Biomimetic manganese-eumelanin nanocomposites for combined hyperthermia-immunotherapy against prostate cancer.

Pro-tumoral and immunosuppressive M2-like tumor-associated macrophages (TAMs) contribute to tumor progression, recurrence and distal metastasis. However, current TAMs-modulating therapeutic strategies often encounter challenges including insufficient immune activation, weak antigen presentation ability and unsatisfactory antitumor immune performance. Herein, cyclic RGD peptide functionalized and manganese doped eumelanin-like nanocomposites (RMnMels) are reported for combined hyperthermia-immunotherapy against PC3 prostate cancer. The RMnMels could promote M2-to-M1 macrophage repolarization via scavenging multiple reactive oxygen species and remodeling the immunosuppressive tumor microenvironment. Following near-infrared light irradiation, RMnMels-mediated thermal ablation not only could destroy tumor cells directly, but also elicit the release of damage associated molecular patterns and tumor-associated antigens, provoking robust tumor immunogenicity and strong antitumor immune responses. The results showed that RMnMels could effectively scavenge reactive oxygen species and promote M2-to-M1 macrophage repolarization both in vitro and in vivo. Synergistically enhanced anti-tumor therapeutic efficacy was achieved following single administration of RMnMels plus single round of laser irradiation, evidenced by decreased primary tumor sizes and decreased number of distant liver metastatic nodules. The as-developed RMnMels may represent a simple and high-performance therapeutic nanoplatform for immunomodulation and enhanced antitumor immune responses.

Intravesical In Situ Immunostimulatory Gel for Triple Therapy of Bladder Cancer.

Bladder cancer displays multiple biological features aided in drug resistance; therefore, single therapy fails to induce complete tumor regression. To address this issue, various kinds of cell death of cancer cells as well as restoring tumor immune microenvironment need to be taken into consideration. Here, we introduce a gel system termed AuNRs&IONs@Gel, which target-delivers a combination of photothermal, ferroptotic, and immune therapy through intravesical instillation. AuNRs&IONs@Gel consists of a gel delivery platform, embedded gold nanorods (AuNRs), and iron oxide nanoparticles (IONs). The targeted delivery gel platform provides dextran aldehyde-selective adhesion with cancer collagen. In this condition, photothermal therapy can be performed by gold nanorods (AuNRs) under imaging-guided near-infrared radiation. Local high concentrations of IONs can be absorbed by cancer cell to induce ferroptosis. Moreover, tumor-associated macrophages which often display an immune-suppressive M2-like phenotype will be repolarized by IONs into the antitumor M1-like phenotype, exerting a direct antitumor effect and professional antigen presentation of dead cancer cells. This process triggers a potent immune response of innate and adapt immunities to protect tumor rechallenge in long terms. Our triple-therapy strategy employs FDA-approved nanoparticles to inhibit bladder cancer which may possess great potential for clinical translation.

Metal-Organic Frameworks as a Theranostic Nanoplatform for Combinatorial Chemophotothermal Therapy Adapted to Different Administration.

With the rapid development of nanotechnology, nanomaterial drug delivery systems have provided an alternative for designing controllable drug delivery systems due to their spatiotemporally controllable properties. As a new type of porous material, metal-organic frameworks (MOFs) have been widely used in biomedical applications, especially drug delivery systems, owing to their tunable pore size, high surface area and pore volume, and easy surface modification. Here, we demonstrate an MOF as a theranostic nanoplatform to combine drug therapy and phototherapy after labeling targeting peptide iRGD. The micropore Fe-MOF was used as MRI agents for locating tumors and as nanocarriers to upload chemotherapeutic drugs. Moreover, MOF showed excellent targeting performance under different administration including intravenous injection for breast cancer and local instillation for bladder cancer. Notably, when irradiated with an 808 nm laser, the agent demonstrates the high efficacy of photothermal therapy and heat release efficiency of the drug around the tumor site. This combination therapy provides an alternative drug administration method and can be adapted to a series of cancer cell types and molecular targets associated with disease progression.

Abundance of Probiotics and Butyrate-Production Microbiome Manages Constipation via Short-Chain Fatty Acids Production and Hormones Secretion.

SCOPE: The characteristics of gut microbiota and host metabolism are hypothesized to be associated with constipation status, but the regulation mechanism is not fully understood. Thus, the current study investigates the effect of constipation symptoms on gut functionality following the modulation of gut microbiota and metabolites via dietary fiber intervention. METHODS AND RESULTS: Constipation causes a significantly reduced short-chain fatty acids (SCFAs) production and a higher level of iso-butyrate. The feces of constipated people are characterized with inhibited Faecalibacterium, Ruminococcaceae and Roseburia abundance. Desulfovibrionaceae is identified to be an important endotoxin producer in constipated patients, and a butyrate-enriched SCFAs profile achieved by dietary fiber supplement accelerates gastrointestinal transit and increases the thickness of the mucosal layer, possibly through triggering the secretion of colonic hormones and enhancing the expression of tight junction proteins for maintaining intestinal barrier integrity. More importantly, an interacting regulatory mechanism among SCFAs, in particular butyrate and propionate, may be involved in signaling between the microbiome and host cells in the colon. CONCLUSION: Gut microbiota, characterized with enriched butyrate-producing and depressed Desulfovibrionaceae bacteria, attenuates constipation symptoms through promoting intestinal hormones secretion and maintaining gut barrier integrity.

