Background:Heparin, a polydisperse glycosaminoglycan, is well-known for its anticoagulant activity and clinical use in preventing venous thromboembolism. In addition to coagulation, heparin and its derivatives have shown therapeutic potential in cancer and infectious, inflammatory, and neurodegenerative diseases. This study aimed to develop and evaluate heparin-capped AgNPs (hep-AgNPs) as multifunctional nanotherapeutics with selective cytotoxicity, antibacterial, and antifungal activity. Methods:Heparin was covalently conjugated to cysteamine-terminated silver nanoparticles via MES-buffer-mediated amide coupling, providing a mild, aqueous alternative to conventional DMF-based methods. The nanoparticles were characterised by UV-Vis spectroscopy, Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), dynamic light scattering (DLS), scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX) analyses. The colloidal stability was assessed over a broad range of pH values. The biological performance of hep-AgNPs was evaluated in vitro against a triple-negative breast cancer (TNBC) cell line (MDA-MB-231), a double-positive cell line (MCF-7), and normal breast cells (MCF-10A), and microbial strains, including Salmonella typhimurium, E. coli, Aspergillus fumigatus, and Candida albicans. Results:The synthesised hep-AgNPs exhibited high yield, effective heparin surface functionalization, and excellent colloidal stability at physiological pH, with stability systematically assessed across a broad pH range. Hep-AgNPs demonstrated time and concentration-dependent selective cytotoxicity, toward breast cancer cells, including MCF-7 and triple-negative MDA-MB-231, with a favourable selectivity index (>1) compared to MCF-10A cells, and the strongest selectivity observed in the TNBC model at 48 h. In addition, hep-AgNPs showed potent antibacterial activity (IC50 = 24.3 µg/mL) and antifungal activity (IC50 = 6.2 µg/mL for A. fumigatus and 24.43 µg/mL for C. albicans). In addition, they exhibit strong biocompatibility with keratinocytes and fibroblasts. Conclusion:Heparin-capped silver nanoparticles combine the biological functionality of heparin with the antimicrobial and selective cytotoxic properties of the silver nanoparticles. Their selective cytotoxicity, antimicrobial efficacy, and favourable cellular interaction profiles highlight their potential as multifunctional nanoplatforms for applications such as chronic wound management in neutral to alkaline wound environments, and dose-controlled, targeted therapeutic strategies relevant to aggressive cancer models, including TNBC.

Human studies have shown the anticancer effects of dietary isothiocyanates (ITCs), but there are some inconsistencies, and more evidence supports that such anticancer effect is from higher doses of ITCs. The inconsistencies found in epidemiological studies may be due to many factors, including the biphasic dose-response (so called hormetic effect) of ITCs, which was found to be more profound under hypoxia conditions. In this comprehensive review, we aim to shed light on the intriguing synergistic interactions between dietary ITCs, focusing on sulforaphane (SFN) and various anticancer drugs. Our exploration is motivated by the potential of these combinations to enhance cancer management strategies. While the anticancer properties of ITCs have been recognized, our review delves deeper into understanding the mechanisms and emphasizing the significance of the hormetic effect of ITCs, characterized by lower doses stimulating both normal cells and cancer cells, whereas higher doses are toxic to cancer cells and inhibit their growth. We have examined a spectrum of studies unraveling the multifaceted interaction and combinational effects of ITCs with anticancer agents. Our analysis reveals the potential of these synergies to augment therapeutic efficacy, mitigate chemoresistance, and minimize toxic effects, thereby opening avenues for therapeutic innovation. The review will provide insights into the underlying mechanisms of action, for example, by spotlighting the pivotal role of Nrf2 and antioxidant enzymes in prevention. Finally, we glimpse ongoing research endeavors and contemplate future directions in this dynamic field. We believe that our work contributes valuable perspectives on nutrition and cancer and holds promise for developing novel and optimized therapeutic strategies.

