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Background: Neuroblastoma is a common childhood malignancy with approximately 800 new cases diagnosed each year in the United States. Treatment of neuroblastoma directly depends on patient risk categories and includes combinations of surgery, radiation therapy, chemotherapy, stem cell therapy, immunotherapy, and retinoid therapy. Various characteristics of cancer in general and some specific to neuroblastoma cell lines contribute to a difficulty in delivering clinically relevant concentrations of therapeutic agents to neuroblastoma masses. Amplification of the MYCN gene in certain neuroblastoma cell lines correlates with increased cellular surface glycosylation levels as well as a worse prognosis for patients. Overexpression of the MUC1 gene is also associated with increased glycosylation, specifically type-O, in various cancers, but the role of MUC1 in neuroblastoma has not been thoroughly defined. The objective of this study was to evaluate the influence of type-O glycosylation on therapeutic uptake in different neuroblastoma cell lines. Methods: The neuroblastoma cell line SK-N-DZ, a MYCN-amplified line, was compared to SK-N-SH, a non-MYCN-amplified line (negative control) and BT-20, a highly glycosylated breast cancer cell line (positive control). Benzyl-α-GalNAc, an O-glycosylation inhibitor, was introduced to each cell line. To determine glycosylation levels in the respective cell lines, fluorescence assays were performed using CD227 (anti-MUC1) antibody. In vitro cytotoxicity assays were performed to determine maximum non-toxic concentrations of the glycosylation inhibitor (benzyl-α-GalNAc) and antibody (CD227) and to subsequently evaluate the functional role of glycosylation using cellular models of neuroblastoma. Results: The maximum non-toxic concentrations per 10,000 cells for each neuroblastoma cell line was 0.05 mg/ml of benzyl-α-GalNAc, and 6 µl of CD227 stock preparation. Preliminary results from fluorescence detection studies showed an increase in CD227-FITC antibody uptake by the MYCN-amplified neuroblastoma cells (SK-N-DZ) following exposure to the O-glycosylation inhibitor (benzyl-α-GalNAc). Cellular uptake of CD227-FITC by non-MYCN-amplified cell line (SK-N-SH) was less by comparison. Conclusion: Preliminary findings suggest that O-glycosylation is a barrier capable of limiting cellular uptake of agents in MYCN-amplified neuroblastoma cell lines. Ongoing studies are focused on investigating the influence of glycosylation inhibition on cytotoxicity of FDA-approved therapeutic agents. Citation Format: Meghan Cook, Alma Garcia, Katie Konieczny, Meghan Ferguson, Robert Campbell. Investigating the influence of glycosylation using cellular models of neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3045.

Nanotechnology has brought about the advent of personalized medicine in the era of targeted therapeutic strategies for cancer therapy. The ability to exploit tumor features for therapeutic gain has made it possible to manufacture more effective nanomedicines for cancer treatment. However, known obstacles, including the inability to overcome pathophysiological barriers of tumors, have impeded disease management. In spite of this, recent efforts have been made to develop more functionalized nanosystems that utilize the active-targeting approach. This article reviews the FDA-approved cancer drug delivery systems in the general framework of personalized nanomedicine. We discuss the latest efforts in the development of functionalized nano-systems, and summarize relevant ongoing preclinical and clinical trials.

The goal of this research was to evaluate the effectiveness of cationic liposomes for intranasal administration of proteins to the brain. Cationic liposomes were loaded with a model protein, ovalbumin (OVAL), and a 50 microg dose was administered intranasally to rats. In qualitative studies, liposomes were loaded with Alexa 488-OVAL and delivery was assessed by fluorescence microscopy. By 6 and 24 h after administration, Alexa 488-OVAL deposits were widely distributed throughout brain, with apparent cellular uptake in midbrain by 6 h after administration. In quantitative studies, liposomes were loaded with (111)In-OVAL, and distribution to brain and peripheral tissues was monitored by gamma counting at 1, 4, 6, and 24 h after administration. The highest brain concentrations were achieved at the shortest time point, 1 h, for both liposomal and aqueous OVAL. However, the liposomes yielded higher (111)In-OVAL concentrations in brain than (111)In-OVAL in PBS. Moreover, a 2 microg/microL form of liposomal OVAL yielded a higher percentage of dose in brain, and a lower percentage in stomach and intestines, than twice the volume of a 1 microg/microL preparation. Cationic liposomes may provide a novel, noninvasive strategy for delivery of neuroactive proteins to the brain for treatment of central nervous system disorders.

