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Breast tumors have their own specific microbiota, distinct from normal mammary gland tissue. Patients with breast cancer that present with locally advanced disease often undergo neoadjuvant chemotherapy to reduce tumor size prior to surgery to allow breast conservation or limit axillary lymph node dissection. The purpose of our study was to evaluate whether neoadjuvant chemotherapy modulates the tumor microbiome and the potential impact of microbes on breast cancer signaling. Using snap-frozen aseptically collected breast tumor tissue from women who underwent neoadjuvant chemotherapy (n = 15) or women with no prior therapy at time of surgery (n = 18), we performed 16S rRNA-sequencing to identify tumoral bacterial populations. We also stained breast tumor microarrays to confirm presence of identified microbiota. Using bacteria-conditioned media, we determined the effect of bacterial metabolites on breast cancer cell proliferation and doxorubicin therapy responsiveness. We show chemotherapy administration significantly increased breast tumor Pseudomonas spp. Primary breast tumors from patients who developed distant metastases displayed increased tumoral abundance of Brevundimonas and Staphylococcus. We confirmed presence of Pseudomonas in breast tumor tissue by IHC staining. Treatment of breast cancer cells with Pseudomonas aeruginosa conditioned media differentially effected proliferation in a dose-dependent manner and modulated doxorubicin-mediated cell death. Our results indicate chemotherapy shifts the breast tumor microbiome and specific microbes correlate with tumor recurrence. Further studies with a larger patient cohort may provide greater insights into the role of microbiota in therapeutic outcome and develop novel bacterial biomarkers that could predict distant metastases.Implications:Breast tumor microbiota are modified by therapy and affects molecular signaling.

Obesity influences breast tumor microbiota populations. Breast tumor 16S sequencing results were stratified based upon patient body mass index (BMI). Tumor bacterial populations from non-obese patients with a BMI of 20-27 (n=9) were compared with bacterial populations from obese patients with a BMI of 31-48 (n=8). A. Relative abundance of bacterial genera in different tumor samples is visualized by bar plots. Each bar represents a single tumor and each colored box a bacterial taxon. The height of a color box represents the relative abundance of that organism within the sample. ''Other'' represents lower abundance taxa. B. Phylum level distribution in tumors from obese and non-obese patients. Primary breast tumors from obese patients have decreased proportional abundance of Comamonadaceae (C) and Ruminococcaceae (D) family level taxa. E. Obese patients' breast tumors display elevated abundance of Enterobacteriaceae_unclassified. *p

Eighty percent of bacterial infections associated with living tissue and medical devices are linked to drug-resistant biofilms, leading to lengthy and costly recoveries. Laser-induced hyperthermia can disrupt cell proliferation within biofilms and increase susceptibility to antibiotics. However, there can be bacterial survival differences dependent upon laser irradiation times, and prolonged time at elevated temperature can damage healthy tissue. The objective of this study was to use survival analysis to model the impact of temperature increases on reducing viable biofilm bacteria. In vitro biofilms of Escherichia coli were grown on silicone discs or silicone doped with photothermal poly(3,4-ethylenedioxythiophene) hydrate (PEDOT) nanotubes, and subjected to laser-induced hyperthermia, using a 3 W continuous wave laser at 800 nm for varying times. The number of colony forming units per milliliter (CFU/mL) and maximum temperature were measured after each trial. Survival analysis was employed to estimate bacterial cell proliferation post-treatment to provide a quantitative framework for future studies evaluating photothermal inactivation of bacterial biofilms. The results demonstrate the first application of survival analysis for predicting the likelihood of bacterial cell proliferation based on temperature.

Triple-negative breast cancer (TNBC) is highly aggressive with a poor 5-year survival rate. Targeted therapy options are limited and most TNBC patients are treated with chemotherapy. This study aimed to determine whether doxorubicin (Dox) shifts the gut microbiome and whether gut microbiome populations influence chemotherapeutic responsiveness. Female BALB/c mice (n = 115) were injected with 4T1-luciferase cells (a murine syngeneic TNBC model) and treated with Dox and/or antibiotics, high-fat diet-derived fecal microbiota transplant (HFD-FMT), or exogenous lipopolysaccharide (LPS). Metagenomic sequencing was performed on fecal DNA samples. Mice that received Dox were stratified into Dox responders or Dox nonresponders. Mice from the Dox responders and antibiotics + Dox groups displayed reduced tumor weight and metastatic burden. Metagenomic analysis showed that Dox was associated with increased Akkermansia muciniphila proportional abundance. Moreover, Dox responders showed an elevated proportional abundance of Akkermansia muciniphila prior to Dox treatment. HFD-FMT potentiated tumor growth and decreased Dox responsiveness. Indeed, lipopolysaccharide, a structural component of Gram-negative bacteria, was increased in the plasma of Dox nonresponders and FMT + Dox mice. Treatment with exogenous LPS increases intestinal inflammation, reduces Dox responsiveness, and increases lung metastasis. Taken together, we show that modulating the gut microbiota through antibiotics, HFD-FMT, or by administering LPS influenced TNBC chemotherapy responsiveness, lung metastasis, and intestinal inflammation.