Triple-negative breast cancer (TNBC) presents a therapeutic challenge due to its complex pathology and limited treatment options. Addressing this challenge, our study focuses on the effectiveness of combination therapy, which has recently become a critical strategy in cancer treatment, improving therapeutic outcomes and combating drug resistance and metastasis. We explored a novel combination therapy employing Benzyl isothiocyanate (BITC) and Sorafenib (SOR) and their nanoformulation, aiming to enhance therapeutic outcomes against TNBC. Through a series of in vitro assays, we assessed the cytotoxic effects of BITC and SOR, both free and encapsulated. The BITC–SOR-loaded nanoparticles (NPs) were synthesized using an amphiphilic copolymer, which demonstrated a uniform spherical morphology and favorable size distribution. The encapsulation efficiencies, as well as the sustained release profiles at varied pH levels, were quantified, revealing distinct kinetics that were well-modeled by the Korsmeyer–Peppas equation. The NP delivery system showed a marked dose-dependent cytotoxicity towards TNBC cells, with an IC50 of 7.8 μM for MDA-MB-231 cells, indicating improved efficacy over free drugs, while exhibiting minimal toxicity toward normal breast cells. Furthermore, the NPs significantly inhibited cell migration and invasion in TNBC models, surpassing the effects of free drugs. These findings underscore the potential of BITC–SOR-NPs as a promising therapeutic approach for TNBC, offering targeted delivery while minimizing systemic toxicity.

Silver nanoparticles (AgNPs) demonstrate potential in treating aggressive cancers such as triple-negative breast cancer (TNBC) in preclinical models. To further the development of AgNP-based therapeutics for clinical use, it is essential to clearly define the specific physicochemical characteristics of the nanoparticles and connect these properties to biological outcomes. This study addresses this knowledge gap through detailed investigations into the structural and surface functional relationships, exploring the mechanisms, safety, and efficacy of AgNPs in targeting TNBC. The surface functionality of nanoparticles is crucial not only for their internalization into cancer cells but also for enhancing their toxicity toward tumor cells. Although the nanoparticles internalized into cancer cells, they failed to exhibit their full toxicity against the cancer. Herein we report a solvent-assisted synthesis amine, mercaptohexanol and bifunctional silver nanoparticles and performing comparative study to understand their selectivity and toxicity toward TNBC cells. The nanoparticles are fully characterized by UV–visible absorption spectroscopy, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and dynamic light scattering measurement (DLS). The synthesis method achieves an extremely high yield and surface coating ratio of synthesized colloidal AgNPs. Our findings reveal that the amine-capped AgNPs exhibit significant selective toxicity against TNBC cell lines MCF7 and MDA-MB-231 at a concentration of 40 µg/mL without affecting normal breast cell lines MCF10A. This study underscores the potential of functionalized AgNPs in developing safe and targeted therapeutic approaches for treating aggressive cancers like TNBC, laying the groundwork for future clinical advancements.

Due to the chemodynamic and photothermal effects, cobalt sulfide quantum dots (CoS QDs) have a promising application prospect in tumor therapy. However, poor targeting and non-specific uptake limit their clinical application. To address these problems, a dual-targeting peptide/exosome/CoS QDs (PEP/Exo/CoS) was constructed to treat bladder cancer comprehensively. CoS QDs were firstly loaded into mesenchymal stem cellderived exosomes by electrotransfection method. Transmission electron microscope and nano-flow cytometry showed that the diameter of exosome/CoS QDs was 50-120 nm. We further found that exosome/CoS QDs had excellent photothermal effects and stability, similar to CoS QDs. We then designed a dual-targeting peptide that can specifically bind both exosomes and bladder cancer cells. Targeting peptide modification promoted the specific binding of exosome/CoS QDs and delivery into cancer cells. Cell experiments showed that PEP/Exo/CoS specifically induced the increase of reactive oxygen species (ROS) concentration in bladder cancer cells, but had no significant effect on transitional epithelial cells. In vitro and in vivo results demonstrated that PEP/Exo/CoS enabled remarkable anticancer properties through chemodynamic and photothermal effects. Moreover, PEP/ Exo/CoS can significantly reduce the damage of CoS QD to normal tissues under laser irradiation. Our study provided a new method for the comprehensive treatment of advanced bladder cancer.

