969 research outputs found
Engineered Exosomes for the Multimodal Imaging Directed Photo-Immunotherapy of Colorectal Cancer
Background: Rio Grande Valley experience severe cancer health disparity. A novel therapeutic modality may serve as better therapeutic option. Nanohybrids endowed with multifunctionality, longer circulation time, large surface area have emerged as an active preference for cancer research. However, rising concern of nanomaterials toxicity and scalability issues has slowed their translation to clinics. Exosomes (Exo) are endogenous endocytic origin 40-100 nm vesicles found in various body fluids, which in comparison to synthetic nanoparticles, are biodegradable, highly biocompatible as well as immunocompatible in nature. Although bulk isolation of exosomes from human body fluids is still a problem and engineering of exosomes to harness its potential is still in infancy.
Methods: The Exo were isolated from dairy milk using EDTA precipitation method, and superparamagnetic iron oxide nanoparticles (MNPs) were synthesized by ammonium hydroxide co-precipitation method. The Exo were sonicated (60 sec) with MNPs and near-infrared (NIR) light-absorbing dye indocyanine green (ICG) and then incubated overnight at 37 oC. The characterization of ICG@Exo-MNPs was done using several techniques. The targeting nature of ICG@Exo-MNPs was determined on colorectal cancer cells SW480 and SW680. The phototransduction and in-vitro photothermal therapy were performed using 1W, 808 nm NIR laser.
Results: The ICG@Exo-MNPs nanohybrid found to have size around 100 nm with good dispersity. The coating of exosomes and magnetic field actuation increased the targeting efficacy of ICG@Exo-MNPs in colorectal cancer cells by 10% in SW40 and 30% in SW680. ICG@Exo-MNPs killed the SW480 cells to more than 80% within 2 min. of NIR light irradiation.
Conclusions: This study shows enhanced photothermal therapeutic behavior of ICG@Exo-MNPs for near-infrared fluorescence imaging directing killing of colorectal cancer cells
A Novel Exo-Glow Nano-system for Cellular Imaging
Background: Indocyanine green (ICG) based Near-Infrared (NIR) fluorescent imaging is an attractive and safer technique used for number of clinical applications. However, ICG tend to have poor photostability, short half-life, non-specific proteins binding, and concentration-dependent aggregation. Therefore, there is an unmet clinical need to develop newer modalities to package and deliver ICG. Bovine milk exosomes are natural, biocompatible, safe, and feasible nanocarriers that facilitate the delivery of micro and macro molecules. Herein, we developed a novel exosomes based ICG nano imaging system that offers improved solubility and photostability of ICG.
Methods: Following acetic acid based extracellular vesicles (EV) extraction method, we extracted the bovine milk exosomes from a variety of pasteurized fat-free milks. The EVs were screened for their physicochemical properties such as particle size and concentration, and zeta potential. Stability of these exosomes was also determined under different conditions including storage temperatures, pH, and salt concentrations. Next, ICG dye was loaded into these exosomes (Exo-Glow) via sonication method and further assessed for its fluorescence intensity and photostability using an IVIS imaging system.
Results: Initial screening suggested that size of the selected bovine milk exosomes was from 100 - 135 nm with an average particle concentration of 5.8x102 particles/mL. Exo-Glow (ICG loaded exosomes) further showed higher fluorescence intensity of ~ 2x1010 MFI compared to free ICG (~ 8.1x109 MFI).
Conclusions: These results showed that Exo-Glow has the potential to improve solubility, photostability, and biocompatibility of ICG and may serve as a safer NIR imaging tool for cells/tissues
Nanotechnology Synergised Immunoengineering for Cancer
Novel strategies modulating the immune system yielded enhanced anticancer responses and improved cancer survival. Nevertheless, the success rate of immunotherapy in cancer treatment has been below expectation(s) due to unpredictable efficacy and off-target effects from systemic dosing of immunotherapeutic. As a result, there is an unmet clinical need for improving conventional immunotherapy. Nanotechnology offers several new strategies, multimodality, and multiplex biological targeting advantage to overcome many of these challenges. These efforts enable programming the pharmacodynamics, pharmacokinetics, delivery of immunomodulatory agents/co-delivery of compounds to prime at the tumor sites for improved therapeutic benefits. This review provides an overview of the design and clinical principles of biomaterials driven nanotechnology and their potential use in personalized nanomedicines, vaccines, localized tumor modulation, and delivery strategies for cancer immunotherapy. In this review, we also summarize the latest highlights and recent advances in combinatorial therapies avail in the treatment of cold and complicated tumors. It also presents key steps and parameters implemented for clinical success. Finally, we analyse, discuss, and provide clinical perspectives on the integrated opportunities of nanotechnology and immunology to achieve synergistic and durable responses in cancer treatment
Tumor-Derived Exosome and Immune Modulation
