Elizabeth M. Enlow

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 poly(lactic acid-co-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 (32-46% encapsulation efficiency). Lipid-coated PLGA/siRNA PRINT particles were used to deliver therapeutic siRNA in vitro to knockdown genes relevant to prostate cancer.

Potent engineered PLGA nanoparticles by virtue of exceptionally high chemotherapeutic loadings.

Herein we report the fabrication of engineered poly(lactic acid-co-glycolic acid) nanoparticles via the PRINT (particle replication in nonwetting templates) process with high and efficient loadings of docetaxel, up to 40% (w/w) with encapsulation efficiencies >90%. The PRINT process enables independent control of particle properties leading to a higher degree of tailorability than traditional methods. Particles with 40% loading display better in vitro efficacy than particles with lower loadings and the clinical formulation of docetaxel, Taxotere.

Plasma, tumor and tissue pharmacokinetics of Docetaxel delivered via nanoparticles of different sizes and shapes in mice bearing SKOV-3 human ovarian carcinoma xenograft

UNLABELLED The particle fabrication technique PRINT® was used to fabricate monodisperse size and shape specific poly(lactide-co-glycolide) particles loaded with the chemotherapeutic Docetaxel. The pharmacokinetics of two cylindrical shaped particles with diameter=80nm; height=320nm (PRINT-Doc-80×320) and d=200nm; h=200nm (PRINT-Doc-200×200) were compared to Docetaxel in mice bearing human ovarian carcinoma SKOV-3 flank xenografts. The Docetaxel plasma exposure was ~20-fold higher for both particles compared to docetaxel. Additionally, the volume of distribution (Vd) of Docetaxel in PRINT formulations was ~18-fold (PRINT-Doc-80×320) and ~33-fold (PRINT-Doc-200×200) lower than Docetaxel. The prolonged duration of Docetaxel in plasma when dosed with PRINT formulations subsequently led to increased tumor exposure of Docetaxel from 0 to 168h (~53% higher for PRINT-Doc-80×320 and ~76% higher for PRINT-Doc-200×200 particles). PRINT-Doc-80×320 had lower exposures in the liver, spleen and lung compared with PRINT-Doc-200×200. Thus, the use of particles with smaller feature size may be preferred to decrease clearance by organs of the mononuclear phagocyte system. FROM THE CLINICAL EDITOR In this study, the plasma, tumor, and tissue pharmacokinetics of different Docetaxel nanoparticles of precise shape and size were characterized in mice with human ovarian carcinoma xenograft. It is concluded that the use of particles with smaller feature size may be preferred to decrease clearance by organs of the mononuclear phagocyte system.

Mucus-penetrating nanoparticles made with “mucoadhesive” poly(vinyl alcohol)

Nanoparticles that readily penetrate mucosal layers are desirable for a variety of biomedical applications. Nevertheless, most nanoparticles tend to be immobilized in mucus via steric and/or adhesive interactions. Contrary to the established opinion that poly(vinyl alcohol) (PVA) is mucoadhesive, we discovered that coating otherwise mucoadhesive nanoparticles with certain partially hydrolyzed PVAs can aid particle mobility in mucus. We describe two approaches to producing such mucus-penetrating particles (non-covalent modification of pre-formed nanoparticles and emulsification in the presence of PVA) and provide mobility data in human cervicovaginal mucus ex vivo as measured by multiple particle tracking and bulk permeation. When coated with PVAs that are ≥95% hydrolyzed, nanoparticles as small as ~210nm were immobilized in mucus similarly to well-established mucoadhesive controls (P>0.05). However, nanoparticles coated with PVAs that are <95% hydrolyzed penetrated mucus with velocities significantly exceeding those for the mucoadhesive controls (P<0.001) and were mobile in the bulk permeation assay.