Burapol Singhana

Light-Activatable Gold Nanoshells for Drug Delivery Applications

Gold nanoshells (AuNSs) are currently being investigated as nanocarriers for drug delivery systems and have both diagnostic and therapeutic applications, including photothermal ablation, hyperthermia, drug delivery, and diagnostic imaging, particularly in oncology. AuNSs are valuable for their localized surface plasmon resonance, biocompatibility, low immunogenicity, and facile functionalization. AuNSs used for drug delivery can be spatially and temporally triggered to release controlled quantities of drugs inside the target cells when illuminated with a near-infrared (NIR) laser. Recently, many research groups have demonstrated that these AuNS complexes are able to deliver antitumor drugs (e.g., doxorubicin, paclitaxel, small interfering RNA, and single-stranded DNA) into cancer cells, which enhances the efficacy of treatment. AuNSs can also be functionalized with active targeting ligands such as antibodies, aptamers, and peptides to increase the particles’ specific binding to the desired targets. This article reviews the current research on NIR light-activatable AuNSs used as nanocarriers for drug delivery systems and cancer theranostics.

Radiopaque Resorbable Inferior Vena Cava Filter Infused with Gold Nanoparticles

Failure to remove a retrievable inferior vena cava (IVC) filter can cause severe complications with high treatment costs. Polydioxanone (PPDO) has been shown to be a good candidate material for resorbable IVC filters. However, PPDO is radioluscent under conventional imaging modalities. Thus, the positioning and integrity of these PPDO filters cannot be monitored by computed tomography (CT) or x-ray. Here we report the development of radiopaque PPDO IVC filters based on gold nanoparticles (AuNPs). Commercially available PPDO sutures were infused with AuNPs. Scanning electron microscopy analysis confirmed the presence of AuNP on the surface of PPDO. Micro-CT and x-ray images of the AuNP-infused PPDO sutures showed significant signal enhancement compared to untreated PPDO sutures. Elemental analysis showed that gold loading exceeded 2000 ppm. Tensile strength and in vitro cytotoxicity showed no significant difference between AuNP-infused and untreated PPDO. In a 10-week stability study, neither the gold content nor the radiopacity of the infused PPDO sutures significantly changed in the first 6 weeks. The increased attenuation of AuNP-infused PPDO sutures indicates their major advantage as a radiopaque resorbable filter material, as the radiopacity allows monitoring of the position and integrity of the filter, thereby increasing its safety and efficacy.

Development of radiopaque resorbable medical device

Purpose: We aimed to compare the safety of permanent (pIVC) and potentially retrievable (rIVC) inferior vena cava filters by reviewing the U.S. Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database. We hypothesize that self-reported complication rates respectively associated with rIVC and pIVC filters are equivalent. Materials and Methods: The MAUDE database was reviewed from January 1, 2009 to December 31, 2012. Product class search criteria were “filter, intravascular, cardiovascular.”. The total number of complications per year and complication type/rates were recorded for pIVC and rIVC devices. Binomial test was used for statistical analysis with rejection of the null hypothesis at po0.05. Results: 1,606 reported adverse events (AE) involving 1,057 IVC filters were identified. 1,394 (86.8%) AEs involved rIVC and 212 (13.2%) involved pIVC (po0.0001). The number and percentage of each specific AE was higher in rIVC compared to pIVC (see table). The most commonly reported AE varied depending on filter brand: fracture (27.1%) for Bard (Bard Peripheral Vascular, Tempe, AZ) devices, IVC penetration(29.9%) for Celect (Cook Medical, Bloomington, IN), placement difficulties for Optease (Cordis Endovascular, Warren, NJ) (30.8%) and Gunther Tulip (Cook Medical, Bloomington, IN) (45%). Conclusion: MAUDE database review reveals statistically significantly higher complication rate associated with rIVC compared to pIVC filters. Among rIVC filters prevalence of each specific complication varied widely among brands. This study suggests that optional filters are inferior to permanent devices in terms of self-reported, deviceassociated complications.

In vivo imaging of radiopaque resorbable inferior vena cava filter infused with gold nanoparticles

Radiopaque resorbable inferior vena cava filter (IVCF) were developed to offer a less expensive alternative to assessing filter integrity in preventing pulmonary embolism for the recommended prophylactic period and then simply vanishes without intervention. In this study, we determined the efficacy of gold nanoparticle (AuNP)-infused poly-p-dioxanone (PPDO) as an IVCF in a swine model. Infusion into PPDO loaded 1.14±0.08 % AuNP by weight as determined by elemental analysis. The infusion did not alter PPDO’s mechanical strength nor crystallinity (Kruskal−Wallis one-way ANOVA, p<0.05). There was no cytotoxicity observed (one-way ANOVA, p<0.05) when tested against RF24 and MRC5 cells. Gold content in PPDO was maintained at ~2000 ppm during the 6-week incubation in PBS at 37oC. As a proof-of-concept, two pigs were deployed with IVCF, one with AuNP-PPDO and the other without coating. Results show that the stent ring of AuNP-PPDO was highly visible even in the presence of iodine-based contrast agent and after clot introduction, but not of the uncoated IVCF. Autopsy at two weeks post-implantation showed AuNP-PPDO filter was endothelialized onto the IVC wall, and no sign of filter migration was observed. The induced clot was also still trapped within the AuNP-PPDO IVCF. As a conclusion, we successfully fabricated AuNP-infused PPDO IVCF that is radiopaque, has robust mechanical strength, biocompatible, and can be imaged effectively in vivo. This suggests the efficacy of this novel, radiopaque, absorbable IVCF for monitoring its position and integrity over time, thus increasing the safety and efficacy of deep vein thrombosis treatment.