Background The goal of US Department of Agriculture Supplemental Nutrition Assistance Program-Education (SNAP-Ed) is to improve the likelihood that those eligible for SNAP will make healthy choices aligned with the Dietary Guidelines for Americans, 2020-2025.Objective The objective of the study was to evaluate the long-term effects of a direct SNAP-Ed intervention in which participants actively engage in learning with educator instruction about dietary quality and usual intake of key nutrient and food groups among Indiana SNAP-Ed-eligible women participants as an example sample in the context of no similar existing evaluation.Design The study design was a parallel-arm, randomized controlled, nutrition educa-tion intervention, with follow-up at 1 year. Participants/setting Participants (18 years and older; n = 97 women) eligible for SNAP-Ed and interested in receiving nutrition education lessons were recruited from 31 Indiana counties from August 2015 to May 2016 and randomized to an intervention (n = 53) or control (n = 44) group.ntervention The intervention comprised core lessons of Indiana SNAP-Ed delivered between 4 and 10 weeks after baseline assessment. Each participant completed a baseline and 1-year follow-up assessment. Dietary intake was assessed using repeated 24-hour dietary recalls (up to 2).Main outcome measures Mean usual nutrient, food group intake, diet quality (ie, Healthy Eating Index-2010 scores), and proportion of intervention and control groups meeting Dietary Guidelines for Americans, 2020-2025 recommendations and Dietary Reference Intake indicators of requirement or adequacy, were determined using the National Cancer Institute method and the simple Healthy Eating Index-2010 scoring algorithm method. Dietary changes between intervention and control groups were examined over time using mixed linear models.Statistical analyses performed Bonferroni-corrected significance levels were applied to the results of the mixed linear models for comparisons of usual intake of nutrients and foods.Results No differences in diet quality, intake of food group components, food group intake, or nutrients were observed at 1-year follow-up, except that vitamin D intake was higher among those who received SNAP-Ed compared with the control group.Conclusions A direct SNAP-Ed intervention did not improve diet quality, food group intake, or key nutrient intake, except for vitamin D, among Indiana SNAP-Ed-eligible women up to 1 year after the nutrition education.

Stochastic differential equations (SDEs) or diffusions are continuous-valued continuous-time stochastic processes widely used in the applied and mathematical sciences. Simulating paths from these processes is usually an intractable problem, and typically involves time-discretization approximations. We propose an exact Markov chain Monte Carlo sampling algorithm that involves no such time-discretization error. Our sampler is applicable to the problem of prior simulation from an SDE, posterior simulation conditioned on noisy observations, as well as parameter inference given noisy observations. Our work recasts an existing rejection sampling algorithm for a class of diffusions as a latent variable model, and then derives an auxiliary variable Gibbs sampling algorithm that targets the associated joint distribution. At a high level, the resulting algorithm involves two steps: simulating a random grid of times from an inhomogeneous Poisson process, and updating the SDE trajectory conditioned on this grid. Our work allows the vast literature of Monte Carlo sampling algorithms from the Gaussian process literature to be brought to bear to applications involving diffusions. We study our method on synthetic and real datasets, where we demonstrate superior performance over competing methods.

