11 research outputs found
Nanofabricated particles for engineered drug therapies: A preliminary biodistribution study of PRINT⢠nanoparticles
A novel method for the fabrication of polymeric particles on the order of tens of nanometers to several microns is described. This imprint lithographic technique called PRINT⢠(Particle Replication In Non-wetting Templates), takes advantage of the unique properties of elastomeric molds comprised of a low surface energy perfluoropolyether network, allowing the production of monodisperse, shape-specific nanoparticles from an extensive array of organic precursors. This engineered nature of particle production has a number of advantages over the construction of traditional nanoparticles such as liposomes, dendrimers, and colloidal precipitates. The gentle âtop downâ approach of PRINT enables the simultaneous and independent control over particle size and shape, composition, and surface functionality, and permits the loading of delicate cargos such as small organic therapeutics and biological macromolecules. Thus, this single tool serves as a comprehensive platform for the rational design and investigation of new nanocarriers in medicine, having applications ranging from therapeutics to advanced diagnostics. Preliminary in vitro and in vivo studies were conducted, demonstrating the future utility of PRINT particles as delivery vectors in nanomedicine. Monodisperse 200 nm poly(ethylene glycol)-based (PEG) particles were fabricated using PRINT methodology and characterized via scanning electron microscopy and dynamic light scattering. Incubation with HeLa cells showed very little cytotoxicity, even at high concentrations. The biodistribution and pharmacokinetics of [125I]-labeled particles were studied in healthy mice following bolus tail vein administration. The particles were distributed mainly to the liver and the spleen with an apparent distribution t1/2 of approximately 17 min followed by slow redistribution with a t1/2 of 3.3 h. The volume of distribution for the central and peripheral compartments was found to be approximately 3 mL and 5 mL, respectively
Reductively Responsive siRNA-Conjugated Hydrogel Nanoparticles for Gene Silencing
A critical need still remains for effective delivery of RNA interference (RNAi) therapeutics to target tissues and cells. Self-assembled lipid- and polymer-based systems have been most extensively explored for transfection with small interfering RNA (siRNA) in liver and cancer therapies. Safety and compatibility of materials implemented in delivery systems must be ensured to maximize therapeutic indices. Hydrogel nanoparticles of defined dimensions and compositions, prepared via a particle molding process that is a unique off-shoot of soft lithography known as PRINT (Particle Replication in Non-wetting Templates), were explored in these studies as delivery vectors. Initially, siRNA was encapsulated in particles through electrostatic association and physical entrapment. Dose-dependent gene silencing was elicited by PEGylated hydrogels at low siRNA doses without cytotoxicity. To prevent disassociation of cargo from particles after systemic administration or during post-fabrication processing for surface functionalization, a polymerizable siRNA pro-drug conjugate with a degradable, disulfide linkage was prepared. Triggered release of siRNA from the prodrug hydrogels was observed under a reducing environment while cargo retention and integrity were maintained under physiological conditions. Gene silencing efficiency and cytocompatibility were optimized by screening the amine content of the particles. When appropriate control siRNA cargos were loaded into hydrogels, gene knockdown was only encountered for hydrogels containing releasable, target-specific siRNAs, accompanied by minimal cell death. Further investigation into shape, size, and surface decoration of siRNA-conjugated hydrogels should enable efficacious targeted in vivo RNAi therapies
The Pursuit of a Scalable Nanofabrication Platform for Use in Material and Life Science Applications
In this Account, we describe the use of perfluoropolyether (PFPE)-based materials that are able to accurately mold and replicate micro- and nanosized features using traditional techniques such as embossing as well as new techniques that we developed to exploit the exceptional surface characteristics of fluorinated substrates. Because of the unique partial wetting and nonwetting characteristics of PFPEs, we were able to go beyond the usual molding and imprint lithography approaches and have created a technique called PRINT (Particle [or Pattern] Replication In Nonwetting Templates)
Highly Diastereoselective Synthesis of Tetrahydrofurans via Lewis Acid-Catalyzed Cyclopropane/Aldehyde Cycloadditions
Lewis Acid-Promoted CarbonâCarbon Bond Cleavage of Aziridines: Divergent Cycloaddition Pathways of the Derived Ylides  [ J. Am. Chem. Soc.
Reductively Responsive siRNA-Conjugated Hydrogel Nanoparticles for Gene Silencing
A critical need still remains for effective delivery
of RNA interference
(RNAi) therapeutics to target tissues and cells. Self-assembled lipid-
and polymer-based systems have been most extensively explored for
transfection with small interfering RNA (siRNA) in liver and cancer
therapies. Safety and compatibility of materials implemented in delivery
systems must be ensured to maximize therapeutic indices. Hydrogel
nanoparticles of defined dimensions and compositions, prepared via
a particle molding process that is a unique off-shoot of soft lithography
known as particle replication in nonwetting templates (PRINT), were
explored in these studies as delivery vectors. Initially, siRNA was
encapsulated in particles through electrostatic association and physical
entrapment. Dose-dependent gene silencing was elicited by PEGylated
hydrogels at low siRNA doses without cytotoxicity. To prevent disassociation
of cargo from particles after systemic administration or during postfabrication
processing for surface functionalization, a polymerizable siRNA pro-drug
conjugate with a degradable, disulfide linkage was prepared. Triggered
release of siRNA from the pro-drug hydrogels was observed under a
reducing environment while cargo retention and integrity were maintained
under physiological conditions. Gene silencing efficiency and cytocompatibility
were optimized by screening the amine content of the particles. When
appropriate control siRNA cargos were loaded into hydrogels, gene
knockdown was only encountered for hydrogels containing releasable,
target-specific siRNAs, accompanied by minimal cell death. Further
investigation into shape, size, and surface decoration of siRNA-conjugated
hydrogels should enable efficacious targeted in vivo RNAi therapies
Delivery of Multiple siRNAs Using Lipid-Coated PLGA Nanoparticles for Treatment of Prostate Cancer
Nanotechnology can provide a critical advantage in developing
strategies
for cancer management and treatment by helping to improve the safety
and efficacy of novel therapeutic delivery vehicles. This paper reports
the fabrication of polyÂ(lactic acid-<i>co</i>-glycolic acid)/siRNA
nanoparticles coated with lipids for use as prostate cancer therapeutics
made via a unique soft lithography particle molding process called
Particle Replication In Nonwetting Templates (PRINT). The PRINT process
enables high encapsulation efficiency of siRNA into neutral and monodisperse
PLGA particles (32â46% encapsulation efficiency). Lipid-coated
PLGA/siRNA PRINT particles were used to deliver therapeutic siRNA
in vitro to knockdown genes relevant to prostate cancer