Previous studies have shown that glial cell line-derived neurotrophic factor (GDNF) exerts significant neuroprotective effects on substantia nigra (SN) neurons in the rat 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD). In this study we used enzyme-linked immunosorbent assay (ELISA) to determine GDNF brain levels and distribution to target regions (i.e. striatum and SN) following intranasal administration of GDNF at different time points after administration. Brain levels increased significantly within 1h following a single 50-μg dose of GDNF in a liposomal formulation, returning to baseline by 24h. In a second study, different doses of GDNF (10-150 μg) in phosphate-buffered saline (PBS) were studied at the 1-h time point. Dose-dependent increases in brain GDNF levels were observed with apparent saturation of uptake at doses above 100 μg. Liposomes delivered 10-fold more GDNF to brain than PBS despite yielding similar neuroprotective efficacy in the 6-OHDA model, suggesting incomplete release of GDNF from liposomes in tissue. In a third study, autoradiography was performed on brain sections taken 1h after intranasal (125)I-labeled GDNF. Radioactivity was detected throughout the brain along the rostral-to-caudal axis, indicating that nasally administered GDNF can reach target areas. Collectively, these results demonstrate that intranasal administration of GDNF in liposomes or PBS achieves significant increases in GDNF in target brain areas, supporting use of intranasal administration as a non-invasive means of delivering GDNF to the brain to protect dopamine neurons and arrest disease progression in PD.

Glial cell line-derived neurotrophic factor (GDNF) exerts neurotrophic and neuroprotective effects on substantia nigra (SN) dopamine neurons and has great therapeutic potential for Parkinson's disease (PD). Hindering this potential is the fact that GDNF cannot cross the blood-brain barrier. The aim of this study was to assess the effects of GDNF administered by the intranasal route in normal rats, and in the unilateral 6-hydroxydopamine (6-OHDA) model of PD. In the first study, rats received single intranasal doses of 50-μg GDNF in phosphate-buffered saline (PBS) or cationic liposomes, but no 6-OHDA. In the second study, rats were nasally administered 10, 50 or 150 μg of GDNF in PBS or cationic liposomes 1h before injection of 6-OHDA. All groups were sacrificed 3-4 weeks later. Both intranasal GDNF treatments induced a neurotrophic effect in the SN insofar as the number of tyrosine hydroxylase (TH)-positive neurons was significantly higher than in controls given intranasal PBS liposomes. Dopamine cell counts were also higher in the intact SN of 6-OHDA-lesioned rats compared to controls given PBS liposomes. Most importantly, intranasal GDNF provided significant neuroprotective efficacy indicated by greater TH immunostaining density in the lesioned versus intact SN of rats given single 50-μg doses of GDNF in PBS, or 150-μg doses of liposomal GDNF, compared to lesioned rats given PBS liposomes. Three 50-μg doses given at daily intervals (1 day before, 1h before, and 1 day after 6-OHDA) provided even greater protection than single 150-μg doses. Multiple doses at short intervals may therefore provide greater neuroprotection than single bolus doses. These results demonstrate both a neurotrophic effect of intranasal GDNF in the intact SN as well as neuroprotective efficacy in the unilateral 6-OHDA model, supporting pursuit of this approach as a potential treatment for PD.

Aims: The development of noninvasive imaging techniques for the assessment of cancer treatment is rapidly becoming highly important. The aim of the present study is to show that magnetic cationic liposomes (MCLs), incorporating superparamagnetic iron oxide nanoparticles (SPIONs), are a versatile theranostic nanoplatform for enhanced drug delivery and monitoring of cancer treatment. Materials & methods: MCLs (with incorporated high SPION cargo) were administered to a severe combined immunodeficiency mouse with metastatic (B16-F10) melanoma grown in the right flank. Pre- and post-injection magnetic resonance (MR) images were used to assess response to magnetic targeting effects. Biodistribution studies were conducted by 111In-labeled MCLs and the amount of radioactivity recovered was used to confirm the effect of targeting for intratumoral administrations. Results: We have shown that tumor signal intensities in T2-weighted MR images decreased by an average of 20 ± 5% and T2* relaxation times decreased by 14 ± 7 ms 24 h after intravenous administration of our MCL formulation. This compares to an average decrease in tumor signal intensity of 57 ± 12% and a T2* relaxation time decrease of 27 ± 8 ms after the same time period with the aid of magnetic guidance. Conclusion: MR and biodistribution analysis clearly show the efficacy of MCLs as MRI contrast agents, prove the use of magnetic guidance, and demonstrate the potential of MCLs as agents for imaging, guidance and therapeutic delivery.