Regulation of hyperglycemia in diabetic mice by autolysates from ß-mannanase-treated brewer's yeast.

BACKGROUND: Diabetes mellitus is a serious chronic disease, characterized by hyperglycemia. This study administered either ß-mannanase-treated yeast cell autolysis supernatant (YCS) or yeast cell-wall residues after autolysis (YCR) to investigate their influence on the alleviation of diabetes in a diabetic mouse model. RESULTS: Application of either YCS or YCR led to body weight gain, blood glucose reduction, and an improvement in lipid composition in the diabetic mice. Administration of YCS was more effective in inhibiting oxidative stress than YCR. The expression of PPARα and CPT1α was enhanced, improving lipid biosynthesis, and Trx1 and HIF-1-α genes were downregulated due to the activation of thioredoxin following the interventions, indicating that the processes of lipid metabolism and oxidative stress were heavily involved in the reduction of diabetic characteristics following the interventions. The current study revealed that consumption of YCR also led to a reduction in hyperglycemia, this being associated with its richness in mineral elements, such as chromium and selenium. CONCLUSION: This study may highlight the potential of both YCS and YCR as functional ingredients in dietary formula for improving diabetic syndromes. © 2019 Society of Chemical Industry.

Targeting carbon nanotubes based on IGF-1R for photothermal therapy of orthotopic pancreatic cancer guided by optical imaging.

Pancreatic cancer is one of the most lethal malignancies worldwide. The existing therapeutic regimen in the clinic for advanced inoperable carcinomas are far from satisfactory, thus it is urgent to seek more effective anticancer strategies. In the pursuit of novel, more effective interventions, photothermal therapy (PTT) based on nanomaterials has attracted increased attention. Recent advances in related fields have catalyzed the generation of novel nanoprobes, such as organic dyes, metal nanoparticles. However, organic dyes are poorly stable and easy to quench while metal nanoparticles with potential metal toxicity are difficult to degrade, both of which have low light-to-heat conversion efficiency, broad spectrum of anti-tumor effects, and lack of tumor targeting specificity. Single-walled carbon nanotubes (SWNTs) can remedy the above inadequacies. Herein, we report our water-soluble, bio-stable and low-toxicity SWNTs with excellent photothermal conversion efficiency. Specific modifications can enable visualization of the aggregate characteristics of SWNTs at the macroscopic or microscopic level in tumors. The dye-conjugated SWNTs bound with targeting antibodies that can induce them specifically targeting to pancreatic tumors for purposes of performing dyes imaging-guided cytotoxic PTT. PTT using this method achieves precise and excellent curative effects with minimal adverse effects, thus providing a promising strategy for anticancer therapy.

Neoadjuvant nano-photothermal therapy used before operation effectively assists in surgery for breast cancer.

Nano-photothermal therapy (NPTT) has attracted increasing interest recently due to its high efficiency, excellent selectivity and non-ionizing radiation damage. Despite a tremendous amount of exciting pre-clinical results reported in the past few years, however, the further clinic application of NPTT is still difficult. To combine NPTT with clinical surgery more closely, novel multifunctional optical-magnetic nanosystems have been synthesized and applied for preoperative NPTT to assist in the follow-up surgery, termed "neoadjuvant NPTT". Remarkably, nanoparticles are mainly aggregated in the cytoplasm of tumor cells in vitro and largely accumulated in the tumor in vivo 24 h after injection. Under the guidance of tri-modality imaging, preoperative NPTT could shrink the tumor in a short time and make the boundary between the tumor and surrounding normal tissues clearer, which is conducive to subsequent surgery resection. Furthermore, the 50% survival rate is up to 50 days compared with 35 days for standard surgery, 31 days for PTT alone and 24 days for non-surgery groups. Therefore, NPTT can effectively assist in surgery used before operation. This study provides a new idea for the clinical transformation of NPTT in the future.

γ-Aminobutyric Acid Attenuates High-Fat Diet-Induced Cerebral Oxidative Impairment via Enhanced Synthesis of Hippocampal Sulfatides.

Long-term high-fat diet (HFD) in rats triggered cerebral oxidative stress, reflected by reactive oxygen species accumulation and antioxidant decline in peripheral and cerebral tissues, together with hippocampal lipid disturbance, particularly for triglyceride accumulation and sulfatide deficiency. Hippocampal formation and cerebral cortex also exhibited pathological changes, characterized by neurofibrillary tangle and reduced Nissl bodies. Sulfatides were noted to protect hippocampal neurons from oxidative damage through the clearance of ß-amyloid protein, with apolipoprotein E transporting and low-density lipoprotein receptor binding. Delightedly, we found γ-aminobutyric acid (GABA) supplement delivered by rice bran to rats significantly promoted hippocampal sulfatide synthesis and reversed the HFD-induced sulfatide deficiency and oxidative-triggered cerebral impairment. Elevated GABA concentration in hippocampus and the activation of GABA B-type receptors might be the primary contributors. This study demonstrated the potential of GABA-enriched rice bran as a novel dietary supplement to enhance a sulfatide-based therapeutic approach for neurodegenerative diseases in the early stages.

