Targeted nanoparticles are being pursued for a range of medical applications. Here, we utilized targeted nanoparticles (synthetic platelets) to halt bleeding in acute trauma. One of the major questions that arises in the field is the role of surface ligand density on targeted nanoparticles’ performance. We developed intravenous hemostatic nanoparticles (GRGDS-NP1), and previously demonstrated their ability to reduce bleeding following femoral artery injury and increase survival after lethal liver trauma in the rat. These nanoparticles are made from block copolymers, poly(lactic-co-glycolic acid)-b- poly-ι-lysine-b-poly(ethylene glycol). Surface-conjugated targeting ligand density can be tightly controlled with this system, and here we investigated the effect of varying density on hemostasis and biodistribution. We increased the targeting peptide (GRGDS) concentration 100-fold (GRGDS-NP100) and undertook an in vitro dose-response study using rotational thromboelastometry (ROTEM), finding GRGDS-NP100 hemostatic nanoparticles were efficacious at doses at least 10-fold lower than the GRGDS-NP1. These results were recapitulated in vivo, demonstrating efficacy at 8-fold lower concentration after lethal liver trauma. 1-hour survival increased to 92%, compared to a scrambled peptide control, 45% (OR=14.4, 95% CI=[1.36, 143]), a saline control, 47% (OR=13.5, 95% CI=[1.42, 125]), and GRGDS-NP1, 80% (OR=1.30, n.s.). This work demonstrates the impact of changing synthetic platelet ligand density on hemostasis, and lays the foundation for methods to determine optimal ligand concentration parameters.
The
CD44 receptor is common among
many cancer types where overexpression is synonymous with poor prognosis
in prostate, glioma, and breast cancer. More notably CD44 overexpression
has been shown in a number of different cancer stem cells (CSC) which
are present in many solid tumors and drive growth, recurrence, and
resistance to conventional therapies. Triple negative breast cancer
CSCs correlate to worse prognosis and early relapse due to higher
drug resistance and increased tumor heterogeneity and thus are prime
targets for anticancer therapy. To specifically target cells overexpressing
CD44 receptors, including CSCs, we synthesized a pentameric nanocomplex
(PNC) containing gold nanoparticles, doxorubicin (Dox) conjugated
to thiolated hyaluronic acid via an acid-labile hydrazone bond, and
thiolated poly(ethylene glycol) DNA CD44 aptamer. In vitro drug release
was highest at 8 h time point at acidic pH (pH 4.7) and in 10 mM glutathione.
The PNC is almost an order of magnitude more effective than Dox alone
in CD44+ cells versus CD44 low cells. Functionally, the PNC reduced
CSC self-renewal. The PNC provides a therapeutic strategy that can
improve the efficiency of Dox and decrease nontargeted toxicity thereby
prolonging its use to individual patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.