Aims: Cationic liposomes have been shown to preferentially target the tumor vasculature, but not uniformly. Bevacizumab antibody selectively accumulates in tumors expressing VEGF. We thus developed bevacizumab-modified, pegylated cationic liposomes (PCLs) to improve the distribution of liposomes along tumor vessels, and to enhance tumor targeting. Materials & methods: We evaluated the delivery vehicle both in the absence and presence of VEGF, using human pancreatic cancer (Capan-1, HPAF-II and PANC-1) and endothelial (MS1-VEGF and HMEC-1) cell lines. Results: All cell lines except for HMEC-1 secreted VEGF. Modification of PCLs with bevacizumab did not alter ζ-potential, but increased overall liposome size. The toxicity profile for bevacizumab-modified PCLs was cell line dependent and, in general, bevacizumab improved cellular uptake and tumor targeting of PCLs. Conclusion: Bevacizumab-modified PCLs represent a potential improvement over the unmodified variety, supporting their future development for the treatment of cancer.

Offshore platforms transported long distances across open ocean can be subjected to significant fatigue loadings prior to installation. The standard design practice for tow, as well as in-place conditions, is based on use of the long-term average environment. While this is appropriate for long in-place service lives, weather encountered during a tow may deviate significantly from the average due to the relatively short tow duration. If severe weather is encountered during tow, the resulting fatigue life estimate can be considerably shorter than one based on long-term average conditions. While the implication of severe weather during tow is generally well known, design methods that explicitly address this issue have yet to be established. This paper presents a design procedure for combining tow and in-place fatigue that accounts for the possibility of severe weather during the tow. The method provides the engineer with a technical basis for choosing design values for tow fatigue such that combined fatigue damage estimates will not exceed code allowables after installation, with a given level of exceedance. Use of the proposed procedure is briefly examined in terms of its impact on fatigue reliability.

The use of magnetic drug targeting (MDT) to selectively deliver chemotherapeutic drugs to tumor cells is a widely investigated approach; however, the notion of targeting tumor endothelial cells by this method is a fairly new concept. Positively-charged (cationic) liposomes have an extraordinarily high affinity for tumor vessels, but heterogeneous targeting is frequently observed. In order to improve on the overall efficiency of targeting tumor vessels, we investigated the use of an externally applied magnetic field together with magnetic cationic liposomes (MCLs) for cancer treatment. We examined the antitumor effect of the chemotherapeutic agent vinblastine loaded in MCLs, using a murine model of melanoma. Two hours following i.v. administration of MCLs, we observed significant tumor vascular uptake with use of an external magnet (15.9 +/- 6.3%) compared to no magnet (5 +/- 1.3%). The administration of vinblastine-loaded MCLs with the magnet produced a significant antitumor effect, reducing the presence of tumor nodules in preferential sites of metastasis compared to untreated and free drug control groups. CD31 immunostaining revealed a decrease in the general length of tumor blood vessels, altered vascular morphology and interruptions in the tumor vascular lining for the vinblastine-loaded MCL groups. Drug-loaded MCLs with magnetic fields may represent a promising combination approach for cancer treatment.

The use of second generation cationic liposomes to deliver cytotoxic drugs to solid tumors is a rational and promising therapeutic approach, given the natural affinity of cationic carrier molecules for the tumor microvasculature. Cationic liposomal therapeutics are effective in the treatment of cancers that are resistant to conventional chemotherapy and other treatment modalities. Researchers are now exploring novel ways to combine cationic nanosystems with other treatment approaches. For example, strategies for using cationic liposomes with hyperthermia or magnetic fields have been evaluated. Drug-loaded cationic liposomes have been documented to induce tumor vascular defects, alter vascular function and limit the growth of the primary tumors and metastasis. In this review, we discuss general features of the endothelium as a function of its tissue environment. We discuss the rationale for targeting tumor vessels over the tumor interstitial matrix, and for the development of second generation cationic lipids and liposomes for tumor vascular targeting. We evaluate the benefits of incorporating the polymer polyethylene-glycol (PEG) in conventional and cationic liposomes for nonspecific and relatively vascular-specific tumor targeting, respectively. Finally, we review preclinical and clinical investigations evaluating drug-loaded cationic liposomes in cancer treatment.