Colorectal cancer (CRC) treatment is currently hindered by micrometastatic relapse that cannot be removed completely during surgery and is often chemotherapy resistant. Targeted theranostic nanoparticles (NPs) that can produce heat for ablation and enable tumor visualization via their fluorescence offer advantages for detection and treatment of disseminated small nodules. A major hurdle in clinical translation of nanoparticles is their interaction with the 3D tumor microenvironment. To address this problem tumor organoid technology was used to evaluate the ablative potential of CD44-targeted polymer nanoparticles using hyaluronic acid (HA) as the targeting agent and coating it onto hybrid donor acceptor polymer particles (HDAPPs) to form HA-HDAPPs. Additionally, nanoparticles composed from only the photothermal polymer, poly[4,4-bis(2-ethylhexyl)-cyclopenta[2,1-b;3,4-b’]dithiophene-2,6-diyl-alt-2,1,3-benzoselenadiazole-4,7-diyl] (PCPDTBSe), were also coated with HA, to form HA-BSe NPs, and evaluated in 3D. Monitoring of nanoparticle transport in 3D organoids revealed uniform diffusion of non-targeted HDAPPs in comparison to attenuated diffusion of HA-HDAPPs due to nanoparticle-matrix interactions. Computational diffusion profiles suggested that HA-HDAPPs transport may not be accounted for by diffusion alone, which is indicative of nanoparticle/cell matrix interactions. Photothermal activation revealed that only HA-BSe NPs were able to significantly reduce tumor cell viability in the organoids. Despite limited transport of the CD44-targeted theranostic nanoparticles, their targeted retention provides increased heat for enhanced photothermal ablation in 3D, which is beneficial for assessing nanoparticle therapies prior to in vivo testing.

Theranostic nanoplatforms integrating fluorescence imaging and photothermal therapy have shown great potential in cancer research for tumor detection and image-guided treatment. Herein, a unique th...

Polymer dynamic organic theranostic spheres (PolyDOTS) are being studied as a photothermal ablation treatment of cancer and are activated by blue or near-infrared light. PolyDOTS or related hybrid polymeric nanoparticle products could be mass-produced, and it is expected that they, like any other engineered nanoparticle (ENP), could be found in aquatic environments. The purpose of this study was to investigate the potential toxicity of these types of hybrid nanoparticles on nontarget marine organisms. To investigate the potential of even greater toxicity due to solar exposure, the PolyDOTS were exposed to the sun for 12 h and "charged". Once charged, hepatopancreas and gill tissues from oysters (Crassostrea virginica) were exposed to concentrations of both uncharged and charged PolyDOTS for 24 h in vitro. The effects of PolyDOTS on lysosomal destabilization, cell viability, and free radical damage were analyzed. Significant sublethal toxicity was observed with the charged particles, and reduced viability was observed with uncharged particles in vitro. In vivo imaging studies using IVIS (In Vivo Imaging System) indicated PolyDOTS uptake in tissues. These types of studies are important for understanding the potential effects of light sensitive ENPs in oysters and their broader ecological impacts on estuarine ecosystems.

Breast tumors have their own specific microbiota, distinct from normal mammary gland tissue. Patients with breast cancer that present with locally advanced disease often undergo neoadjuvant chemotherapy to reduce tumor size prior to surgery to allow breast conservation or limit axillary lymph node dissection. The purpose of our study was to evaluate whether neoadjuvant chemotherapy modulates the tumor microbiome and the potential impact of microbes on breast cancer signaling. Using snap-frozen aseptically collected breast tumor tissue from women who underwent neoadjuvant chemotherapy (n = 15) or women with no prior therapy at time of surgery (n = 18), we performed 16S rRNA-sequencing to identify tumoral bacterial populations. We also stained breast tumor microarrays to confirm presence of identified microbiota. Using bacteria-conditioned media, we determined the effect of bacterial metabolites on breast cancer cell proliferation and doxorubicin therapy responsiveness. We show chemotherapy administration significantly increased breast tumor Pseudomonas spp. Primary breast tumors from patients who developed distant metastases displayed increased tumoral abundance of Brevundimonas and Staphylococcus. We confirmed presence of Pseudomonas in breast tumor tissue by IHC staining. Treatment of breast cancer cells with Pseudomonas aeruginosa conditioned media differentially effected proliferation in a dose-dependent manner and modulated doxorubicin-mediated cell death. Our results indicate chemotherapy shifts the breast tumor microbiome and specific microbes correlate with tumor recurrence. Further studies with a larger patient cohort may provide greater insights into the role of microbiota in therapeutic outcome and develop novel bacterial biomarkers that could predict distant metastases. Implications: Breast tumor microbiota are modified by therapy and affects molecular signaling.

