Localization of Multi-Lamellar Vesicle Nanoparticles to Injured Brain Tissue in a Controlled Cortical Impact Injury Model of Traumatic Brain Injury in Rodents.

Severe traumatic brain injury (TBI), such as that suffered by patients with cerebral contusion, is a major cause of death and disability in young persons. Effective therapeutics to treat or mitigate the effects of severe TBI are lacking, in part because drug delivery to the injured brain remains a challenge. Promising therapeutics targeting secondary injury mechanisms may have poor pharmacokinetics/pharmacodynamics, unwanted side effects, or high hydrophobicity. To address these challenges, we have developed a multi-lamellar vesicle nanoparticle (MLV-NP) formulation with a narrow size distribution (243 nm in diameter, 0.09 polydispersity index) and the capability of encapsulating hydrophobic small molecule drugs for delivery to the injured brain. To demonstrate the utility of these particles, we produced dual-fluorescent labeled nanoparticles containing the organic dyes, coumarin 153 and rhodamine B, that were delivered intravenously to Sprague-Dawley rats and C57Bl6/J mice at 1, 1 and 4, 24, or 48 h after controlled cortical impact injury. Distribution of particles was measured at 5, 25, 48, or 49 h post-injury by fluorescence microscopy of coronal brain sections. In all cases of MLV administration, a 1.2- to 1.9-fold enhancement of ipsilateral fluorescence signal was observed compared to the contralateral cortex. Enhanced fluorescence was also observed in the injured hippocampal tissue in these animals. MLV-NPs administered at 1 h were observed intracellularly in the injured hemisphere at 48 h, suggesting the possibility of concentrated drug delivery to injured cells. These results suggest that MLV-NP delivery of therapeutic agents may be a viable strategy for treating cerebral contusion TBI.

Nucleic acid biohybrid nanocarriers with high-therapeutic payload and controllable extended release of daunomycin for cancer therapy.

We have developed a novel, nanosized drug carrier with high-therapeutic payload, controllable release, and the potential for active tumor targeting. It consists of a 15 nm gold nanoparticle with dense surface loading of DNA duplexes. We utilize the natural intercalating behavior of daunomycin to load the drug between DNA base pairs. We obtained a high-therapeutic payload of >1,000 drug molecules per gold nanoparticle (AuNP), one of the highest loadings reported in literature to date. We have engineered unique DNA sequences to control release of daunomycin for over 48 hr and show higher cell death compared to equivalent concentrations of free daunomycin. We have also explored cell internalization mechanisms to identify the pathways by which our gold nanoparticles enter the cell. This nanocarrier is in the ideal size range of 16-100 nm in diameter to utilize the enhanced permeability and retention effect for passive targeting to tumors. Our AuNP platform is effective as a therapeutic drug delivery device and can easily incorporate any aptamer of choice through complementary base pairing. Our work has produced an innovative nanoscale drug-delivery platform potentially leading to personalized cancer therapies through careful selection of aptamers and an adjustable drug release profile.