Antitumor efficacy of liposome-encapsulated NVP-BEZ 235 in combination with irreversible electroporation

Abstract Irreversible electroporation (IRE) is an emerging minimally invasive tumor ablation technique that delivers short pulses of strong electric fields and kills cancer cells by disrupting their cell membranes with the electric pulses. However, clinical studies report that more than 10% of local tumor recurrences occur at the original ablated site. NVP BEZ-235 (BEZ) is a dual PI3K/mTOR inhibitor that has substantial anticancer effects. However, the clinical trials of BEZ was not satisfactory because of its low bioavailability and high toxicity, which stemmed from the use of oral administration of high doses over a long period of time. In this research, we prepared a liposomal formulation of BEZ (L-BEZ) for intratumoral injection and studied its antitumor efficacy alone and in combination with IRE. We hypothesized that IRE could release BEZ from the liposomes and that the combination could decrease tumor viability. Our results show that IRE released BEZ from its liposomal encapsulation. The combination of L-BEZ and IRE killed more Hep3B tumor cells in vitro than did L-BEZ or IRE alone and also inhibited cancer cell proliferation in nude mice bearing Hep3B xenografts. Combination of chemotherapeutic agent loaded nanoparticles could enhance the antitumor efficacy of IRE.

Abstract 3905: Anti-tumor effect of combined irreversible electroporation and liposome-encapsulated NVP-BEZ235

Introduction Irreversible electroporation (IRE) is a technique that uses electrical pulses to cause disruption in the lipid bilayer integrity by creating nanopores. Regions that are close to the probe will have a permanent, irreversible damage to the cells, while farther away regions will subject the cell membranes to re-seal (reversible). This reversible region provides opportunity for enhanced nanoparticle uptake. In this study, we tested the efficacy of combined IRE and nanoparticle-mediated drug delivery in vitro and in vivo in a hepatocellular carcinoma model. Methods Liposome-encapsulated NVP-BEZ235 (L-BEZ) was made from hydration-sonication, followed by an optional extrusion step. Particle size was tested via dynamic light scattering. BEZ concentration was quantified by fluorescence. Cytotoxicity of IRE and its drug combinations was tested on Hep3B cells using ECM 830 (BTX Harvard Apparatus) at 1600 V/cm field strength. In vivo efficacy was studied on nude mice bearing Hep3B xenografts with single dose of IRE, or drug alone (L-BEZ or BEZ at 4 mg/kg, intratumoral injection), and its combinations. Results and Discussion Liposomes range from 100-500 nm in hydrodynamic volume. Highest loading efficiency achieved was 90% (1.8 mg/mL of BEZ). To test the release of BEZ from the liposome, solution of L-BEZ was treated with IRE and the supernatant was tested against Hep3B cells. The extract from L-BEZ had a significantly higher cytotoxicity (51%) as compared to the empty liposome (20%) with a p-value Conclusion The use of minimally invasive IRE in combination with nanoparticle-mediated drug delivery treatment is a promising technique to achieve local disease control in hepatocellular carcinoma. Citation Format: Tian Li, Lucas Wang, Yang Qiao, Burapol Singhana, Marites P. Melancon. Anti-tumor effect of combined irreversible electroporation and liposome-encapsulated NVP-BEZ235. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3905.

Targeted gold nanoshells

: Gold nanoshells, also known as gold nanospheres (AuNSs), have been intensively studied over the past decade owing to their inherent localized surface plasmon resonance. By changing the core size, gold shell thickness, and/or composition of the particles, the plasmomic resonance of AuNSs can be made to absorb from the visible region to the near-infrared (NIR) region of the spectrum. The NIR region is very attractive because water and naturally occurring fluorochromes have the lowest absorption coefficient in this region and therefore, light can penetrate deeper into the tissues. AuNSs can also be conjugated with imaging reporters and can carry drug payloads, genes, and other chemotherapeutic agents for theranostic applications. Although they can passively accumulate in tumors, AuNSs can be functionalized with active targeting ligands such as antibodies, aptamers, and peptides to increase the particles’ specific binding to desired targets. This chapter provides an up-to-date review of targeted, NIR light-activatable AuNSs used in cancer theranostics and drug delivery systems and focuses on AuNSs conjugated with active targeting ligands.