binding compared to spherical and rigid discoidal counterparts and site-selective adhesive and platelet-aggregatory properties under physiological flow conditions in vitro. In vivo studies in a mouse model demonstrated that PLNs accumulate at the wound site and induce ∼65% reduction in bleeding time, effectively mimicking and improving the hemostatic functions of natural platelets. We show that both the biochemical and biophysical design parameters of PLNs are essential in mimicking platelets and their hemostatic functions. PLNs offer a nanoscale technology that integrates platelet-mimetic biophysical and biochemical properties for potential applications in injectable synthetic hemostats and vascularly targeted payload delivery.

Controlling the morphology of copolymeric vectors for next generation nanomedicine

“…6). An excellent example of this is the development of artificial (polymeric) erythrocytes that possess a discoidal shape, mechanical flexibility, biochemically mediated aggregation and heteromultivalent presentation of ligands for platelet binding and wound targeting [86]. Such morphologically diverse NVs show high specific adhesion and limited non-specific interactions with excellent haemostatic capability over more rigid, spherical counterparts, due to their propensity to marginate to the vascular wall, which results in a substantial reduction of bleeding time in vivo.…”

Platelet-mimetic strategies for modulating the wound environment and inflammatory responses

“…[36][37][38] Current research in the field of platelet-mimetic technologies utilizes a wide variety of strategies including both naturally derived platelet derivatives and synthetic platelet strategies. In subsequent sections, we review various strategies that encompass a large range of approaches to achieve various goals such as wound targeting, drug delivery, and immune system evasion through platelet membrane cloaking.…”

“…45 As an alternative approach, studies performed by Nguyen et al 24 demonstrated that the body's existing platelets can be differentially stimulated using the protease activated receptor agonists PAR-1-agonist and PAR-4-agonist to selectively secrete VEGF, to promote angiogenesis, or endostatin, an anti-angiogenic factor. While the conclusions they drew from this study need to be tested under more applicable physiological conditions, such as in the presence of microbial agents, this method may present a useful Figure 2 Synthesis and analysis of platelet-like nanoparticles developed by Anselmo et al 36 (a) schematic and (b) scanning electron microscope images of layer-bylayer synthesis of nanoparticles using alternating layers of bovine serum albumin and poly(allylamine hydrochloride) (PAH) and a degraded core to achieve deformable particles with platelet-like discoid morphology. …”

“…Clearance of nanoparticle-based technologies is low because they are generally not recognized or marked by the immune system, and clearance can be further modified through nanoparticle size or material parameters. 36,50 Synthetic materials have further advantages over natural platelets due to their longer shelf life, scale-up potential, and ease of manufacturing and reproducibility. 3 The material properties of artificial platelet-mimetic devices can also be tuned to reflect the mechanical properties of natural platelets in both their resting and active conformations, giving researchers a greater level of control over obtaining specific desirable characteristics, such as clearance time, for various particular clinical applications.…”

Novel Nanoparticulate Drug Delivery Systems

“…The design of novel nanoparticles capable of delivering drugs to the diseased sites and organs is expected to improve the therapy of various disorders, for which the systemic therapies lack sufficient efficacy. Surface functionalization of such nanoparticles is proposed to extend their circulation time and to reduce the adverse reactions from the circulating immune cells [5]. In a recent study by Hu et al, biomimetic nanoparticles were developed by coating polymeric nanoparticles with the membranes of human platelets.…”