As a gasotransmitter, hydrogen sulfide (H(2)S) has been studied to treat wounds and inflammation, but its potential antimicrobial effects in this context have not been evaluated. An H(2)S-releasing dipeptide hydrogel (S-FE), and several non-H(2)S-releasing control dipeptides, (C-FE, C-GE, FBA-FE, and FE where S = S-aroylthiooxime, an H(2)S donor; C = control, an oxime incapable of H(2)S release; FBA = 4-formylbenzamide, also incapable of H(2)S release; and E, F, G = glutamic acid, phenylalanine, and glycine, respectively), were studied to correlate differences in their chemical structures and H(2)S-releasing abilities with their antimicrobial effects on Staphylococcus aureus bacteria. Dipeptides with Phe (S-FE, C-FE, and FE) self-assembled into nanoribbons in water and displayed β-sheet formation and enhanced fluorescence, while the other two dipeptides (FBA-FE and C-GE) did not form assemblies in water. In vitro experiments with Staphylococcus aureus, which is a commonly found bacterium associated with wounds, showed significant antimicrobial effects from some of the dipeptides. Dipeptide S-FE inhibited bacterial growth more effectively than any of the controls, thereby limiting biofilm formation or disrupting established biofilms. These antimicrobial H(2)S-releasing dipeptide hydrogels provide a promising new approach to treat wound infections.

Hyperthermia has shown tremendous therapeutic efficiency in the treatment of cancer due to its controllability, minimal invasiveness and limited side effects compared to the conventional treatment techniques like surgery, radiotherapy and chemotherapy. To improve the precision of hyperthermia specifically to a tumor location, near infra-red (NIR) light activatable inorganic metal nanoparticles have served as effective photothermal therapy materials, but toxicity and non-biodegradability have limited their clinical applications. Conjugated polymer nanoparticles have overcome these limitations and are emerging as superior photothermal materials owing to their excellent light harvesting nature, biocompatibility and tunable absorption properties. In this review we focus on the development of organic conjugated polymers (polyaniline, polypyrrole, polydopamine etc.) and their nanoparticles, which have broad NIR absorption. Such materials elicit photothermal effects upon NIR stimulation and may also serve as carriers for delivery of therapeutic and contrast agents for combined therapy. Subsequently, the emergence of donor-acceptor based semiconducting polymer nanoparticles with strong absorbance that is tunable across the NIR have been shown to eradicate tumors by either hyperthermia alone or combined with other therapies. The design of multifunctional polymer nanoparticles that absorb near- or mid- infrared light for heat generation, as well as their diagnostic abilities for precise biomedical applications are highlighted.

Nanoparticles offer many promising advantages for improving current surgical regimens through their ability to detect and treat disseminated colorectal cancer (CRC). Hybrid Donor-Acceptor Polymer Particles (HDAPPs) have recently been shown to fluorescently detect and thermally ablate tumors in a murine model. Here, HDAPPS were functionalized with hyaluronic acid (HA) to improve their binding specificity to CT26 mouse CRC cells using HA to target the cancer stem cell marker CD44. In this work, we compared the binding of HA functionalized HDAPPs (HA-HDAPPs) in in vitro, ex vivo, and in vivo environments. The HA-HDAPPs bound to CT26 cells 2-fold more in vitro and 2.3-fold higher than un-functionalized HDAPPs ex vivo. Compared to intraoperative abdominal perfusion, intraperitoneal injection prior to laser stimulation for nanoparticle heat generation provides a superior modality of HA-HDAPPs delivery for CRC tumor selectivity. Photothermal treatment of disseminated CRC showed that only HA-HDAPPs delivered via intraperitoneal injection had a reduction in the tumor burden, and these nanoparticles also remained in the abdomen following resolution of the tumor. The results of this work confirm that HA-HDAPPs selectively bind to disseminated CRC, with ex vivo tumors having bound HA-HDAPPs capable of photothermal ablation. HA-HDAPPs demonstrated superior binding to tumor regions compared to HDAPPs. Overall, this study displays the theranostic potential of HDAPPs, emphasizing their capacity to detect and photothermally treat disseminated CRC tumors.

Novel modalities for overcoming recurrent urinary tract infections associated with indwelling urinary catheters are needed, and rapidly induced hyperthermia is one potential solution. PEDOT nanotubes are a class of photothermal particles that can easily be incorporated into silicone to produce thin, uniform coating on medical grade silicone catheters; subsequent laser stimulation therein imparts temperature elevations that can eliminate bacteria and biofilms. PEDOT silicone coatings are stable following thermal sterilization and repeated heating and cooling cycles. Laser stimulation can induce temperature increases of up to 55 °C in 300 s, but only 45 s was needed for ablation of UTI inducing E. coli biofilms in vitro. This work also demonstrates that mild hyperthermia of 50 °C, applied for only 31 s in the presence of antibiotics could eliminate E. coli biofilm as effectively as high temperatures. This work culminates in the evaluation of the PEDOT NTs for photothermal elimination of E. coli in an in vivo model to demonstrate the safety and effectiveness of a photothermal nanocomposite (16 s treatment time) for rapid clearance of E. coli.

