Targeting DNA damage repair mechanism by using RAD50-silencing siRNA nanoparticles to enhance radiotherapy in triple negative breast cancer.

Radiotherapy (RT) is one of major therapeutic modalities in combating breast cancer. In RT, ionizing radiation is employed to induce DNA double-strand breaks (DSBs) as a primary mechanism that causes cancer cell death. However, the induced DNA damage can also trigger the activation of DNA repair mechanisms, reducing the efficacy of RT treatment.

Biocompatible and bioactivable terpolymer-lipid-MnO Nanoparticle-based MRI contrast agent for improving tumor detection and delineation.

Early and precise detection of solid tumor cancers is critical for improving therapeutic outcomes. In this regard, magnetic resonance imaging (MRI) has become a useful tool for tumor diagnosis and image-guided therapy. However, its effectiveness is limited by the shortcomings of clinically available gadolinium-based contrast agents (GBCAs), i.

Remodeling Tumor Immune Microenvironment by Using Polymer-Lipid-Manganese Dioxide Nanoparticles with Radiation Therapy to Boost Immune Response of Castration-Resistant Prostate Cancer.

Despite substantial progress in the treatment of castration-resistant prostate cancer (CRPC), including radiation therapy and immunotherapy alone or in combination, the response to treatment remains poor due to the hypoxic and immunosuppressive nature of the tumor microenvironment. Herein, we exploited the bioreactivity of novel polymer-lipid manganese dioxide nanoparticles (PLMDs) to remodel the tumor immune microenvironment (TIME) by increasing the local oxygen levels and extracellular pH and enhancing radiation-induced immunogenic cell death. This study demonstrated that PLMD treatment sensitized hypoxic human and murine CRPC cells to radiation, significantly increasing radiation-induced DNA double-strand breaks and ultimately cell death, which enhanced the secretion of damage-associated molecular patterns, attributable to the induction of autophagy and endoplasmic reticulum stress.

Advances in Nanomedicine Design: Multidisciplinary Strategies for Unmet Medical Needs.

Globally, a rising burden of complex diseases takes a heavy toll on human lives and poses substantial clinical and economic challenges. This review covers nanomedicine and nanotechnology-enabled advanced drug delivery systems (DDS) designed to address various unmet medical needs. Key nanomedicine and DDSs, currently employed in the clinic to tackle some of these diseases, are discussed focusing on their versatility in diagnostics, anticancer therapy, and diabetes management.

Redox-responsive nanoparticles enhance radiation therapy by altering multifaceted radio-resistance mechanisms in human castration-resistant prostate cancer cells and xenografts.

Introduction: Radiation therapy (RT) is a major modality for the treatment of prostate cancer (PCa), especially castration-resistant PCa (CRPC). However, hypoxia, often seen in PCa tumors, leads to radiation-resistance. This work investigates the effect of a novel oxygen-generating polymer-lipid manganese dioxide nanoparticle (PLMDs) on improving RT outcomes in CRPC xenograft models by modulating the tumor microenvironment (TME) both before and after RT.

Pharmaceutical nanoformulation strategies to spatiotemporally manipulate oxidative stress for improving cancer therapies - exemplified by polyunsaturated fatty acids and other ROS-modulating agents.

Chronic oxidative stress and inflammation promote tumorigenesis and tumor progression, while certain chemotherapeutic drugs and radiation are applied to produce free radicals against cancer cells. To reduce tumor-promoting oxidative stress and protect normal tissue from chemotherapy and radiation-associated toxicity, dietary antioxidants, such as omega-3 polyunsaturated fatty acids (PUFA), have been combined with cancer therapies. However, the results of clinical studies are mixed with little to no benefit to therapeutic effect, and even exacerbated adverse effects.

Multitargeted Nanoparticles Deliver Synergistic Drugs across the Blood-Brain Barrier to Brain Metastases of Triple Negative Breast Cancer Cells and Tumor-Associated Macrophages.