Background: Canine mammary carcinoma is common in female dogs, and its poor prognosis remains a serious clinical challenge, especially in developing countries. Benzyl isothiocyanate (BITC) has attracted great interest because of its inhibitory effect against tumor activity. However, its effect and the underlying mechanisms of action in canine mammary cancer are not well-understood. Here, we show that BITC suppresses mammary tumor growth, both in vivo and in vitro, and reveal some of the potential mechanisms involved. Methods: The effect of BITC on canine mammary cancer was evaluated on CIPp and CMT-7364, canine mammary carcinoma lines. The cell lines were treated with BITC and then subjected to wound healing and invasion assays. Cell cycles and apoptosis were measured using flow cytometry; TUNEL assay; immunohistochemistry (IHC) for caspase 3, caspase 9, and cyclin D1; hematoxylin and eosin (H&E) staining; and/or quantitative polymerase chain reaction (qPCR). Results: BITC showed a strong suppressive effect in both CIPp and CMT-7364 cells by inhibiting cell growth in vitro; these effects were both dose- and time-dependent. BITC also inhibited migration and invasion of CIPp and CMT-7364 cells. BITC induced G2 arrest and apoptosis, decreasing tumor growth in nude mice by downregulation of cyclin B1 and Cdk1 expression. Conclusion: BITC suppressed both invasion and migration of CIPp and CMT-7364 cells and induced apoptosis. BITC inhibited canine mammary tumor growth by suppressing cyclinB1 and Cdk1 expression in nude mice.

The functionalisation of silicon nanoparticles with a terminal thiocyanate group, producing isothiocyanate-capped silicon nanoparticles (ITC-capped SiNPs) has been successfully attained. The procedure for the synthesis is a two-step process that occurs via thermally induced hydrosilylation of hydrogen terminated silicon nanoparticles (H-SiNPs) and further reaction with potassium thiocyanate (KSCN). The synthesis was confirmed by Fourier transform infrared (FTIR) spectroscopy and X-Ray photoelectron spectroscopy (XPS). At the same time, the internalisation and the cytotoxicity of the ITC-capped SiNPs in vitro were assessed in two cell lines: Caco-2, human colorectal cancer cells and CCD-841, human colon "normal" cells. The results showed that above concentrations of 15 µg ml-1, the cell viability of both cell lines was depleted significantly when treated with ITC SiNPs, particularly over a 48 hour period, to approximately 20% cell viability at the highest treatment concentration (70 µg ml-1). Flow cytometry was employed to determine cellular uptake in Caco-2 cells treated with ITC SiNPs. It was observed that at lower SiNP concentrations, uptake efficiency was significantly improved for time periods under 12 hours; overall it was noted that cellular uptake was positively dependent on the period of incubation and the temperature of incubation. As such, it was concluded that the mechanism of uptake of ITC SiNPs was through endocytosis. Synchrotron FTIR spectroscopy, by means of line spectral analysis and IR imaging, provided further evidence to suggest the internalisation of ITC SiNPs displays a strong localisation, with an affinity for the nucleus of treated Caco-2 cells.

Background Food security and socioeconomic status have been associated with diet quality. Supplemental Nutrition Assistance Program‐Education (SNAP‐Ed) aims to improve the diet quality of low resource populations; however, little is known about the association of food security status with diet quality in the SNAP‐Ed eligible population. Objective The objective of this study was to determine whether food security status is associated with diet quality in a sample of Indiana SNAP‐Ed eligible adult participants. Methods SNAP‐Ed eligible adults age ≥18 y ( n = 261) from 31 Indiana counties were recruited to participate from August 2015 to May 2016. Baseline food security score was assigned for household adults using the 10‐item United States Household Food Security Survey Module and used to classify participants as food secure (0–2) or food insecure (3–10). Baseline Healthy Eating Index‐2010 (HEI‐2010) score was assigned using dietary data collected from the National Cancer Institute Automated Self‐Administered 24‐Hour Recall Tool (2014 version with 1–2 days of recalls per participant). A generalized linear regression model was used to estimate the association between food security status and HEI‐2010 score for this cross‐sectional study. Results Food security status is significantly associated with total HEI‐2010 score (β = 4.7; p = 0.01) at baseline. The mean total HEI‐2010 score was 45.1 ± 14.0 (Mean ± SD) for food secure participants ( n = 68) and 40.4 ± 12.1 (Mean ± SD) for food insecure participants ( n = 139). Conclusion Diet quality is lower in food insecure SNAP‐Ed eligible Indiana adults compared with their food secure counterparts. There is a strong need for nutrition interventions to improve diet quality, particularly targeting food insecure audiences within in low‐resource populations. Support or Funding Information This activity was funded, by Purdue, as part of AgSEED Crossroads funding to support Indiana's Agriculture and Rural Development and the Purdue Health and Human Sciences Cooperative Extension Nutrition Education Program.