Breast cancer is a major cause of cancer death in women worldwide. Breast cancer is a heterogeneous disease characterized by variant pathological features, disparate responses to therapeutics, and substantial differences in patient's long-term survival. The use of drug delivery systems such as liposomes can favorably alter the pharmacokinetic and biodistribution profile of commonly used drugs used to treat breast cancer disease. An important feature of a drug delivery system is its ability to recognize and selectively target tumor cells with relatively high affinity when compared to healthy tissues. For this reason, the goal of this study was to develop a novel nanoliposome system that would target tumor cells to a significantly greater extent when compared to more conventional liposome systems. In this study, natural lipids extracted directly from breast cancer cells were used to prepare cellular lipid-extracted nanoliposomes (CLENs). The rationale is that an array of different lipids with a unique composition profile would represent a more relevant source of lipid material when compared to more traditional methods of liposome preparation. We therefore investigated whether the inclusion of extracted lipids derived from breast cancer cells would improve the selective uptake of liposomes by breast cancer cells, and related formulation features. To achieve these goals, three breast cancer cell lines were used (4T1, BT-20, and SK-BR-3), a normal breast fibroblast (CRL-2089), and an ovarian cancer cell line (SK-OV-3- used as a negative control). The size of CLENs fell within the size range of 120- 203 nm and possessed a negatively-charged liposome surface charge potential (ranging between -10.97 and -20.97 mV). The nanoliposomes were also non-toxic to cells within the concentration range evaluated (up to 1μmol). Furthermore, without exception, the cellular uptake of CLENs was greatest when the extracted material used to prepare CLENs was the same as the target cell from which the lipids were extracted. In addition, when the breast cancer cell lines (4T1, SK-BR-3 and BT-20) were used to prepare CLENs, SK-OV-3 and CRL-2089 cell lines took up CLENs to a lesser extent, suggesting a more selective and differential cellular uptake. In conclusion, the novel nanoliposome platform represents a promising drug delivery alternative to more conventional nano drug delivery systems. Additional formulation studies are currently underway. Citation Format: Hanan M. Alharbi, Robert B. Campbell. Employing a unique panel of breast cancer cellular lipids extracts in the development of a novel nanoliposome drug platform. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5513. doi:10.1158/1538-7445.AM2015-5513

MUC1 is a transmembrane glycoprotein that is overexpressed in epithelial ovarian cancer. Due to extensive O-glycosylation, mucins form a physical barrier that limits the intracellular accumulation and cytotoxic effect of chemotherapeutic drugs. Our investigation represents a key step in determining if drug resistance in ovarian cancer develops due to altered MUC1 expression and glycosylation. Immunoblotting and ELISA techniques were utilized to characterize the extent of membrane-bound and shed MUC1 expression in drug-resistant and drug-sensitive ovarian cancer cells. An (anti-MUC1) antibody-based in vitro model was employed to determine if the inhibition of O-glycosylation enhanced functional access of small molecule drugs using FACS and fluorescence microscopic analyses. Expression of MUC1 was detected in both the drug resistant ovarian cancer cell line SK-OV-3 (MDR) and the parent cell line SK-OV-3 (WT), with the highest levels observed in the drug resistant sub-clone. The greatest improvement in functional anti-MUC1 antibody access following inhibition of O-glycosylation was observed in the drug-resistant ovarian cancer cells. Our results provide evidence to support drug resistance in ovarian cancer due in part to a mucin barrier mesh. The inhibition of mucin O-glycosylation may be a viable strategy to improve drug delivery and efficacy of small molecule delivery to ovarian carcinomas. Citation Format: Steven M. Richards, Robert B. Campbell. An evaluation of the role of Mucin in drug resistant ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4554. doi:10.1158/1538-7445.AM2015-4554

