Multimodal Magnetic Resonance and Near-Infrared-Fluorescent Imaging of Intraperitoneal Ovarian Cancer Using a Dual-Mode-Dual-Gadolinium Liposomal Contrast Agent.

The degree of tumor removal at surgery is a major factor in predicting outcome for ovarian cancer. A single multimodality agent that can be used with magnetic resonance (MR) for staging and pre-surgical planning, and with optical imaging to aid surgical removal of tumors, would present a new paradigm for ovarian cancer. We assessed whether a dual-mode, dual-Gadolinium (DM-Dual-Gd-ICG) contrast agent can be used to visualize ovarian tumors in the peritoneal cavity by multimodal MR and near infra-red imaging (NIR). Intraperitoneal ovarian tumors (Hey-A8 or OVCAR3) in mice enhanced on MR two days after intravenous DM-Dual Gd-ICG injection compared to controls (SNR, CNR, p < 0.05, n = 6). As seen on open abdomen and excised tumors views and confirmed by optical radiant efficiency measurement, Hey-A8 or OVCAR3 tumors from animals injected with DM-Dual Gd-ICG had increased fluorescence (p < 0.05, n = 6). This suggests clinical potential to localize ovarian tumors by MR for staging and surgical planning, and, by NIR at surgery for resection

The effect of shape on the margination dynamics of non-neutrally buoyant particles in two-dimensional shear flows

The margination dynamics of microparticles with different shapes has been analyzed within a laminar flow mimicking the hydrodynamic conditions in the microcirculation. Silica spherical particles, quasi-hemispherical and discoidal silicon particles have been perfused in a parallel plate flow chamber. The effect of the shape and density on their margination propensity has been investigated at different physiologically relevant shear rates S. Simple scaling laws have been derived showing that the number n of marginating particles scales as S(-0.63) for the spheres; S(-0.85) for discoidal and S(-1) for quasi-hemispherical particles, regardless of their density and size. Within the range considered for the shear rate, discoidal particles marginate in a larger number compared to quasi-hemispherical and spherical particles. These results may be of interest in drug delivery and bio-imaging applications, where particles are expected to drift towards and interact with the walls of the blood vessels

Non Inflammatory Boronate Based Glucose-Responsive Insulin Delivery Systems

Boronic acids, known to bind diols, were screened to identify non-inflammatory cross-linkers for the preparation of glucose sensitive and insulin releasing agglomerates of liposomes (Agglomerated Vesicle Technology-AVT). This was done in order to select a suitable replacement for the previously used cross-linker, ConcanavalinA (ConA), a lectin known to have both toxic and inflammatory effects in vivo. Lead-compounds were selected from screens that involved testing for inflammatory potential, cytotoxicity and glucose-binding. These were then conjugated to insulin-encapsulating nanoparticles and agglomerated via sugar-boronate ester linkages to form AVTs. In vitro, the particles demonstrated triggered release of insulin upon exposure to physiologically relevant concentrations of glucose (10 mmoles/L–40 mmoles/L). The agglomerates were also shown to be responsive to multiple spikes in glucose levels over several hours, releasing insulin at a rate defined by the concentration of the glucose trigger

Sustained small interfering RNA delivery by mesoporous silicon particles

RNA interference (RNAi) is a powerful approach for silencing genes associated with a variety of pathologic conditions; however, in vivo RNAi delivery has remained a major challenge due to lack of safe, efficient, and sustained systemic delivery. Here, we report on a novel approach to overcome these limitations using a multistage vector composed of mesoporous silicon particles (stage 1 microparticles, S1MP) loaded with neutral nanoliposomes (dioleoyl phosphatidylcholine, DOPC) containing small interfering RNA (siRNA) targeted against the EphA2 oncoprotein, which is overexpressed in most cancers, including ovarian. Our delivery methods resulted in sustained EphA2 gene silencing for at least 3 weeks in two independent orthotopic mouse models of ovarian cancer following a single i.v. administration of S1MP loaded with EphA2-siRNA-DOPC. Furthermore, a single administration of S1MP loaded with-EphA2-siRNA-DOPC substantially reduced tumor burden, angiogenesis, and cell proliferation compared with a noncoding control siRNA alone (SKOV3ip1, 54%; HeyA8, 57%), with no significant changes in serum chemistries or in proinflammatory cytokines. In summary, we have provided the first in vivo therapeutic validation of a novel, multistage siRNA delivery system for sustained gene silencing with broad applicability to pathologies beyond ovarian neoplasms

Redox-Sensitive Disassembly of Amphiphilic Copolymer Based Micelles

Amphiphilic polymers of different hydrophilic lipophilic ratios were prepared by free radical polymerization using two monomers consisting of triethylene glycol as the hydrophilic part and an alkyl chain connected by disulfide bond as the hydrophobic part. These polymers form micelle-like nanoassemblies in aqueous media and can encapsulate hydrophobic drug molecules up to 14% of their mass. In a reducing environment, these polymeric micelles disassemble and dissolve in water, since the amphiphilic polymers are converted into hydrophilic polymers upon cleavage of the disulfide bond. This disassembly event results in the release of hydrophobic molecules that had been encapsulated inside the micelle, the rate of which was found to be dependent on the concentration of the reducing agent, glutathione (GSH). In vitro experiments also show that the GSH-dependent release of the doxorubicin can be used to effect cytotoxicity in MCF-7 cells