Nicole Levi-Polyachenko

Long-term survival following a single treatment of kidney tumors with multiwalled carbon nanotubes and near-infrared radiation

Multiwalled carbon nanotubes (MWCNTs) exhibit physical properties that render them ideal candidates for application as noninvasive mediators of photothermal cancer ablation. Here, we demonstrate that use of MWCNTs to generate heat in response to near-infrared radiation (NIR) results in thermal destruction of kidney cancer in vitro and in vivo. We document the thermal effects of the therapy through magnetic resonance temperature-mapping and heat shock protein-reactive immunohistochemistry. Our results demonstrate that use of MWCNTs enables ablation of tumors with low laser powers (3 W/cm2) and very short treatment times (a single 30-sec treatment) with minimal local toxicity and no evident systemic toxicity. These treatment parameters resulted in complete ablation of tumors and a >3.5-month durable remission in 80% of mice treated with 100 μg of MWCNT. Use of MWCNTs with NIR may be effective in anticancer therapy.

Rapid photothermal intracellular drug delivery using multiwalled carbon nanotubes.

Carbon nanotubes are unique materials that absorb infrared (IR) radiation, especially between 700 and 1100 nm, where body tissues are most transparent. Absorbed IR promotes molecular oscillation leading to efficient heating of the surrounding environment. A method to enhance drug localization for peritoneal malignancies is perfusion of warm (40-42 degrees C) chemotherapeutic agents in the abdomen. However, all tissues in the peritoneal cavity are subjected to enhanced drug delivery due to increased cell membrane permeability at hyperthermic temperatures. Here we show that rapid heating (within ten seconds) of colorectal cancer cells to 42 degrees C, using infrared stimulation of nanotubes as a heat source, in the presence of the drugs oxaliplatin or mitomycin C, is as effective as two hours of radiative heating at 42 degrees C for the treatment of peritoneal dissemination of colorectal cancer. We demonstrate increased cell membrane permeability due to hyperthermia from multiwalled carbon nanotubes in close proximity to cell membranes and that the amount of drug internalized by colorectal cancer cells heated quickly using carbon nanotubes equals levels achieved during routine application of hyperthermia at 42 degrees C. This approach has the potential to be used as a rapid bench to bedside clinical therapeutic agent with significant impact for localizing chemotherapy agents during the surgical management of peritoneal dissemination of colorectal cancer.

Chitosan wound dressing with hexagonal silver nanoparticles for hyperthermia and enhanced delivery of small molecules

Chitosan films were synthesized with hexagonal silver nanoparticles (Ag NP). The unique shape and size of the Ag NP shift the optical absorption into the infrared. Stimulation of the nanoparticles with infrared light was used to generate heat and facilitate intracellular delivery of fluorescently-labeled dextran molecules. Chitosan films prepared with hexagonal or spherical Ag NP were characterized by optical and thermal analyses, and X-ray diffraction. There were found to be slight differences between how the chitosan molecular chains interface with the Ag NP depending upon shape of the nanoparticle. Viability of cells associated with dermal wound healing was evaluated on chitosan films prepared with hexagonal or spherical Ag NP, with both keratinocytes and fibroblasts having normal or moderately enhanced growth on films containing hexagonally-shaped nanoparticles.

Differential response of MCF7, MDA-MB-231, and MCF 10A cells to hyperthermia, silver nanoparticles and silver nanoparticle-induced photothermal therapy

Abstract Purpose: Silver nanoparticles (Ag NP) can generate heat upon exposure to infrared light. The in vitro response of breast cell lines to Ag NP, both with and without nanoparticle-induced heating was evaluated. Materials and methods: Ag NP heat generation, intracellular silver concentration, and cell viability of MDA-MB-231, MCF7, and MCF 10A breast cells with Ag NP alone, or after exposure to 0.79 or 2.94 W/cm2 of 800 nm light were evaluated. Results: The concentration of Ag NP to induce sufficient heat for cell death, upon exposure to 800 nm light, was 5–250 μg/mL. Clonogenics assay indicates a cytotoxic response of MCF7 (45% decrease) and MDA-MB-231 (80% decrease) cells to 10 µg/mL, whereas MCF 10A had a 25% increase. Without Ag NP, MDA-MB-231 cells were more susceptible to hyperthermia, compared to MCF7 and MCF 10A cells. Clonogenics assay of Ag NP-induced photothermal ablation demonstrated that MCF 10A cells have the highest survival fraction. MCF7 cells had more silver in the cytoplasm, MDA-MB-231 cells had more in the nuclei, and MCF 10A cells had equivalent concentrations in the cytoplasm and nuclei. Conclusions: Ag NP are effective photothermal agents. A secondary benefit is the differential response of breast cancer cells to Ag NP-induced hyperthermia, due to increased intracellular silver content, compared to non-tumorigenic breast epithelial cells.

