Dual Enhancement in the Radiosensitivity of Prostate Cancer Through Nanoparticles and Chemotherapeutics

BACKGROUND: Radiotherapy (RT) is an essential component in the treatment regimens for many cancer patients. However, the dose escalation required to improve curative results is hindered due to the normal tissue toxicity that is induced. The introduction of radiosensitizers to RT treatment is an avenue that is currently being explored to overcome this issue. By introducing radiosensitizers into tumor sites, it is possible to preferentially enhance the local dose deposited. Gold nanoparticles (GNPs) are a potential candidate that have shown great promise in increasing the radiosensitivity of cancer cells through an enhancement in DNA damage. Furthermore, docetaxel (DTX) is a chemotherapeutic agent that arrests cells in the G2/M phase of the cell cycle, the phase most sensitive to radiation damage. We hypothesized that by incorporating DTX to GNP-enhanced radiotherapy treatment, we could further improve the radiosensitization experienced by cancer cells. To assess this strategy, we analyzed the radiotherapeutic effects on monolayer cell cultures in vitro, as well as on a mice prostate xenograft model in vivo while using clinically feasible concentrations for both GNPs and DTX. RESULTS: The introduction of DTX to GNP-enhanced radiotherapy further increased the radiotherapeutic effects experienced by cancer cells. A 38% increase in DNA double-strand breaks was observed with the combination of GNP/DTX vs GNP alone after a dose of 2 Gy was administered. In vivo results displayed significant reduction in tumor growth over a 30-day observation period with the treatment of GNP/DTX/RT when compared to GNP/RT after a single 5 Gy dose was given to mice. The treatment strategy also resulted in 100% mice survival, which was not observed for other treatment conditions. CONCLUSIONS: Incorporating DTX to work in unison with GNPs and RT can increase the efficacy of RT treatment. Our study suggests that the treatment strategy could improve tumor control through local dose enhancement. As the concentrations used in this study are clinically feasible, there is potential for this strategy to be translated into clinical settings

Interventions for treating cholestasis in pregnancy

BACKGROUND Obstetric cholestasis has been linked to adverse maternal and fetal/neonatal outcomes. As the pathophysiology is poorly understood, therapies have been empiric. The first version of this review, published in 2001, and including nine randomised controlled trials involving 227 women, concluded that there was insufficient evidence to recommend any of the interventions alone or in combination. This is the first update. OBJECTIVES To evaluate the effectiveness and safety of therapeutic and delivery interventions in women with cholestasis of pregnancy. SEARCH METHODS We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (20 February 2013) and reference lists of identified studies. SELECTION CRITERIA Randomised controlled trials that compared two intervention strategies for women with a clinical diagnosis of obstetric cholestasis. DATA COLLECTION AND ANALYSIS The review authors independently assessed trials for eligibility and risk of bias. We independently extracted data and checked these for accuracy. MAIN RESULTS We included 21 trials with a total of 1197 women. They were mostly at moderate to high risk of bias. They assessed 11 different interventions resulting in 15 different comparisons. Compared with placebo, ursodeoxycholic acid (UDCA) showed improvement in pruritus in five (228 women) out of seven trials. There were no significant differences in instances of fetal distress in the UDCA groups compared with placebo (average risk ratio (RR) 0.67; 95% confidence interval (CI) 0.22 to 2.02; five trials, 304 women; random-effects analysis: T² = 0.74; I² = 48%). There were significantly fewer total preterm births with UDCA (RR 0.46; 95% CI 0.28 to 0.73; two trials, 179 women). The difference for spontaneous preterm births was not significant (RR 0.99; 95% CI 0.41 to 2.36, two trials, 109 women). Two trials (48 women) reported lower (better) pruritus scores for S-adenosylmethionine (SAMe) compared with placebo, while two other trials of 34 women reported no significant differences between groups. UDCA was more effective in improving pruritus than either SAMe (four trials; 133 women) or cholestyramine (one trial; 84 women), as was combined UDCA+SAMe when compared with placebo (one trial; 16 women) and SAMe alone (two trials; 68 women). However, combined UDCA+SAMe was no more effective than UDCA alone in regard to pruritus improvement (one trial; 53 women) and two trials (80 women) reported data were insufficient to draw any conclusions from. In one trial comparing UDCA and dexamethasone (83 women), a significant improvement with UDCA was seen only in a subgroup of women with severe obstetric cholestasis (23 women). Danxiaoling significantly improved pruritus in comparison to Yiganling. No significant differences were seen in pruritus improvement with other interventions. Eight trials reported fetal or neonatal deaths, with two deaths reported overall (both in the placebo groups). Women receiving UDCA and cholestyramine experienced nausea, vomiting and diarrhoea. Guar gum caused mild abdominal distress, diarrhoea and flatulence during the first days of treatment. Women found charcoal suspension unpleasant to swallow. Dexamethasone caused nausea, dizziness and stomach pain in one woman. One trial (62 women) looked at the timing of delivery intervention. There were no stillbirths or neonatal deaths in 'early delivery' or the 'await spontaneous labour' group. There were no significant differences in the rates of caesarean section, meconium passage or admission to neonatal intensive care unit between the two groups. AUTHORS' CONCLUSIONS Different approaches to assessing and reporting pruritus precluded pooling of trials comparing the effects of UDCA versus placebo on pruritus, but examination of individual trial s suggests that UDCA significantly improves pruritus, albeit by a small amount. Fewer instances of fetal distress/asphyxial events were seen in the UDCA groups when compared with placebo but the diff...Gurung V, Middleton P, Milan SJ, Hague W, Thornton J

