The use of siRNA-based therapies for the treatment of neurodegenerative disease requires efficient, nontoxic distribution to the affected brain parenchyma, notably the striatum and cortex. Here, we describe the synthesis and activity of a fully chemically modified siRNA that is directly conjugated to docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the mammalian brain. DHA conjugation enables enhanced siRNA retention throughout both the ipsilateral striatum and cortex following a single, intrastriatal injection (ranging from 6-60 mug). Within these tissues, DHA conjugation promotes internalization by both neurons and astrocytes. We demonstrate efficient and specific silencing of Huntingtin mRNA expression in both the ipsilateral striatum (up to 73%) and cortex (up to 51%) after 1 week. Moreover, following a bilateral intrastriatal injection (60 mug), we achieve up to 80% silencing of a secondary target, Cyclophilin B, at both the mRNA and protein level. Importantly, DHA-hsiRNAs do not induce neural cell death or measurable innate immune activation following administration of concentrations over 20 times above the efficacious dose. Thus, DHA conjugation is a novel strategy for improving siRNA activity in mouse brain, with potential to act as a new therapeutic platform for the treatment of neurodegenerative disorders.

Biodegradable polymers have been widely utilized as drug delivery vehicles and tissue engineering scaffolds. We previously designed amphiphilic triblock copolymer poly(lactic acid)-b-poly(ethylene glycol)-b-poly(lactic acid) (PELA) and its hydroxyapatite (HA) composites for bone tissue engineering applications. The hydrophilic electrospun PELA-HA composite exhibited aqueous stability and elastic handling characteristics, and was able to template the proliferation and osteogenesis of bone marrow stromal cells (BMSCs) in vitro and in vivo when spiral-wrapped into cylinders and press-fit into critical size femoral segmental defects in rats. However, the slow degradation of PELA has prevented timely disappearance of the scaffold and impeded more effective restoration of biomechanical integrity of the defect. To accelerate degradation, in this work we designed poly(lactic/glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic/glycolic acid) (PELGA) with varying ratios of glycolide and lactide and confirmed their more accelerated degradations as compared to PELA. Processing conditions (e.g. solvent-casting vs. electrospinning, with or without hydration) significantly impacted the structural characteristics of PELGA and their HA composites. The PEG crystallization in PELGA was not as strong as in PEG homopolymers, giving rise to a lower Tm. HA could be well dispersed in PELGA and electrospun to give a uniform composite where the crystallization of PEG was promoted by water resulting in enhanced mechanical strength upon hydration. These HA-contained electrospun meshes exhibited excellent cytocompatibility and efficacy in templating osteogenesis of rat BMSCs in vitro.

Cardiovascular diseases are the leading cause of death in the United States. Treatment often requires surgical interventions to re-open occluded vessels, bypass severe occlusions, or stabilize aneurysms. Despite the short-term success of such interventions, many ultimately fail due to thrombosis or restenosis (following stent placement), or incomplete healing (such as after aneurysm coil placement). Bioactive molecules capable of modulating host tissue responses and preventing these complications have been identified, but systemic delivery is often harmful or ineffective. This review discusses the use of localized bioactive molecule delivery methods to enhance the long-term success of vascular interventions, such as drug-eluting stents and aneurysm coils, as well as nanoparticles for targeted molecule delivery. Vascular grafts in particular have poor patency in small diameter, high flow applications, such as coronary artery bypass grafting (CABG). Grafts fabricated from a variety of approaches may benefit from bioactive molecule incorporation to improve patency. Tissue engineering is an especially promising approach for vascular graft fabrication that may be conducive to incorporation of drugs or growth factors. Overall, localized and targeted delivery of bioactive molecules has shown promise for improving the outcomes of vascular interventions, with technologies such as drug-eluting stents showing excellent clinical success. However, many targeted vascular drug delivery systems have yet to reach the clinic. There is still a need to better optimize bioactive molecule release kinetics and identify synergistic biomolecule combinations before the clinical impact of these technologies can be realized.