In 2014, an estimated 46,420 people will be diagnosed with pancreatic cancer in the United States, and approximately 39,590 will die from the disease. Gemcitabine has been established as the first-line treatment for advanced pancreatic cancer. However, this type of cancer has responded poorly to many therapeutic agents including gemcitabine, mainly due to inadequate drug accumulation at the desired tumor location and drug resistance. Liposomes represent a convenient method to deliver drugs to solid tumors. The drug carrier enhances the accumulation of the drug at the tumor site and has been shown to overcome drug resistance. Liposomes can direct the drug away from normal tissue and minimize unwanted drug side effects. However, more selective tumor targeting of cytotoxic drug-loaded liposomes to pancreatic tumors will further improve efficacy and will likely reduce toxicity. The present study investigated whether the inclusion of extracted lipids derived from pancreatic cancer cells would improve the selective uptake of liposomes by pancreatic cancer cells and formulation effects. We hypothesized that the inclusion of cell membrane lipid-extracted materials in the preparation of nanoliposomes will promote selective cellular uptake and improved cytotoxic drug effects. To test the hypothesis, two different pancreatic cancer cell lines were employed for the study (PANC-1 and Capan-2), and hTERT (a human immortalized normal pancreatic duct cell line) used as a healthy cell control. The human prostate (LNCap) and colorectal cancer (COLO-205) cell lines were used as negative controls. Various nanoliposome preparations were prepared and evaluated in terms of particle size, zeta potential and relative affinity of CLENs for target cells and fluorescence microscopy. The particle size of these nanoliposomes ranged between 92-176 nm and the zeta potential was negatively-charged (-14.07 and -34.95 mV). The Sulforhodamine B cell viability assay showed that CLENs was non-toxic to cells over the full concentration range evaluated when compared to conventional liposomes. The cellular uptake of the five different nanoliposome preparations was highest for the cell line from which the lipid material used to prepare CLENs was extracted (P0.05). Fluorescence microscopic analyses supported the cellular uptake studies. The incorporation of gemcitabine in CLENs may represent a promising approach for the treatment of pancreatic cancer. Cytotoxic drug studies with gemcitabine are currently underway. Citation Format: Taha Y. Alqahtani, Robert Campbell. Development and evaluation of cell membrane lipid-extracted nanoliposomes (CLENs) for the treatment of cancer using cellular models of human pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5528. doi:10.1158/1538-7445.AM2015-5528

Over the past few decades significant advances have been made in the development of nanopharmaceuticals (including phospholipid and polymer-based therapeutics) against cancer. There is still, however, room for improvement. Today, many researchers are focusing on the development of innovative approaches to selectively deliver drugs to solid tumors, while minimizing insult to healthy tissues. Unfortunately, the majority of these efforts are confronted by physiological barriers that reduce the clinical dose required to effectively manage the disease state. In an effort to develop promising nanopharmaceutical products of the future, we review the most important problems facing drug delivery experts today. We discuss here, the physiological role of solid tumors in delivery and transport of nanopharmaceutical products. The nature of tumors in terms of their unique anatomical structure and functions is also discussed. Finally, an overview of ways to overcome physiological barrier functions and exploit tumor pathogenesis for therapeutic gain is provided.

We have studied the feasibility of using the 3D fully electromagnetic implicit hybrid particle code LSP (Large Scale Plasma) to study laser plasma interactions with dense, compressed plasmas like those created with Z, and which might be created with the planned ZR. We have determined that with the proper additional physics and numerical algorithms developed during the LDRD period, LSP was transformed into a unique platform for studying such interactions. Its uniqueness stems from its ability to consider realistic compressed densities and low initial target temperatures (if required), an ability that conventional PIC codes do not possess. Through several test cases, validations, and applications to next generation machines described in this report, we have established the suitability of the code to look at fast ignition issues for ZR, as well as other high-density laser plasma interaction problems relevant to the HEDP program at Sandia (e.g. backlighting).