Introduction Metastatic colorectal cancer (CRC) is complicated by chemotherapy-resistant cell populations. Oxaliplatin is used in heated intraperitoneal hyperthermic chemoperfusion (HIPEC) for treatment of disseminated CRC. Photothermal nanoparticles can provide focal heating to improve the response of CRC cells to oxaliplatin, by confining heating near individual cells. Reduction in cellular luciferase signal may allow single-cell-resolution recording of thermal dosimetry. Methods Oxaliplatin resistant (OxR) variants of luciferase-expressing CT26.WT-Fluc-Neo CRC cells were developed and their sensitivity to hyperthermia was evaluated. Polymer-based photothermal nanoparticles were developed, characterized and used to explore their potential for imparting a thermal dose to improve cell response to oxaliplatin. A correlation of thermal dose to intracellular luciferase activity was established using quantitative luminescence monitoring and microscopy. Results Luciferase-based monitoring of thermal dose within CT26 cell lines was validated within the ranges of 0.04–8.33 CEM43 for parental cells and 0.05–9.74 CEM43 for OxR CT26 cells. This was further confirmed using nanoparticle-induced hyperthermia, where the single-cell resolution of the thermal dose can be achieved. The nanoparticles enhance cell killing of resistant cells when combined with oxaliplatin and stimulated to generate heat. Conclusion Nanoparticle-based hyperthermia is effective for augmenting chemotherapy and can be coupled with reductions in CT26 luciferase expression to monitor thermal dose at single-cell resolution. The development of OxR CT26.WT-Fluc-Neo CRC cells sets the stage for pre-clinical evaluations to measure nanoparticle-induced hyperthermia to augment chemotherapy (Nano-HIPEC) in a chemotherapy-resistant model of disseminated CRC.

Polymer dynamic organic theranostic spheres (PolyDOTS) are being studied as a photothermal ablation treatment of cancer and are activated by blue or near-infrared light. PolyDOTS or related hybrid polymeric nanoparticle products could be mass-produced, and it is expected that they, like any other engineered nanoparticle (ENP), could be found in aquatic environments. The purpose of this study was to investigate the potential toxicity of these types of hybrid nanoparticles on nontarget marine organisms. To investigate the potential of even greater toxicity due to solar exposure, the PolyDOTS were exposed to the sun for 12 h and "charged". Once charged, hepatopancreas and gill tissues from oysters (

Background Reproduction of the perfusion used in therapy (hyperthermic intraperitoneal chemotherapy) procedures preclinically represents a valuable asset for investigating new therapeutic agents that may improve patient outcomes. This article provides technical descriptions of our execution of closed and open “coliseum” abdominal perfusion techniques in a mouse model of peritoneal carcinomatosis of colorectal cancer. Materials and Methods BALB/c mice presenting with disseminated colorectal cancer (CT26-luciferin cells) underwent 30-min perfusions mimicking either the closed perfusion or the coliseum perfusion technique. Disease burden was monitored by bioluminescence signaling using an in vivo imaging system. Perfusion circuits consisted of single inflow lines with either a single or dual outflow line. Results Twelve mice presenting with disseminated disease underwent the closed perfusion technique. Surgical complications included perfusate leakage and organ constriction/suction into the outflow line(s). Nine mice underwent the coliseum perfusion technique with surgical debulking, using bipolar cauterization to remove tumors attached to the peritoneum. All mice survived the coliseum perfusion with limited intraoperative complications. Conclusions Fewer intraoperative complications were experienced with our coliseum perfusion technique than the closed perfusion. The methods described here can be used as a guideline for developing future perfusion murine models for investigating perfusion models useful for delivery of chemotherapy or other tumor-sensitization agents, including selective targeted agents, nanoparticles, and heat.

Judicious combination of semiconducting polymers with alternating electron donor (D) and acceptor (A) segments created hybrid nanoparticles with amplified energy transfer and red-shifted emission, while simultaneously providing photothermal capabilities. Hybrid D-A polymer particles (H-DAPPs) passively localized within orthotopic breast tumors, serving as bright fluorescent beacons. Laser stimulation induced heat generation on par with gold nanorods, resulting in selective destruction of the tumor. H-DAPPs can also undergo multiple thermal treatments, with no loss of fluorescence intensity or photothermal potential. These results indicate that H-DAPPs provide new avenues for the synthesis of hybrid nanoparticles useful in localized detection and treatment of disease.