Clinical Relevance of Nanoparticle Induced Hyperthermia for Drug Delivery and Treatment of Abdominal Cancers

The aim of this review is to introduce the reader to the potential clinical utility for the delivery of chemotherapy in the context of nanoparticles. We will present traditional methods of hyperthermia and then focus on the clinical technique for using intraperitoneal hyperthermic chemoperfusion for the treatment of peritoneal surface dissemination of colorectal cancer. Cellular mechanisms of hyperthermia as well as clinically effective chemotherapeutic agents are discussed. In the past decade carbon and metal nanoparticles have been explored for their ability to induce hyperthermia; however, many of these studies examine nanoparticles for tumor ablation at high temperatures. There are currently few studies that evaluate mild hyperthermia (below 43°C) generated by nanoparticles to enhance the delivery of chemotherapeutic agents. The fundamentals for generation of hyperthermia from carbon and metal nanoparticles is discussed as are the limitations and benefits of specific nanoparticles with chemotherapeutic agents. This review will show that there is significant potential for the use of nanoparticles to induce hyperthermia and increase the delivery of chemotherapeutic agents for treatment of colorectal cancer and other peritoneal disease.

Swelling and pressure-volume relationships in the dermis measured by osmotic-stress technique

Water transfer across the extracellular matrix (ECM) involves interstitial osmotic forces in as yet unclear ways. In particular, the traditional values of Starling forces cannot adequately explain fluid transfer rates. Here, we reassess these forces by analyzing fluid transfer in live pig and human dermal explants. Pressure potentials were controlled with inert polymers adjusted by membrane osmometry (range = 3-219 mmHg), and fluid transfer in and out of the explants was followed by sequential precision weighing. Water motional freedom in the dermis was examined by NMR. In pigs, mean hydration pressure (HP; the pressure at which volume did not change) was 107 +/- 22 and 47 +/- 12 (SE) mmHg at 4 degrees C and 37 degrees C (P = 0.012, paired t-test, n = 7). Volume changes observed in response to pressure potential were reversible. The equation, Volume change = V(max)/[1+(time/T(1/2))(d)], where V(max) is maximal volume change; T(1/2), time at volume = 1/2 V(max); and d, a rate parameter, was fitted to experimental progression curves (r(2) > 0.9), yielding V(max) values linearly related to pressure, with mean slopes -3.5 +/- 0.28 and -2.6 +/- 0.21(SE) mul.g(-1).mmHg(-1) at 4 degrees C and 37 degrees C. NMR spin-spin relaxation times (T(2)) varied within 200- to 400-mum distances in directions perpendicular to the epidermis, with slopes reaching 0.03 ms/mum. Results support a mechanism in which fluid transport across the ECM is locally regulated at micrometer scales by cell- and fiber-gel-dependent osmomechanical forces. The large HP helps to explain the fast interstitial in/out flow rates observed clinically.

Encapsulated Staphylococcus aureus strains vary in adhesiveness assessed by atomic force microscopy.

Staphylococcus aureus capsular polysaccharides are believed to play a role in adhesion to surfaces and may contribute to their antimicrobial resistance, thereby increasing the rates and severity of associated infections. The purpose of this study was to compare the adhesiveness of distinct S. aureus capsular polysaccharides to determine whether adhesiveness was a general or specific feature across different S. aureus strains. Atomic force microscopy was used to confirm the presence or absence of capsular polysaccharides and to measure adhesive forces on a noncapsulated, serotype 8, and serotype 2 strain of S. aureus. Serotype 8 displayed a larger range of adhesive forces (1-19 nN) than the noncapsulated (0-4 nN) and serotype 2 (0-4 nN) strain. The majority of adhesive forces for serotype 8 were in the 10-15 nN range. Removal of capsular polysaccharides gave a marked decrease in adhesive forces measured for serotype 8 and, to a lesser extent, a decrease for serotype 2. Noncapsulated, serotype 8, and serotype 2 S. aureus had water contact angles of 23.8 (+/-8.9), 34.4 (+/-2.5), and 56.7 (+/-11.2) degrees (mean +/- standard deviation), respectively. For the first time, capsular polysaccharides from serotype 8 (clinically common) and serotype 2 (clinically rare) were demonstrated to have different physical properties, which may account for variations in studies in which clinical isolates are utilized, and the conflict in proposed roles for capsular polysaccharides on S. aureus is explained.

