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Publications (27)
New lipid-like nanomaterials are developed to simultaneously regulate expression of multiple genes. Self-assembled nanoparticles are capable of efficiently encapsulating pDNA and siRNA. These nanoparticles are shown to induce simultaneous gene expression and silencing both in vitro and in vivo.
Significance
The safe, selective, and efficient delivery of siRNA is a key challenge to the broad application of siRNA therapeutics in humans. Motivated by the structure of lipoproteins, we developed lipopeptide nanomaterials for siRNA delivery. In vivo in mice, siRNA–lipopeptide particles provide the most potent delivery to hepatocytes (ED 50 ∼ 0....
Nanoparticle-mediated siRNA delivery is a complex process that requires transport across numerous extracellular and intracellular barriers. As such, the development of nanoparticles for efficient delivery would benefit from an understanding of how parameters associated with these barriers relate to the physicochemical properties of nanoparticles. H...
Despite efforts to understand the interactions between nanoparticles and cells, the cellular processes that determine the efficiency of intracellular drug delivery remain unclear. Here we examine cellular uptake of short interfering RNA (siRNA) delivered in lipid nanoparticles (LNPs) using cellular trafficking probes in combination with automated h...
Degradable, cationic poly(β-amino ester)s (PBAEs) with alkyl side chains are developed for non-viral gene delivery. Nanoparticles formed from these PBAE terpolymers exhibit significantly enhanced DNA transfection potency and resistance to aggregation. These hydrophobic PBAE terpolymers, but not PBAEs lacking alkyl side chains, support interaction w...
Synthetic small interfering RNAs (siRNAs) have emerged as powerful tools for the regulation and silencing of endogenous genes. To achieve efficient gene silencing, siRNAs must be encapsulated or conjugated to delivery vehicles that can ensure cytosolic delivery of intact siRNAs across the cellular membrane. So far, liposomal delivery vehicles have...
As a Postdoctoral fellow, my current research involves the design of non-invasive probes for tracking the assembly and stability of siRNA nanoparticles in both extracellular and intracellular environments. So far, I have designed two different siRNA-based fluorescent probes whose fluorescence emission changes in response to the assembly state of th...
Small interfering RNA (siRNA) therapeutics have broad potential uses in medicine but require safe and effective delivery vehicles to function. An ideal delivery system should encapsulate and protect the siRNA cargo from serum proteins, exhibit target tissue and cell specificity, penetrate the cell surface, and release its cargo in the desired intra...
One important barrier facing the delivery of short interfering RNAs (siRNAs) via synthetic nanoparticles is the rate of nanoparticle disassembly. However, our ability to optimize the release kinetics of siRNAs from nanoparticles for maximum efficacy is limited by the lack of methods to track their intracellular disassembly. Towards this end, we des...
Ever since the ground breaking discovery of RNA interference (RNAi), an endogenous mechanism for sequence specific regulation of gene expression via short interfering RNAs (siRNA), researchers and pharmaceutical companies alike have devoted immense time and capital into the design of nanocarriers that can mediate safe and effective delivery. After...
The assembly, stability, and timely disassembly of short interfering RNA (siRNA) nanocomplexes have the potential to affect the efficiency of siRNA delivery and gene silencing. As such, the design of new probes that can measure these properties without significantly perturbing the nanocomplexes or their environment may facilitate the study and furt...
Amine end-modified poly(β-amino ester)s (PBAEs) have generated interest as efficient, biodegradable polymeric carriers for plasmid DNA (pDNA). For cationic, non-degradable polymers, such as polyethylenimine (PEI), the polymer molecular weight (MW) and molecular weight distribution (MWD) significantly affect transfection activity and cytotoxicity. T...
Despite the promise of RNA interference (RNAi) therapeutics, progress toward the clinic has been slowed by the difficulty of delivering short interfering RNA (siRNA) into cellular targets within the body. Nearly all siRNA delivery vehicles developed to date employ a single cationic or ionizable material. In order to increase the material space avai...
Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans, and the potential use of RNAi for human therapy has been demonstrated by the finding that small interfering R...
PEGylated gold nanoparticles are decorated with various amounts of human transferrin (Tf) to give a series of Tf-targeted particles with near-constant size and electrokinetic potential. The effects of Tf content on nanoparticle tumor targeting were investigated in mice bearing s.c. Neuro2A tumors. Quantitative biodistributions of the nanoparticles...
A nitrogen-containing heterocycle (NCH), 4,4-1H-1H-bi-1,2,3-triazole (bitriazole), capable of mimicking the hydrogen bonding of water in the solid state is synthesized and its ability to conduct protons in the presence of poly(ethylene oxides) under anhydrous conditions is investigated. Bitriazole is shown to have sufficient thermal and electrochem...
IT-101, a cyclodextrin polymer-based nanoparticle containing camptothecin, is in clinical development for the treatment of
cancer. Multiorgan pharmacokinetics and accumulation in tumor tissue of IT-101 is investigated by using PET. IT-101 is modified
through the attachment of a 1,4,7,10-tetraazacyclododecane-1,4,7-Tris-acetic acid ligand to bind 64...
The underlying theme of the research outlined in both parts of this report is centered on the ability to use synthetic design as a probe to investigate and answer fundamental mechanistic questions in an effort to improve the function of materials employed in energy and biological research. Specifically in the field of energy research, we have desig...
The enhancement of proton conductivity in solid electrolytes by the synthesis of densely packed carboxylic acid groups via the ozonolysis of cationic ammonium organoalkoxysilane surfactant templated MCM-41 was analyzed. These modified surfactants have a siloxane head group capable of being incorporated in to the pore walls during the assembly of th...
A new conjugated porphyrin−fullerene dyad featuring a styrene linkage has been prepared in 11% overall yield from previously synthesized starting materials. In contrast to the singlet and triplet excited states commonly observed in analogous systems with zinc and free base porphyrins, the present investigation involves doublet and quartet ground an...