Background and Objective Photothermal therapy (PTT) has several applications in the areas of wound healing, pain management, bacterial infection control, and cancer treatment dependent on the temperature that is generated. PTT is often used exclusively with near infrared (NIR) light and most nanoparticles (NP) used for PTT are designed to absorb within one narrow range of wavelengths. We have developed a dual-wavelength photothermal therapy by capitalizing on the dual absorption of nanoparticles in the blue and NIR range. Materials and Methods Our lab has previously developed NP based on the semiconducting, conjugated polymer poly[4,4-bis(2-ethylhexyl)-cyclopenta[2,1-b;3,4-b′]dithiophene-2,6-diyl-alt-2,1,3-benzoselenadiazole-4,7-diyl] (PCPDTBSe). The NP have strong absorption in the blue and NIR regions. In this report, we have explored the heat generated by PCPDTBSe NP using simultaneous delivery of 450 and 800 nm light, either independently or together for photothermal ablation of mouse colorectal cancer cells. Results The heat generation studies indicated that the use of either 450 or 800 nm wavelengths at the same fluences produced approximately the same temperature change of deionized water. Fluences of 114.6 and 229.2 J/cm2, utilizing 450 or 800 nm light applied individually resulted in temperatures of 8–47°C above ambient temperature, leading to a 90% reduction in cell viability. Simultaneous stimulation of the PCPDTBSe NP with 450 and 800 nm light effectively doubles the effective power delivered, resulting in temperatures 18–63°C above ambient and 100% photothermal ablation of the colorectal cancer cells. Conclusion The results of this study demonstrate that PCPDTBSe polymer NP can be utilized as effective PTT agents by capitalizing on their dual absorption of both blue and NIR light. Lasers Surg. Med. © 2016 Wiley Periodicals, Inc.

Ultrafast optical nonlinearity in chitosan (CS) films doped with multi-walled boron nitride nanotubes (MWBN) has been investigated using 800 nm, 100 fs laser pulses, employing the open aperture Z-scan technique. Two-photon absorption coefficients (β) of CS–MWBN films have been measured at 800 nm by Z-scan. While chitosan with 0.01% MWBN doping gives a β value of 0.28×10−13 m/W, 1% doping results in a higher β value of 1.43×10−13 m/W, showing nonlinearity enhancement by a factor of 5. These nonlinearity coefficients are comparable to those reported for silver nanoclusters in glass matrix and Pt-PVA nanocomposites, indicating potential photonic applications for MWBN doped chitosan films. Characterization of the synthesized films using Fourier transform infrared photoacoustic spectroscopy (FTIR-PAS) reveals significant interactions between the NH and CO groups of chitosan with boron nitride.

Triple negative breast cancer is exceptionally difficult to treat due to the lack of distinguishing biomarkers for drug targeting. An alternative approach based on recent data indicates that these cells may be more susceptible to mechanical influences, such as alterations in the tumor stroma. Three dimensional collagen gels containing co-cultures of mesenchymal cells and MDA-MB-231 cancer cells were utilized to explore the effects of multi-walled nanotubes (MWNT) on cell contraction, invasion, viability, MMP-9 expression, and migration of breast cancer cells. MWNT were able to restrict each of these features for the cancer cells without impeding the associated mesenchymal cells. MWNT-collagen gels are useful tools for cellular reprogramming of cancer cells and should be considered in greater detail as a potential agent for therapeutic treatment of triple-negative breast cancer.Breast cancer is still a leading cause of death for women worldwide. One subtype of this cancer which is very aggressive is the triple negative breast cancer. The behavior of tumors may be affected by the tumor stromal environment. In this study, the authors investigated the effects of multi-walled nanotubes (MWNT) on tumor cell biology. The positive findings may point a new way in using this modality for treatment of triple-negative breast cancer in the future.

e23570 Background: Sarcomas represent 1% of all adult cancers and 20% of all pediatric cancers worldwide.Sarcomas are heterogeneous with more than 50 histologic subtypes involving the mesenchyme including bones, muscle, fat, blood vessels, and nerves. Patients with high-risk localized or advanced disease are treated with the combination of neoadjuvant or adjuvant chemotherapy, radiation, and surgical resection have all failed to substantially improve overall survival (OS).4 Novel treatments are desperately needed in the management of soft tissue sarcoma. Thermal ablation of sarcoma may offer a novel method for eradicating the disease. Polymer based nanoparticles that can be stimulated with light to generate heat (photothermal nanoparticles) have been developed previously and used to induce. The goal of the current work is to utilize these nanoparticles for selected ablation of sarcoma. Methods: Polymer nanoparticles were first prepared in the in our lab through the synthesis of 2‐ethylhexyl cyclopentadithiophene 2,1,3‐benzoselenadiazole (PCPDTBSe). Nanoparticles of this polymer were prepared using an oil-water emulsion technique, with FITC labeled polyethylene glycol as the stabilizing agent, to create an aqueous suspension. The nanoparticles were characterized for their size and ability to generate heat when stimulated with 800 nm laser light (180J/cm2). Fresh Soft tissue sarcoma samples are obtained through informed consent and approval of the institutional IRB. Nanoparticles were injected into sarcoma in a volume of 100ul, at a concentration of 250ug/ml. The tissues were then exposed to the laser source to generate heat. Controls included the injection of the sarcoma with the nanoparticles and no laser exposure, as well as the injection of water, plus laser exposure. Results: Sarcomas vary in their ability to take up and response to nanoparticles. We have found that liposarcoma samples are extremely leaky and do not hold the injection of nanoparticles, which leach out of the tumor. Conclusions: Future directions include studies that would involve targeted, immunotherapy and chemotherapy given with nanoparticles that facilitate combinatory and unique individual cytotoxic effects of the soft tissue sarcoma subtypes.