Sphingosine kinases 1 and 2 (SK1 and SK2) are proto-oncogenic isozymes expressed in many human tumors and associated with chemoresistance and poor prognosis. They are well-recognized therapy targets and their inhibition was shown to induce tumor volume reduction and chemosensitization in multiple cancer models. Oncogenic signaling is extremely complex and often cross-regulated. Designing molecular therapies and their combinations requires rational approaches to avoid redundant targeting or developing resistance. In this study, we have performed RNA transcriptome microarray analysis of two breast and two prostate metastatic cancer cell lines treated with siRNAs targeting SK1 or SK2. In prostate cancer cell lines SK1 knockdown (KD) has significantly changed expression of several genes including downregulation of NSUN2, G3BP2 and upregulation of ETS1. SK2 KD also affected expression of multiple genes including downregulation of CAPZA1 NSUN3 and ADPGK and upregulation of VDAC1, IBTK, ETS1, and MKNK2. Similarly, in breast cancer cells SK1 KD led to downregulation of NSUN2, NFATC3, CDK2, and G3BP2 and upregulation of GTF2B, TTC17, and RAB23. SK2 KD in breast cancer cells has decreased expression of ITGAV and CAPZA1 and increased expression of GTF2B and ST13. Gene-set enrichment analysis of known biochemical pathways showed that in prostate and breast cell lines SKs KD have altered multiple pathways. SK1 KD altered chromatin assembly, regulation of G1/S transition and mitosis, Wnt and MAP kinase signaling and cell motility. SK2 KD altered RAS protein signal transduction, regulation of MAP kinase and serine/threonine kinase activity, cell motility, small GTPase mediated signal transduction and phosphatidylinositol 3-kinase (PI3K) signaling. Through genome-wide microarray analysis, we have identified important molecular pathways affected by SK1 and SK2 KD. It appears that while KD of both genes leads to a decrease in individual pro-tumorigenic genes, there is a universal cellular response resulting in upregulation of several known pro-survival and pro-tumorigenic pathways such as MAPK, RAS, and PI3K, which may mediate cancer resistance to anti-SKs therapies. Our data point out to the potential advantage of certain molecular therapy combinations in targeting prostate and breast cancer. Further signaling studies are required to confirm the individual involvement of identified pathways.

Funding for this research was provided by Purdue University as part of AgSEED Crossroads funding to support Indiana's Agriculture and Rural Development, Purdue University Frederick N. Andrews Fellowship, Purdue University Center for Families Justice Family Nutrition Award, the Purdue University Nutrition Education Program, and a USDA NIFA Hatch Project.

Allyl isothiocyanate (AITC), a dietary phytochemical in some cruciferous vegetables, exhibits promising anticancer activities in many cancer models. However, previous data showed AITC to have a biphasic effect on cell viability, DNA damage and migration in human hepatoma HepG2 cells. Moreover, in a 3D co-culture of HUVEC with pericytes, it inhibited tube formation at high doses but promoted this at low doses, which confirmed its biphasic effect on angiogenesis. siRNA knockdown of Nrf2 and glutathione inhibition abolished the stimulation effect of AITC on cell migration and DNA damage. The biological activity of a novel AITC-conjugated silicon quantum dots (AITC-SiQDs) has been investigated for the first time. AITC-SiQDs showed similar anti-cancer properties to AITC at high doses while avoiding the low doses stimulation effect. In addition, AITC-SiQDs showed a lower and long-lasting activation of Nrf2 translocation into nucleus which correlated with their levels of cellular uptake, as detected by the intrinsic fluorescence of SiQDs. ROS production could be one of the mechanisms behind the anti-cancer effect of AITC-SiQDs. These data provide novel insights into the biphasic effect of AITC and highlight the application of nanotechnology to optimize the therapeutic potential of dietary isothiocyanates in cancer treatment.