Gamma-aminobutyric Acid Enriched Rice Bran Diet Attenuates Insulin Resistance and Balances Energy Expenditure via Modification of Gut Microbiota and Short-Chain Fatty Acids.

In this study, gamma-aminobutyric acid (GABA) enriched rice bran (ERB) was supplemented to obese rats to investigate the attenuation of metabolic syndromes induced by high-fat diet. ERB-containing diet stimulated butyrate and propionate production by promoting Anaerostipes, Anaerostipes sp., and associated synthesizing enzymes. This altered short-chain fatty acid (SCFA) distribution further enhanced circulatory levels of leptin and glucagon-like peptide-1, controlling food intake by downregulating orexigenic factors. Together with the enhanced fatty acid ß-oxidation highlighted by Prkaa2, Ppara, and Scd1 expression via AMPK signaling pathway and nonalcoholic fatty liver disease pathway, energy expenditure was positively modulated. Serum lipid compositions showed ERB supplement exhibited a more efficient effect on lowering serum sphingolipids, which was closely associated with the status of insulin resistance. Consistently, genes of Ppp2r3b and Prkcg, involved in the function of ceramides in blocking insulin action, were also downregulated following ERB intervention. Enriched GABA and phenolic acids were supposed to be responsible for the health-beneficial effects.

A Comparative Study of Clinical Intervention and Interventional Photothermal Therapy for Pancreatic Cancer.

Although nanoparticle-based photothermal therapy (PTT) has been intensively investigated recently, its comparative efficiency with any clinical cancer treatments has been rarely explored. Herein for the first time we report a systematic comparative study of clinical iodine-125 (125 I) interstitial brachytherapy (IBT-125-I) and interventional PTT (IPTT) in an orthotopic xenograft model of human pancreatic cancer. IPTT, based on the nanoparticles composing of anti-urokinase plasminogen activator receptor (uPAR) antibody, polyethylene glycol (PEG), and indocyanine green (ICG) modified gold nanoshells (hereinafter uIGNs), is directly applied to local pancreatic tumor deep in the abdomen. In comparison to IBT-125-I, a 25% higher median survival rate of IPTT with complete ablation by one-time intervention has been achieved. The IPTT could also inhibit pancreatic tumor metastasis which can be harnessed for effective cancer immunotherapy. All results show that this IPTT is a safe and radical treatment for eradicating tumor cells, and may benefit future clinical pancreatic cancer patients.

Dye-conjugated single-walled carbon nanotubes induce photothermal therapy under the guidance of near-infrared imaging.

Recently, photothermal therapy (PTT) has become viewed as an ideal auxiliary therapeutic treatment for cancers. However, the development of safe, convenient, and highly effective photothermal agents remains a great challenge. In this study, we prepared single-walled carbon nanotubes (SWNTs) for PTT against breast tumors under the guidance of infrared fluorescent cyanines. Tumors were accurately located using near-infrared imaging (NIR) and then exposed to laser irradiation. Both the in vivo and in vitro results showed that the SWNTs have high stability and low cytotoxicity. Introducing polyethylene glycol into our nanoparticles increased the blood-circulation time. Our in vivo results further showed that Cy5.5-conjugated SWNTs mediated PTT, resulting in efficient tumor suppression in mice under the guidance of near-infrared imaging. Due to the small amount of absorption at 808-nm, Cy5.5 increased the efficiency of PTT. Breast tumors significantly shrunk after irradiation under the 808-nm near-infrared laser. The treated mice developed scabs, but otherwise recovered after 15 days, and their physical conditions restored gradually. These data indicate that our unique photothermal-responsive SWNT-Cy5.5-based theranostic agent can serve as a promising candidate for PTT.

Cancer Diagnosis and Imaging-Guided Photothermal Therapy Using a Dual-Modality Nanoparticle.

To improve patient outcome and decrease overall health-care costs, highly sensitive and precise detection of a tumor is required for its accurate diagnosis and efficient therapy; however, this remains a challenge when using conventional single mode imaging. Here, we successfully designed a near-infrared (NIR)-response photothermal therapy (PTT) platform (Au@MSNs-ICG) for the location, diagnosis, and NIR/computer tomography (CT) bimodal imaging-guided PTT of tumor tissues, using gold (Au) nanospheres coated with indocyanine green (ICG)-loaded mesoporous silica nanoparticles (MSNs), which would have high sensitivity and precision. The nanoparticles (NPs) exhibited good monodispersity, fluorescence stability, biocompatibility, and NIR/CT signaling and had a preferable temperature response under NIR laser irradiation in vitro or in vivo. Using a combination of NIR/CT imaging and PTT treatment, the tumor could be accurately positioned and thoroughly eradicated in vivo by Au@MSNs-ICG injection. Hence, the multifunctional NPs could play an important role in facilitating the accurate treatment of tumors in future clinical applications.