Patients with brain metastases of triple negative breast cancer (TNBC) have a poor prognosis owing to the lack of targeted therapies, the aggressive nature of TNBC, and the presence of the blood-brain barrier (BBB) that blocks penetration of most drugs. Additionally, infiltration of tumor-associated macrophages (TAMs) promotes tumor progression. Here, a terpolymer-lipid hybrid nanoparticle (TPLN) system is designed with multiple targeting moieties to first undergo synchronized BBB crossing and then actively target TNBC cells and TAMs in microlesions of brain metastases.

Combining Tumor Microenvironment Modulating Nanoparticles with Doxorubicin to Enhance Chemotherapeutic Efficacy and Boost Antitumor Immunity.

Background: Tumor microenvironment (TME) and associated multiple factors are found to contribute to the failures in cancer therapies, including chemo- and immunotherapy. Here we report a new multimodal strategy that uses a bioreactive multifunctional hybrid polymer-lipid encapsulated manganese dioxide nanoparticle (PLMD NP) system to remodel the TME, suppress drug resistance factors, reverse immunosuppressive conditions, and enhance chemotherapy efficacy.

Methods: The influence of PLMD NPs on enhancing cellular uptake in EMT6 mouse breast cancer cells and tumor penetration of doxorubicin (DOX) in EMT6 orthotopic breast tumor mouse model was evaluated using confocal microscopy (n = 3-4).

Importance of integrating nanotechnology with pharmacology and physiology for innovative drug delivery and therapy - an illustration with firsthand examples.

Nanotechnology has been applied extensively in drug delivery to improve the therapeutic outcomes of various diseases. Tremendous efforts have been focused on the development of novel nanoparticles and delineation of the physicochemical properties of nanoparticles in relation to their biological fate and functions. However, in the design and evaluation of these nanotechnology-based drug delivery systems, the pharmacology of delivered drugs and the (patho-)physiology of the host have received less attention.

Risk factors for colorectal cancer in man induce aberrant crypt foci in rats: Preliminary findings.

Epidemiological studies have demonstrated clear associations between specific dietary and environmental risk factors and incidence of colorectal cancer, but the mechanisms responsible for these associations are not known. An animal model could facilitate such an understanding. Both genotoxic and nongenotoxic carcinogens induce aberrant crypt foci (ACF) in the colons of F344 rats.

Protective effects of ferulic acid and related polyphenols against glyoxal- or methylglyoxal-induced cytotoxicity and oxidative stress in isolated rat hepatocytes.

Glyoxal (GO) and methylglyoxal (MGO) cause protein and nucleic acid carbonylation and oxidative stress by forming reactive oxygen and carbonyl species which have been associated with toxic effects that may contribute to cardiovascular disease, complications associated with diabetes mellitus, Alzheimer's and Parkinson's disease. GO and MGO can be formed through oxidation of commonly used reducing sugars e.g.

Glyoxal and methylglyoxal: autoxidation from dihydroxyacetone and polyphenol cytoprotective antioxidant mechanisms.

Previously, this laboratory had shown that fructose and its downstream metabolites can be enzymatically metabolized to form glyoxal and methylglyoxal. Fructose metabolites, glycoaldehyde, glyceraldehyde and hydroxypyruvate have also been shown to be autoxidizable. In this study, however, fructose did not cause protein carbonylation itself and instead protected against apparent carbonylation by Fenton's reagent; fructose did not form significant levels of dicarbonyl compounds over a period of 6 days under standard conditions (37°C, pH 7.

Cytotoxic molecular mechanisms and cytoprotection by enzymic metabolism or autoxidation for glyceraldehyde, hydroxypyruvate and glycolaldehyde.

Previously, we showed that dietary fructose or its carbonyl metabolites, glyceraldehyde and glycolaldehyde, could be oxidized by inflammatory reactive oxygen species (ROS), products of immune cells, to form highly toxic and genotoxic products, such as glyoxal. Glycolaldehyde-caused hepatocyte protein carbonylation likely resulted from glyoxal, an autoxidation product formed by ROS. Although hepatocyte protein carbonylation by glyoxal or d-glycolaldehyde was rapid, the product was unstable.