Background: Interstitial and vascular targeting with cytotoxic agents has proven to be an effective approach for cancer therapy (1). Ceramide, a sphingolipid, plays an important role in apoptosis, regulation of differentiation, growth suppression, and in cell senescence (2). Liposomes containing ceramide exert an anti-proliferative effect against the growth of tumor cells in vitro (3). In this study, we attempted to apply a rational approach to the development of ceramide liposomes for tumor targeting. Methods: We first determined the relative amounts of ceramide produced by cells normally found in the tumor interstitial matrix (ZR-75-1- human breast cancer cells), and by those lining tumor endothelia (HMEC-1 -human microvascular endothelial cells). For this experiment we measured sphingomyelinase activity. We next determined the cytotoxic effects of various liposome systems containing 0 to 20% ceramide (C6:1) content. The optimal ceramide content was determined from this study, and 2-methoxyestradiol (2-ME) was loaded in the optimal ceramide liposome preparation type. We next evaluated cytotoxic effects of the drug-loaded liposomes compared to ceramide liposomes alone. Results: ZR-75-1 cells showed a higher level of sphingomyelinase activity (4.4 fold) as compared to that of HMEC-1. The 20% ceramide formulation demonstrated the most significant anti-proliferative effect, regardless of the cell line. The cytotoxic drug effects were favorably influenced by the ceramide content. Finally, preliminary studies suggest that the overall effectiveness of ceramide liposomes against the growth of proliferating tumor cells correlated with the sphingomyelinase activity expressed by the target cells. Conclusion: Future studies will determine whether sphingomyelinase activity can be used to determine the population of cells (i.e., interstitial vs vascular) most likely to benefit from ceramide (cytotoxic) drug-loaded liposomes as a therapeutic approach. Citation Format: Shaohua Cheng, William Crall, Bryan Nguyen, Charles Dang, Musaed Alkholief, Robert B. Campbell. Development of ceramide liposomes for tumor interstitial and vascular drug targeting. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4473. doi:10.1158/1538-7445.AM2014-4473

We have developed magnetic nano-liposomes (MNL), incorporating superparamagnetic iron oxide nanoparticles (SPION), that are versatile theranostic nanoplatform for enhanced drug delivery and monitoring of cancer treatment. MNL are prepared with a formuation of DPPC:DOTAP:CHOL and DOPE-PEG5000. Incorporation of SPIONs results in MNL with mean diameter of 150-250 nm. MNL are easily taken up by B16-F10 melanoma, HUMVEC-D and breast cancer cell lines. They preferentially target the tumor vasculature as shown in a dorsal skin fold chamber using fluorescently labeled MNL. MNL display superparamagnetic response that is essential for magnetic targeting, MR contrast enhancement and magnetic heating. MNL was administrated to SCID mouse with metastatic (B16-F10) melanoma grown in the right flank. Pre-injection and post-injection MR images were used to assess response to magnetic targeting effects. Biodistribution studies were conducted by 111In labeled MNL and amount of radioactivity recovered was used to confirm the effect of targeting for intratumoral administrations. We have shown that tumor signal intensities in T2 weighted images decreased an average of 20±5% and T2* values decreased and average of 14±7ms in the absence of magnetic targeting. This compares to an average signal decrease of 57±12% and a decrease in T2* relaxation times of 27±8ms with the aid of external magnet showing up to 2-fold greater accumulation by magnetic targeting. 111In radio-labeled MNL have been shown to enable multi-modal imaging in vivo using MRI and SPeCT/CT. The images show that an MNL bolus injected intra-tumorally was retained in the tumor 24 hours after injection. Application of a magnetic field enables redistribution of the MNL in the tumor. These MNL are also responsive to ac magnetic fields applied using a Copper coil at 360 kHz and 170A driving current. Both hyperthermia (upto 45C) and thermo-ablative temperatures upto 90C were achieved in 10 – 30 minutes ex vivo in buffer. The results indicate high efficiency for magnetic heating using MNL (Specific Absorption Rate ∼ 104 W/kg) and demonstrate the capability to couple ac magnetic fields to MNL to achieve any set of temperatures needed for hyperthermia and thermal ablation. To date there are no truly theranostic platforms that have been approved for clinical use that combine targeting, thermal heating and MRI imaging capabilities. Existing FDA approved magnetic nanoparticle formulations like ferridex and ferumoxytol, are optimized for MR imaging, and have not been shown to be usable for thermal therapy.The MNL platform is a novel nanoplatform combining multi-modal imaging capabilities, with magnetic targeting and thermal therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 380. doi:10.1158/1538-7445.AM2011-380

