Microemulsion-Inspired Polysaccharide Nanoparticles for an Advanced Targeted Thrombolytic Treatment

Among cardiovascular
diseases, thrombotic diseases such as ischemic heart disease and acute
ischemic strokes are the most lethal, responsible by themselves for
a quarter of worldwide deaths. While surgical treatments exist, they
may not be used in all situations, and systemic thrombolytic drug
injection, such as recombinant tissue plasminogen activators (rtPA),
often remains necessary, despite serious limitations including short
therapeutic window, severe side effects, and failure to address the
complex nature of thrombi. This prompted intense research into alternative
thrombolytics or delivery methods, including nanomedicine. However,
most nanoparticles face issues of stability, biocompatibility, or
synthesis robustness; among them, polymeric nanoparticles, though
usually versatile and biocompatible, sometimes lack robustness and
may involve toxic or complex synthesis. Here, we present polysaccharide
hydrogel nanoparticles designed with an improved microemulsion-based
approach that allowed a critical size reduction from microparticles
to 315 nm nanoparticles. They were decorated with fucoidan, a sulfated
polysaccharide capable of high affinity binding to P-selectin, a thrombi
biomarker. These nanoparticles exhibited good stability, adequate
size, biocompatibility, and targeting capacity and could be loaded
with two different drugs, rtPA (fibrin degradation) or DNase I (degradation
of neutrophil extracellular traps, or NETs), to exert thrombolysis.
Notably, improved synergic thrombolysis was demonstrated on NET-containing
thrombi, while in vivo thrombolysis shed light into improved thrombolysis
of rtPA-loaded nanoparticles at 50 and 10% the recommended dose without
secondary embolization. These safe, robust, and easy-to-make nanoparticles
could provide effective delivery strategies for thrombolytic treatments
while demonstrating the potential of polysaccharide nanoparticles
as drug-delivery agents.