Recovery from systemic or local bacterial infections can be lengthy and costly, with the clinical challenges being further complicated when bacteria acquire resistance to current antibiotics. Hyperthermia offers new mechanisms for removing bacteria via ablation, or sensitising them to chemical agents. The first part of this review provides a background on the bacterial biofilms, their response to hyperthermia, and acquired resistance to antibiotics, followed by the clinical challenges they present in managing infections associated with soft tissues and biomedical implants. The second part of the review discusses the thermal modalities used to combat infections, including radiofrequency, ultrasound, high-intensity focussed ultrasound, microwave thermotherapy, and photothermal and magnetic nanoparticles (NP). The overall aim of this review is to demonstrate the tremendous potential of hyperthermia for mitigating bacterial infections and foster new research ventures to help remedy these challenging occurrences.

According to the American Cancer Society, breast cancer is the second leading cause of cancer death in the US. Cancerous cells may have inadequate adhesions to the extracellular matrix and adjacent cells. Previous work has suggested that restoring these contacts may negate the cancer phenotype. This work aims to restore those contacts using multi-walled carbon nanotubes (MWNTs). Varying concentrations of carboxylated MWNTs in water, with or without type I collagen, were dried to create a thin film upon which one of three breast cell lines were seeded: cancerous and metastatic MDA- MB-231 cells, cancerous but non-metastatic MCF7 cells, or non-cancerous MCF10A cells. Proliferation, adhesion, scratch and autophagy assays, western blots, and immunochemical staining were used to assess adhesion and E-cadherin expression. Breast cancer cells grown on a MWNT-collagen coated surface displayed increased adhesion and decreased migration which correlated with an increase in E-cadherin. This work suggests an alternative approach to cancer treatment by physically mediating the cells' microenvironment.

Poly(glycerol sebacate) (PGS)/nanohydroxyapatite (nHA) composites were assessed to develop new materials for closure via tissue transport for nonhealing defects (e.g., cleft palate and large skin wounds). The elastic shape memory polymer, PGS, was reinforced with nHA at 3 and 5% loading to increase the mechanical properties compared with the undoped PGS. Differential scanning calorimetry (DSC) was utilized to identify a glass transition temperature (Tg ) of -25°C. X-ray diffraction demonstrated a reduction in the amorphous nature of the material. The Fourier transform infrared photoacoustic spectral (FTIR-PAS) data showed decreased CO bonding and increased hydrogen bonding with increased nHA incorporation. Composites exhibited Young's moduli in the range of 0.25-0.5 MPa and tensile strength of 1.5-3 N. No significant difference in extension to break (∼50 mm) with addition of nHA was observed. The elastic modulus significantly increased for 5% PGS/nHA compared to 0 and 3% PGS/nHA and tensile strength significantly increased for 3% PGS/nHA compared to 0 and 5% PGS/nHA. Degradation of 5% nHA/PGS significantly increased during the second week compared to PGS 0 and 3% PGS/nHA. The accelerated degradation for 5% PGS/nHA coupled with decreased flexibility and tensile strength implies an interruption in crosslinking. By maintaining flexibility and extension while increasing tensile strength, the 3% PGS/nHA doped satisfied the force range desired for closure of soft tissue defects. Based on this work, PGS with 3% nHA shape memory polymers should serve as a good candidate for closure of nonhealing soft tissues. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1366-1373, 2016.

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.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/cm(2) 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.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/cm(2) 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.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.

