Sustained release polymeric gene delivery systems offer increased resistance to nuclease degradation, increased amounts of plasmid DNA (pDNA) uptake, and the possibility of control in dosing and sustained duration of pDNA administration. Furthermore, such a system lacks the inherent problems associated with viral vectors. Biodegradable and biocompatible poly(DL-lactide-co-glycolide) polymer was used to enacapsulate pDNA (alkaline phosphatase, AP, a reporter gene) in submicron size particles. Gene expression mediated by the nanoparticles (NP) was evaluated in vitro and in vivo in comparison to cationic-liposome delivery. Nano size range (600 nm) pDNA-loaded in poly(DL-lactideco-glycolide) polymer particles with high encapsulation efficiency (70%) were formulated, exhibiting sustained

Background-Inflammation is critical to vascular repair after mechanical injury. Excessive inflammation enhances neointimal formation and restenosis. We examined whether transient systemic inactivation of macrophages at the time of vascular intervention could attenuate the degree of expected restenosis. Methods and Results-Liposomal clodronate (LC) inhibited the growth of cultured macrophages but had no effect on endothelial or smooth muscle cells and suppressed neointimal hyperplasia in hypercholesterolemic rabbits and rats after intravenous administration of LC, with no adverse effects. LC treatment reduced the number of blood monocytes and decreased macrophage infiltration in the injured arteries as well as smooth muscle cell proliferation, interleukin-1␤ transcription, and production and matrix metalloproteinase-2 activity. Conclusions-Macrophages

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There are a number of challenges associated with designing nanoparticles for medical applications. We define two challenges here: (i) conventional targeting against up-regulated cell surface antigens is limited by heterogeneity in expression, and (ii) previous studies suggest that the optimal size of nanoparticles designed for systemic delivery is approximately 50-150 nm, yet this size range confers a high surface area-to-volume ratio, which results in fast diffusive drug release. Here, we achieve spatial control by biopanning a phage library to discover materials that target abundant vascular antigens exposed in disease. Next, we achieve temporal control by designing 60-nm hybrid nanoparticles with a lipid shell interface surrounding a polymer core, which is loaded with slow-eluting conjugates of paclitaxel for controlled ester hydrolysis and drug release over approximately 12 days. The nanoparticles inhibited human aortic smooth muscle cell proliferation in vitro and showed greater in vivo vascular retention during percutaneous angioplasty over nontargeted controls. This nanoparticle technology may potentially be used toward the treatment of injured vasculature, a clinical problem of primary importance.T he field of nanotechnology has crossed significant milestones from the systemic delivery of nanomedicines (1-5). However, the ability to achieve spatiotemporal control may be essential to many medical applications.In this study, we engineer a nanoparticle (NP) system that fundamentally changes the way we control spatiotemporal delivery of therapeutic agents. We designed approximately 60-nm core-shell hybrid NPs (6, 7) consisting of a polymeric core, a lipid interface, and a poly(ethylene glycol) (PEG) corona. For temporal control, we achieved the capacity for slow drug elution over 2 weeks using poly(lactic acid) (PLA) conjugates of paclitaxel as a model therapeutic agent (8), made by a modified drug-alkoxide ring-opening strategy (9, 10). These conjugates allow for controlled drug release by gradual ester hydrolysis despite the large surface area and short diffusion distances of sub-100-nm particles. For spatial control, we functionalized our NPs with ligands (11, 12) that target across a range of diseases in a consistent and reproducible manner. Conventional molecular targeting of relevant cell-based targets can be confounded by inter-and intrapatient heterogeneity in cell surface antigen expression (13,14). More recently, investigators have explored abundant noncellular targets such as the coagulation cascade (15), intraarticular cartilage (16), and extracellular matrix (17). Many human diseases are associated with compromised vasculature and increased vascular permeability (18,19). Therefore, we exploit these vascular breaches by targeting the underlying basement membrane. Toward this goal, we screened for heptapeptide ligands by biopanning a phage library against collagen IV (20), which represents 50% of the vascular basement membrane (21), and characterized specific ligands for targeting affinity against...

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