Three-Dimensional Tumor Spheroids as a Tool for Reliable Investigation of Combined Gold Nanoparticle and Docetaxel Treatment

Radiotherapy and chemotherapy are the gold standard for treating patients with cancer in the clinic but, despite modern advances, are limited by normal tissue toxicity. The use of nanomaterials, such as gold nanoparticles (GNPs), to improve radiosensitivity and act as drug delivery systems can mitigate toxicity while increasing deposited tumor dose. To expedite a quicker clinical translation, three-dimensional (3D) tumor spheroid models that can better approximate the tumor environment compared to a two-dimensional (2D) monolayer model have been used. We tested the uptake of 15 nm GNPs and 50 nm GNPs on a monolayer and on spheroids of two cancer cell lines, CAL-27 and HeLa, to evaluate the differences between a 2D and 3D model in similar conditions. The anticancer drug docetaxel (DTX) which can act as a radiosensitizer, was also utilized, informing future potential of GNP-mediated combined therapeutics. In the 2D monolayer model, the addition of DTX induced a small, non-significant increase of uptake of GNPs of between 13% and 24%, while in the 3D spheroid model, DTX increased uptake by between 47% and 186%, with CAL-27 having a much larger increase relative to HeLa. Further, the depth of penetration of 15 nm GNPs over 50 nm GNPs increased by 33% for CAL-27 spheroids and 17% for HeLa spheroids. These results highlight the necessity to optimize GNP treatment conditions in a more realistic tumor-life environment. A 3D spheroid model can capture important details, such as different packing densities from different cancer cell lines, which are absent from a simple 2D monolayer model

Three dimensional spheroids and gold nanoparticles in combined cancer therapy

One of the major issues in cancer radiotherapy (RT) is normal tissue toxicity. Introduction of radiosensitizers like gold nanoparticles (GNPs) into cancer cells to enhance the local RT dose is a promising technique that is being explored. However, a large portion of experimentation involving GNPs has been done in simple two-dimensional (2D) monolayer models that cannot properly encapsulate the complex heterogeneous interactions that occur in vivo. By introducing an in vitro three-dimensional (3D) model that better mimics the tumour microenvironment (TME), we can more rapidly facilitate a quicker translation of various treatment technologies like GNPs to the clinic. Further, clinical trials show that the chemotherapy drug docetaxel (DTX) given in conjunction with RT can improve survival in high-risk cancers. Addition of GNPs to this current DTX/RT protocol is expected to further improve therapeutic benefits. Elucidation of a combined therapy of GNPs, DTX, and RT to optimize treatment can better improve patient outcome and reduce normal tissue toxicity by specifically targeting tumours and is completely novel research. The work in this dissertation explores the application of GNPs to various elements that are present in a TME. Many cell types are present in TME and contribute in different ways to the proliferation of cancer. One of these cell lines, cancer associated fibroblasts (CAFs), which can promote tumour growth and metastasis, was compared to cancer epithelial cells and normal fibroblasts (FBs). Hence, we used FBs and CAFs to evaluate the differences in GNP uptake and resulting radiation induced damage. It was found that the CAFs had a much larger uptake of GNPs relative to the other cells, with on average 265% more GNPs relative to cervical cancer cells while FBs had only 7.55% the uptake of the tumour cells and 2.87% the uptake of CAFs. This translated to increases in 53BP1-related DNA damage foci in CAFs (13.5%) and tumour cells (9.8%) along with FBs (8.8%), compared to control with RT treatment. This difference in DNA damage due to selective targeting of cancer associated cells over normal cells may allow GNPs to be an effective tool in future cancer RT to battle normal tissue toxicity while improving local RT dose to the tumour. To expedite a quicker clinical translation, 3D tumor spheroid models were optimized and compared to 2D monolayer. The uptake of various sizes of GNPs was tested on monolayer and spheroids to evaluate the differences between a 2D and 3D model in similar conditions. Moreover, combined treatment of GNPs with DTX was introduced and how they effect the uptake of the GNPs was elucidated.iv In the 2D monolayer model, the addition of DTX induced a small increase of uptake of GNPs of between 13% and 24%, while in the 3D spheroid model, DTX increased uptake by between 47% and 186%. It was observed that the more complex spheroid, which introduces an extracellular matrix, had larger uptake and penetration of smaller GNPs (15 nm) relative to larger GNPs (50 nm). Moreover, while the addition of DTX had a beneficial effect on the uptake of GNPs into cells, it also synchronized the cells into a radiosensitive cell cycle phase. This translated to a larger effect when radiation was introduced, in a combined treatment modality with GNP, DTX, and RT. In spheroids, the addition of GNPs to the treatment regime decreased the surviving tumour cells by 16-32% compared to samples not treated with GNPs. Further, the addition of DTX seems to synergistically increase damage in some cancer cell lines. This work highlights the necessity to optimize GNP treatment conditions in a more realistic tumor-like environment. A 3D spheroid model can capture important details which are absent from a simple 2D monolayer model.Graduat