Purpose: The development of non‐invasive imaging techniques for the assessment of cancer treatment is rapidly becoming highly important. Magnetic Cationic Liposomes (MCL) that carry a cargo of anti‐cancer drugs and magnetic nanoparticles that will selectively target primary and metastatic cancertumorsdeliver drugs to them and visualize their effects through magnetic resonance imaging(MRI)single photon emission computed tomography(SPECT) and fluorescence spectroscopy. The aim of the present study is to evaluate MCL as a versatile theranostic nanoplatform for enhanced drug deliveryimaging and monitoring of cancer treatment. Materials and Method: Poly‐ethyleneglycol (PEG) coated cationic liposomes are loaded with superparamagnetic iron oxide nanoparticles (SPIONS) and tagged with the radioisotope Indium‐111. MCL was administered to SCID mouse with metastatic (B16‐F10) melanoma grown in the right flank. Pre‐injection and post‐injection MR and SPECT/CT images were used to assess response to magnetic targeting effects and tumor and organ distribution. Results:Tumor signal intensities in T2 weighted images decreased an average of 20±5% and T2* values decreased and average of 14±7ms in the absence of magnetic targeting. This compares to an average signal decrease of 57±12% and a decrease in T2* relaxation times of 27±8ms with the aid of external magnet showing up to 2‐fold greater accumulation by magnetic targeting. SPECT/CT images showed the localization and distribution of MCL in the tumor.Conclusion: MR SPECT/CT and biodistribution analyses clearly show the efficacy of MCL as MRI contrast agents prove the use of magnetic guidance and demonstrate the potential of MCL as agents for imaging guidance and therapeutic delivery.

Achieving a high degree of radiation symmetry is a critical feature of target designs for indirect-drive inertial confinement fusion. Typically, the radiation flux incident on the capsule is required to be uniform to 1% or better. It is generally possible to design a hohlraum that provides low values of higher-order asymmetry (Legendre mode P10 and above) due to geometric averaging effects. Because low-order intrinsic asymmetry (e.g., Legendre modes P2 and P4) are less strongly reduced by geometric averaging alone, the development of innovative control techniques has been an active area of research in the inertial fusion community over the years. Shields placed inside the hohlraum are one example of a technique that has often been proposed and incorporated into hohlraum target designs. Simple mathematical considerations are presented indicating that radiation shields may be designed to specifically tune lower-order modes (e.g., P4) without deleterious effects on the higher order modes. Two-dimensional vie...

Silicon carbide has been used extensively as an abrasive, but only in the last 25 years has its potential as a semiconductor been exploited. The rationale for SiC semiconductor devices is their high temperature performance. Rectifiers, field effect transistors, charged particle detectors, and other devices operate efficiently at temperatures about 800 K.

• A reproducible model of severe herpetic interstitial keratitis was developed by injecting live herpes simplex virus type 2 intrastromally into the corneas of presensitized rabbits. Herpes-infected corneas showed significantly more stromal infiltration and vascularization, iritis, conjunctivitis, and epithelial disease than the control corneas injected with cell supernatant without virus. Levels of total collagenase detected in the culture media of the herpes-infected corneas were high and were similar to those observed previously in alkali-burned rabbit corneas. Unlike alkali-burned corneas, the herpes-infected corneas showed much more of the enzyme in the latent form during the first two days of culture.

In a masked controlled study we compared 3% acycloguanosine, 0.5% idoxuridine, and 3% vidarabine ointments in therapy of experimental herpes simplex virus keratitis in rabbits. The results of the acycloguanosine group were significantly better than the control groups and both other treatment groups, while producing none of the toxic side effects of increasing iritis, conjunctivitis or stromal keratitis, with continued drug application.

Publisher Summary Silicon carbide (SiC) is perhaps the oldest semiconductor. Although in the last fifty years considerable use has been made of its abrasive properties, only in the past fifteen years has its potentialities as a semiconductor been exploited. The chapter discusses that Sic devices have distinct properties that lead to specific applications: they are operable up to 500oC, they have enhanced radiation resistance, and certain particular characteristics (example, band gap) lead to specific device applications. Applications in these areas determine the final utilization of Sic devices. The future development of Sic devices probably depends more on engineering perseverence than on semiconductor physics breakthrough.. The sophisticated active devices and integrated circuits now being prepared from silicon will be prepared from Sic when suitable crystals are available and the fabrication techniques are refined.

• The present, masked, controlled study compares the therapeutic efficacy of guttate 3% vidarabine, 0.1% idoxuridine, and 1% trifluridine in herpes simplex keratouveitis in rabbits. Vidarabine, whether given every hour, every two hours, or every three hours was significantly better than controls but significantly worse than idoxuridine or trifluridine. Trifluridine and idoxuridine were not significantly different from each other. Viral cultures taken at the end of the six-day treatment period were positive in the majority of all treatment groups except for the trifluridine group, which was 100% negative. Although previous studies have shown that vidarabine is very effective as an antiviral ointment, vidarabine drops are not as effective as guttate idoxuridine or trifluridine.