Tumor cells, like most other cells, release exosomes called tumor-derived exosomes (TEX) and are vital for intercellular communication. TEX are membrane-bound extracellular vesicles (EVs), containing unique cargo reminiscent of the parent tumor cells and possess immunomodulatory functions. TEX carries factors that directly promote immunosuppression in the tumor microenvironment and indirectly attract immunosuppressive T-regulatory (Treg) cells. The tumor-secreted exosomes can transfer their cargo by multiple mechanisms like fusion, phagocytosis, and receptor-mediated endocytosis, activating the recipient cells. TEX directly engages and releases cytokines, inactivating natural killer (NK) cells and T-cells and activating apoptosis. Tumor-derived exosomes also release soluble factors to suppress dendritic cell (DC) maturation while activating the expansion of immune-suppressive cells like Myeloid-derived suppressor cells (MDSCs) and Regulatory T (Treg) cells. Several studies have shown the relevance of TEX containing tumor-associated antigens (TAA) in reducing the efficacy of cancer immunotherapy and adoptive cell therapy. Hence understanding the basic biology and mechanism of TEX-mediated immunosuppression is critical in discovering cancer biomarkers and finding better immunotherapy and cell therapy approaches. In this chapter, we have discussed TEX biogenesis, TEX\u27s structural and molecular features, TEX-mediated immunosuppression, and its relation to immunotherapy
Liposomal nanotheranostics for multimode targeted in vivo bioimaging and near‐infrared light mediated cancer therapy
Developing a nanotheranostic agent with better image resolution and high accumulation into solid tumor microenvironment is a challenging task. Herein, we established a light mediated phototriggered strategy for enhanced tumor accumulation of nanohybrids. A multifunctional liposome based nanotheranostics loaded with gold nanoparticles (AuNPs) and emissive graphene quantum dots (GQDs) were engineered named as NFGL. Further, doxorubicin hydrochloride was encapsulated in NFGL to exhibit phototriggered chemotherapy and functionalized with folic acid targeting ligands. Encapsulated agents showed imaging bimodality for in vivo tumor diagnosis due to their high contrast and emissive nature. Targeted NFGL nanohybrids demonstrated near infrared light (NIR, 750 nm) mediated tumor reduction because of generated heat and Reactive Oxygen Species (ROS). Moreover, NFGL nanohybrids exhibited remarkable ROS scavenging ability as compared to GQDs loaded liposomes validated by antitumor study. Hence, this approach and engineered system could open new direction for targeted imaging and cancer therapy.publishersversionpublishe
Mycobacterium tuberculosis infection drives a type I IFN signature in lung lymphocytes
Mycobacterium tuberculosis (Mtb) infects 25% of the world\u27s population and causes tuberculosis (TB), which is a leading cause of death globally. A clear understanding of the dynamics of immune response at the cellular level is crucial to design better strategies to control TB. We use the single-cell RNA sequencing approach on lung lymphocytes derived from healthy and Mtb-infected mice. Our results show the enrichment of the type I IFN signature among the lymphoid cell clusters, as well as heat shock responses in natural killer (NK) cells from Mtb-infected mice lungs. We identify Ly6A as a lymphoid cell activation marker and validate its upregulation in activated lymphoid cells following infection. The cross-analysis of the type I IFN signature in human TB-infected peripheral blood samples further validates our results. These findings contribute toward understanding and characterizing the transcriptional parameters at a single-cell depth in a highly relevant and reproducible mouse model of TB
Enhanced EPR directed and Imaging guided Photothermal Therapy using Vitamin E Modified Toco-Photoxil
Herein we report synthesis, characterization and preclinical applications of a novel hybrid nanomaterial Toco-Photoxil developed using vitamin E modified gold coated poly (lactic-co-glycolic acid) nanoshells incorporating Pgp inhibitor d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as a highly inert and disintegrable photothermal therapy (PTT) agent. Toco-Photoxil is highly biocompatible, physiologically stable PTT material with an average diameter of 130 nm that shows good passive accumulation (2.3% ID) in solid tumors when delivered systemically. In comparison to its surface modified counterparts such as IR780-Toco-Photoxil, FA-Toco-Photoxil or FA-IR780-Toco-Photoxil accumulation are merely ~0.3% ID, ~0.025% ID and ~0.005% ID in folate receptor (FR) negative and positive tumor model. Further, Toco-Photoxil variants are prepared by tuning the material absorbance either at 750 nm (narrow) or 915 nm (broad) to study optimal therapeutic efficacy in terms of peak broadness and nanomaterial’s concentration. Our findings suggest that Toco-Photoxil tuned at 750 nm absorbance is more efficient (P = 0.0097) in preclinical setting. Toco-Photoxil shows complete passiveness in critical biocompatibility test and reasonable body clearance. High tumor specific accumulation from systemic circulation, strong photothermal conversion and a very safe material property in body physiology makes Toco-Photoxil a superior and powerful PTT agent, which may pave its way for fast track clinical trial in future
Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.
Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability
The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy
Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations.
Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves.
Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p 90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score.
Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care
Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017
A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1–70.8) million) to 6.4% (58.3 (47.6–70.7) million), but is predicted to remain above the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8–38.5) million) in 2000 to 6.0% (55.5 (44.8–67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic
- …