Conventional collagen-based heart valves eventually fail because of insufficient replacement of graft material by host tissue. In this study, type I collagen was blended with silk fibroin and the synthetic elastic polymer poly (glycerol-sebacate) (PGS) in varying proportions to create multifunctional electrospun nanofibrous materials tailored for use as endovascular scaffolds such as heart valve replacement. Depending on the blended material the elastic moduli ranged from 2.3 to 5.0 Mpa; tensile stresses ranged from 0.8 to 1.5 Mpa; and strains ranged from 30% to 70%. Electrospun materials with a weight ratio of 4.5:4.5:1 (collagen, fibroin, and PGS) (termed PFC mats) were the most similar to native heart valves. In vitro degradation of PFC mats was 0.01% per week. Endothelial cells adhered to, proliferated, and formed cell-cell junctions on PFC mats. Compared with collagen hydrogels and electrospun collagen mats respectively 220-290% less platelet adhesion was observed for PFC mats. The study demonstrates that PFC material has superior mechanical properties, low degradation, and reduced thrombogenic potential and suggests that further investigation of this biomaterial for cardiovascular applications is warranted.

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.

Oysters are an ecologically important group of filter-feeders, and a valuable toxicology model for characterizing the potential impacts of nanoparticles to marine organisms. Fullerene (C60) exposure studies with oysters, Crassostrea virginica, were conducted with a variety of biological levels, e.g., developmental studies with embryos, whole organism exposures with adults, and isolated hepatopancreas cells. Significant effects on embryonic development and lysosomal destabilization were observed at concentrations as low as 10 ppb. Moreover, based on our extensive experience with the lysosomal assay, the lysosomal destabilization rates at fullerene concentrationsor = 100 ppb were regarded as biologically significant as they are associated with reproductive failure. Interestingly, there was no significant increase in lipid peroxidation levels in hepatopancreas tissues. Oyster hepatopancreas tissues are composed of lysosomal rich cells, and confocal microscopy studies indicated thatthe fullerene particles readily accumulated inside hepatopancreas cells within 4 h. Fullerene aggregates tended to be localized and concentrated into lysosomes. The microscopic work in conjunction with the lysosomal function assays supports the premise that endocytotic and lysosomal pathways may be major targets of fullerenes and other nanoparticles. Nanoparticles that affect normal lysosomal and autophagic processes may contribute to long-term, chronic problems for individual health as well as ecosystem health.

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. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009

Controlling the relative concentrations of surfactant, oxidant iron (III) chloride, 3,4-ethylenedioxythiophene (EDOT) monomer in water, and mechanical influences such as sonication and stirring, resulted in the synthesis of PEDOT nanoparticles with various dimensions and aspect ratios. Having a ratio of two or more of surfactant compared to the oxidant led to a greater yield of thinner nanofibers, as did utilizing a more dilute concentration of the reactants. These nanoparticles were shown to be cyto-compatible in 3D culture for both human and mouse cells. The key feature is that PEDOT nanoparticles with a variety of morphologies can be obtained using water only without the need for hexanes in the procedures. The synthesized PEDOT nanoparticles absorb light across the infrared spectrum and in turn are capable of generating heat for biologically relevant studies of hyperthermia in three dimensional tissue phantoms. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 43378.

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.

Poly(glycerol sebacate) (PGS)/nanohydroxyapatite (nHA) composites were assessed to develop new materials for closure via tissue transport for nonhealing defects (e.g., cleft palate and large skin wounds). The elastic shape memory polymer, PGS, was reinforced with nHA at 3 and 5% loading to increase the mechanical properties compared with the undoped PGS. Differential scanning calorimetry (DSC) was utilized to identify a glass transition temperature (Tg ) of -25°C. X-ray diffraction demonstrated a reduction in the amorphous nature of the material. The Fourier transform infrared photoacoustic spectral (FTIR-PAS) data showed decreased CO bonding and increased hydrogen bonding with increased nHA incorporation. Composites exhibited Young's moduli in the range of 0.25-0.5 MPa and tensile strength of 1.5-3 N. No significant difference in extension to break (∼50 mm) with addition of nHA was observed. The elastic modulus significantly increased for 5% PGS/nHA compared to 0 and 3% PGS/nHA and tensile strength significantly increased for 3% PGS/nHA compared to 0 and 5% PGS/nHA. Degradation of 5% nHA/PGS significantly increased during the second week compared to PGS 0 and 3% PGS/nHA. The accelerated degradation for 5% PGS/nHA coupled with decreased flexibility and tensile strength implies an interruption in crosslinking. By maintaining flexibility and extension while increasing tensile strength, the 3% PGS/nHA doped satisfied the force range desired for closure of soft tissue defects. Based on this work, PGS with 3% nHA shape memory polymers should serve as a good candidate for closure of nonhealing soft tissues. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1366-1373, 2016.