Lionel Hampton in Sweden

7 x 5 inch photograph. Bill Titone [in Sweden]300 dpi compressed jpg is displayed. Epson Expression 1640 XL Scanner, Epson TWAIN Pro, Adobe Photoshop 7.0, Archival Master file is a TIFF

Lionel Hampton in Sweden

5 x 7 inch photograph. Lionel Hampton, Bill Titone, and unidentified woman in a restaurant, [in Sweden]300 dpi compressed jpg is displayed. Epson Expression 1640 XL Scanner, Epson TWAIN Pro, Adobe Photoshop 7.0, Archival Master file is a TIFF

Advances in Gold Nanoparticle-Based Combined Cancer Therapy

According to the global cancer observatory (GLOBOCAN), there are approximately 18 million new cancer cases per year worldwide. Cancer therapies are largely limited to surgery, radiotherapy, and chemotherapy. In radiotherapy and chemotherapy, the maximum tolerated dose is presently being used to treat cancer patients. The integrated development of innovative nanoparticle (NP) based approaches will be a key to address one of the main issues in both radiotherapy and chemotherapy: normal tissue toxicity. Among other inorganic NP systems, gold nanoparticle (GNP) based systems offer the means to further improve chemotherapy through controlled delivery of chemotherapeutics, while local radiotherapy dose can be enhanced by targeting the GNPs to the tumor. There have been over 20 nanotechnology-based therapeutic products approved for clinical use in the past two decades. Hence, the goal of this review is to understand what we have achieved so far and what else we can do to accelerate clinical use of GNP-based therapeutic platforms to minimize normal tissue toxicity while increasing the efficacy of the treatment. Nanomedicine will revolutionize future cancer treatment options and our ultimate goal should be to develop treatments that have minimum side effects, for improving the quality of life of all cancer patients.</jats:p

Advances in Gold Nanoparticle-Based Combined Cancer Therapy

According to the global cancer observatory (GLOBOCAN), there are approximately 18 million new cancer cases per year worldwide. Cancer therapies are largely limited to surgery, radiotherapy, and chemotherapy. In radiotherapy and chemotherapy, the maximum tolerated dose is presently being used to treat cancer patients. The integrated development of innovative nanoparticle (NP) based approaches will be a key to address one of the main issues in both radiotherapy and chemotherapy: normal tissue toxicity. Among other inorganic NP systems, gold nanoparticle (GNP) based systems offer the means to further improve chemotherapy through controlled delivery of chemotherapeutics, while local radiotherapy dose can be enhanced by targeting the GNPs to the tumor. There have been over 20 nanotechnology-based therapeutic products approved for clinical use in the past two decades. Hence, the goal of this review is to understand what we have achieved so far and what else we can do to accelerate clinical use of GNP-based therapeutic platforms to minimize normal tissue toxicity while increasing the efficacy of the treatment. Nanomedicine will revolutionize future cancer treatment options and our ultimate goal should be to develop treatments that have minimum side effects, for improving the quality of life of all cancer patients.The authors would like to acknowledge Canada Foundation for Innovation (CFI), the British Columbia government, Natural Sciences and Engineering Research Council of Canada (NSERC), British Columbia Cancer, Vancouver Island (BCC), Centre for Advanced Materials and Related Technologies (CAMTEC), and University of Victoria for their financial support.FacultyReviewe