Incorporating both diagnostic and therapeutic functions into a single nanoscale system is an effective modern drug delivery strategy. Combining liposomes with semiconductor quantum dots (QDs) has great potential to achieve such dual functions, referred to in this review as a liposomal QD hybrid system (L-QD). Here we review the recent literature dealing with the design and application of L-QD for advances in bio-imaging and drug delivery. After a summary of L-QD synthesis processes and evaluation of their properties, we will focus on their multifunctional applications, ranging from in vitro cell imaging to theranostic drug delivery approaches.

PURPOSE:Sphingosine kinase 1 (SK1) is a protooncogenic enzyme expressed in many human tumours and is associated with chemoresistance and poor prognosis. It is a potent therapy target and its inhibition chemosensitises solid tumours. Despite recent advances in SK1 inhibitors synthesis and validation, their clinical safety and chemosensitising options are not well described. In this study, we have designed, synthesised and tested a new specific SK1 inhibitor with a low toxicity profile.METHODS:Field template molecular modelling was used for compound design. Lead compounds were tested in cell and mouse cancer models.RESULTS:Field template analysis of three known SK1 inhibitors, SKI-178, 12aa and SK1-I, was performed and compound screening identified six potential new SK1 inhibitors. SK1 activity assays in both cell-free and in vitro settings showed that two compounds were effective SK1 inhibitors. Compound SK-F has potently decreased cancer cell viability in vitro and sensitised mouse breast tumours to docetaxel (DTX) in vivo, without significant whole-body toxicity.CONCLUSION:Through field template screening, we have identified a new SK1 inhibitor, SK-F, which demonstrated antitumour activity in vitro and in vivo without overt toxicity when combined with DTX.

Objective: To investigate the association of policy, systems and environmental factors with improvement in household food security among low-income Indiana households with children after a Supplemental Nutrition Assistance Program-Education (SNAP-Ed) direct nutrition education intervention. Design: Household food security scores measured by the eighteen-item US Household Food Security Survey Module in a longitudinal randomized and controlled SNAP-Ed intervention study conducted from August 2013 to April 2015 were the response variable. Metrics to quantify environmental factors including classification of urban or rural county status; the number of SNAP-authorized stores, food pantries and recreational facilities; average fair market housing rental price; and natural amenity rank were collected from government websites and data sets covering the years 2012-2016 and used as covariates in mixed multiple linear regression modelling. Setting: Thirty-seven Indiana counties, USA, 2012-2016. Subjects: SNAP-Ed eligible adults from households with children (n 328). Results: None of the environmental factors investigated were significantly associated with changes in household food security in this exploratory study. Conclusions: SNAP-Ed improves food security regardless of urban or rural location or the environmental factors investigated. Expansion of SNAP-Ed in rural areas may support food access among the low-income population and reduce the prevalence of food insecurity in rural compared with urban areas. Further investigation into policy, systems and environmental factors of the Social Ecological Model are warranted to better understand their relationship with direct SNAP-Ed and their impact on diet-related behaviours and food security.

Combining molecular therapies with chemotherapy may offer an improved clinical outcome for chemoresistant tumours. Sphingosine-1-phosphate (S1P) receptor antagonist and sphingosine kinase 1 (SK1) inhibitor FTY720 (FTY) has promising anticancer properties, however, it causes systemic lymphopenia which impairs its use in cancer patients. In this study, we developed a nanoparticle (NP) combining docetaxel (DTX) and FTY for enhanced anticancer effect, targeted tumour delivery and reduced systemic toxicity.