Conventional collagen-based heart valves eventually fail because of insufficient replacement of graft material by host tissue. In this study, type I collagen was blended with silk fibroin and the synthetic elastic polymer poly (glycerol-sebacate) (PGS) in varying proportions to create multifunctional electrospun nanofibrous materials tailored for use as endovascular scaffolds such as heart valve replacement. Depending on the blended material the elastic moduli ranged from 2.3 to 5.0 Mpa; tensile stresses ranged from 0.8 to 1.5 Mpa; and strains ranged from 30% to 70%. Electrospun materials with a weight ratio of 4.5:4.5:1 (collagen, fibroin, and PGS) (termed PFC mats) were the most similar to native heart valves. In vitro degradation of PFC mats was 0.01% per week. Endothelial cells adhered to, proliferated, and formed cell-cell junctions on PFC mats. Compared with collagen hydrogels and electrospun collagen mats respectively 220-290% less platelet adhesion was observed for PFC mats. The study demonstrates that PFC material has superior mechanical properties, low degradation, and reduced thrombogenic potential and suggests that further investigation of this biomaterial for cardiovascular applications is warranted.

The photothermal efficiency of two similar organic nanomaterials, poly(3,4-ethylenedioxythiophene):poly(4-styrene-sulfonate) (PEDOT:PSS) nanoparticles and poly(3,4-ethylenedioxythiophene) (PEDOT) nanotubes, are compared. The PEDOT:PSS nanoparticles ranged from 100-200 nm in diameter, while the PEDOT nanotubes ranged from 200-400 nm in diameter and 4-10 microm in length. By changing the aspect ratio of the PEDOT nanomaterials from a spherical to a tubular shape, interesting differences in the optical and electronic properties of the materials were realized. Because of this, the PEDOT nanotubes were shown to generate on average approximately to 10 degrees C better internal heating for similar concentrations compared to the PEDOT:PSS nanoparticles. Cytotoxicity studies of both nanomaterials showed no significant toxicity towards RKO or HCT116 colorectal cancer cells in the absence of NIR light. The NIR-mediated photothermal efficiency of the PEDOT:PSS nanoparticles and the PEDOT nanotubes were compared in-vitro. A cell viability assay was performed and at the highest concentration (0.1 mg/mL) of nanomaterial, cell survival was close to 20% for the PEDOT:PSS nanoparticles with both RKO and HCT116 cells. Consequently, cell survival for the PEDOT nanotubes was less than 5% for both RKO and HCT116 cells. An in-vitro three dimensional tumor model was assembled using collagen gel tissue phantoms. The depth of heat penetration from the PEDOT nanotubes into the tissue phantoms, along with cell viability of RKO and HCT116 cells was determined and quantified.

Peritoneal metastases of colorectal cancer are a significant challenge in the field of medicine today due to poor results of systemic chemotherapy caused by the poor diffusion of drugs across the blood–peritoneal barrier. Multi-walled carbon nanotubes (MWNTs) are a biocompatible nanomaterial that strongly absorb near-infrared light to locally heat the surrounding area. Colorectal cancer is known to overexpress folate receptor; therefore, folic acid (FA) was covalently attached to MWNTs to target colorectal cancer cells. Results from real-time polymerase chain reaction found differing expression of folate receptor-α in two colorectal cancer cell lines, RKO and HCT116, as well as a healthy epithelial cell line, HEPM. A spectrophotometric method was developed to quantify the mass of MWNTs bound to cells, and it was determined that FA-targeted MWNTs resulted in a 400–500 % greater affinity for colorectal cancer cells than untargeted MWNTs. The non-cancerous cell line, HEPM, had higher non-specific MWNT interaction and similar MWNT–FA affinity. Stimulated by 1,064 nm light, FA-functionalized MWNTs caused a 50–60 % decrease in colorectal cancer cell viability compared to a 4–10 % decrease caused by untargeted MWNTs. Our results indicate that FA-targeted MWNTs may increase the therapeutic index of MWNT-induced photothermal therapy.

Low band gap D-A conjugated PNs consisting of 2-ethylhexyl cyclopentadithiophene co-polymerized with 2,1,3-benzothiadiazole (for nano-PCPDTBT) or 2,1,3-benzoselenadiazole (for nano-PCPDTBSe) have been developed. The PNs are stable in aqueous media and showed no significant toxicity up to 1 mg · mL(-1) . Upon exposure to 808 nm light, the PNs generated temperatures above 50 °C. Photothermal ablation studies of the PNs with RKO and HCT116 colorectal cancer cells were performed. At concentrations above 100 µg · mL(-1) for nano-PCPDTBSe, cell viability was less than 20%, while at concentrations above 62 µg · mL(-1) for nano-PCPDTBT, cell viability was less than 10%. The results of this work demonstrate that low band gap D-A conjugated polymers 1) can be formed into nanoparticles that are stable in aqueous media; 2) are non-toxic until stimulated by IR light and 3) have a high photothermal efficiency.

The sections in this article are Introduction Gene Therapy Antibacterial Therapy Wound Healing Chemotherapy Hyperthermic Drug Delivery Using CNTs Drug Transport Using CNTs Summary and Future Perspectives Keywords: Drug delivery; gene therapy; wound healing; antibacterial; chemotherapy; hyperthermia; multi-walled carbon nanotube

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/cm 2 ) 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.

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.