Applications of Carbon-Based Nanomaterials for Drug Delivery in Oncology

The goal of this chapter is to introduce carbon nanomaterials and highlight research focused on their use as cancer therapeutics. The physical properties of fullerenes and carbon nanotubes, including their spectral characteristics are described. Current oncology treatment regimes are described to provide an overview of where carbon nanomaterials may have significant value in further development of the established standards of care procedures. Photodynamic therapy and drug delivery using fullerene C60 is explored. Thermal ablation techniques using carbon nanotubes are explained and alternate hyperthermic methods using carbon nanotubes are described. Specifically, carbon nanotubes are examined for their potential contribution to the currently practiced clinical therapy intraperitoneal hyperthermic chemoperfusion. Nanotubes and nanohorns filled with chemotherapeutic agents are examined as are different methods for filling and containment of drug moieties. The attachment of active molecules to fullerenes is described with examples for use in oncology. Toxicity issues are explored and the future directions and potential for carbon nanomaterial types concludes the chapter.

Eradicating group A streptococcus bacteria and biofilms using functionalised multi-wall carbon nanotubes

Abstract Purpose: The aim of this study was to demonstrate that multi-wall carbon nanotubes can be functionalised with antibodies to group A streptoccocus (GAS) for targeted photothermal ablation of planktonic and biofilm residing bacteria. Materials and methods: Antibodies for GAS were covalently attached to carboxylated multi-wall carbon nanotubes and incubated with either planktonic or biofilm GAS. Bacterium was then exposed to 1.3 W/cm2 of 800 nm light for 10–120 s, and then serially diluted onto agar plates from which the number of colony forming units was determined. Photothermal ablation of GAS on the surface of full thickness ex vivo porcine skin and histological sectioning were done to examine damage in adjacent tissue. Results: Approximately 14% of the GAS antibody-functionalised nanotubes attached to the bacterium, and this amount was found to be capable of inducing photothermal ablation of GAS upon exposure to 1.3 W/cm2 of 800 nm light. Cell viability was not decreased upon exposure to nanotubes or infrared light alone. Compared to carboxylated multi-wall carbon nanotubes, antibody-labelled nanotubes enhanced killing in both planktonic and biofilm GAS in conjunction with infrared light. Analysis of GAS photothermally ablated in direct contact with ex vivo porcine skin shows that heat sufficient for killing GAS remains localised and does not cause collateral damage in tissue adjacent to the treated area. Conclusions: The results of this study support the premise that carbon nanotubes may be effectively utilised as highly localised photothermal agents with the potential for translation into the clinical treatment of bacterial infections of soft tissue.

Development and characterization of elastic nanocomposites for craniofacial contraction osteogenesis.

Development of resorbable elastic composites as an alternative means to apply contractive forces for manipulating craniofacial bones is described herein. Composites made from the biodegradable elastomer, poly (1,8-octanediol co-citric acid) (POC), and hydroxyapatite (nHA) with a 200 nm diameter (0-20% loadings) were created to develop a material capable of applying continuous contractive forces. The composites were evaluated for variation in their mechanical properties, rate of degradation, and interaction of the hydroxyapatite nanoparticles with the polymer chains. First, an ex vivo porcine model of cleft palate was used to determine the rate of cleft closure with applied force. The closure rate was found to be 0.505 mm N(-1) . From this approximation, the ideal maximum load was calculated to be 19.82 N, and the elastic modulus calculated to be 1.98 MPa. The addition of nHA strengthens POC, but also reduces the degradation time by 45%, for 3% nHA loading, compared to POC without nHA. X-ray diffraction data indicates that the addition of nHA to amorphous POC results in the formation of a semicrystalline phase of the POC adjacent to the nHA crystals. Based on the data, we conclude that amongst the 0-20% nHA loadings, a 3% loading of nHA in POC may be an ideal material (1.21 MPa elastic modulus and 13.17 N maximum load) to induce contraction forces capable of facilitating osteogenesis and craniofacial bone repair.