Stochastic weather generators are widely used in hydrological, environmental, and agricultural applications to simulate weather time series. However, such stochastic models produce random outputs hence the question on how representative the generated data are if obtained from only one simulation run (realization) as is common practice. In this study, the impact of different numbers of realizations (1, 25, 50, and 100) on the suitability of generated weather data was investigated. Specifically, 50 years of daily precipitation, and maximum and minimum temperatures were generated for three weather stations in the Western Lake Erie Basin (WLEB), using three widely used weather generators, CLIGEN, LARSWG and WeaGETS. Generated results were compared with 50 years of observed data. For all three generators, the analyses showed that one realization of data for 50 years of daily precipitation, and maximum and minimum temperatures may not be representative enough to capture essential statistical characteristics of the climate. Results from the three generators captured the essential statistical characteristics of the climate when the number of realizations was increased from 1 to 25, 50 or 100. Performance did not improve substantially when realizations were increased above 25. Results suggest the need for more than a single realization when generating weather data and subsequently utilizing in other models, to obtain suitable representations of climate.

Resistance to docetaxel is a key problem in current prostate and breast cancer management. We have recently discovered a new molecular mechanism of prostate cancer docetaxel chemoresistance mediated by the mammalian target of rapamycin (mTOR)/sphingosine-kinase-1 (SK1) pathway. Here we investigated the influence of this pathway on vascular endothelial growth factor (VEGF) production and tumour vascularisation in hormone resistant prostate and breast cancer models. Immunofluorescent staining of tumour sections from human oestrogen receptor (ER)-negative breast cancer patients showed a strong correlation between phosphorylated P70S6 kinase (mTOR downstream target), VEGF and SK1 protein expression. In hormone-insensitive prostate (PC3) and breast (MDA-MB-231 and BT-549) cancer cell lines the mTOR inhibitor RAD001 (everolimus) has significantly inhibited SK1 and VEGF expression, while low dose (5 nM) docetaxel had no significant effect. In these cell lines, SK1 overexpression slightly increased the basal levels of VEGF, but did not block the inhibitory effect of RAD001 on VEGF. In a human prostate xenograft model established in nude mice, RAD001 alone or in combination with docetaxel has suppressed tumour growth, VEGF expression and decreased tumour vasculature. Overall, our data demonstrate a new mechanism of an independent regulation of SK1 and VEGF by mTOR in hormone-insensitive prostate and breast cancers.

Many prostate cancers relapse after initial chemotherapy treatment. Combining molecular and chemotherapy together with encapsulation of drugs in nanocarriers provides effective drug delivery and toxicity reduction. We developed core shell lipid-polymer hybrid nanoparticles (CSLPHNPs) with poly (lactic-co-glycolic acid) (PLGA) core and lipid layer containing docetaxel and clinically used inhibitor of sphingosine kinase 1 (SK1) FTY720 (fingolimod). We show for the first time that FTY720 (both free and in CSLPHNPs) re-sensitizes castrate resistant prostate cancer cells and tumors to docetaxel, allowing a four-fold reduction in effective dose. Our CSLPHNPs showed high serum stability and a long shelf life. CSLPHNPs demonstrated a steady uptake by tumor cells, sustained intracellular drug release and in vitro efficacy superior to free therapies. In a mouse model of human prostate cancer, CSLPHNPs showed excellent tumor targeting and significantly lower side effects compared to free drugs, importantly, reversing lymphopenia induced by FTY720. Overall, we demonstrate that nanoparticle encapsulation can improve targeting, provide low off-target toxicity and most importantly reduce FTY720-induced lymphopenia, suggesting its potential use in clinical cancer treatment.