Indocyanine Green Nanoparticles : Are They Compelling for Cancer Treatment?

Indocyanine green (ICG) is a Food and Drug Administration\u2013approved near-infrared fluorescent dye, employed as an imaging agent for different clinical applications due to its attractive physicochemical properties, high sensitivity, and safety. However, free ICG suffers from some drawbacks, such as relatively short circulation half-life, concentration-dependent aggregation, and rapid clearance from the body, which would confine its feasible application in oncology. Here, we aim to discuss encapsulation of ICG within a nanoparticle formulation as a strategy to overcome some of its current limitations and to enlarge its possible applications in cancer diagnosis and treatment. Our purpose is to provide a short but exhaustive overview of clinical outcomes that these nanocomposites would provide, discussing opportunities, limitations, and possible impacts with regard to the main clinical needs in oncology

Everolimus Nanoformulation in Biological Nanoparticles Increases Drug Responsiveness in Resistant and Low-Responsive Breast Cancer Cell Lines

Everolimus (Eve) is an FDA approved drug that inhibits mammalian target of rapamycin (mTOR). It is employed in breast cancer treatment even if its responsiveness is controversial. In an attempt to increase Eve effectiveness, we have developed a novel Eve nanoformulation exploiting H-ferritin nanocages (HEve) to improve its subcellular delivery. We took advantage of the natural tumor targeting of H-Ferritin, which is mediated by the transferrin receptor-1 (TfR1). Breast cancer cells overexpressing TfR-1 were successfully recognized by H-Ferritin, displaying quick nanocage internalization. HEve has been tested and compared to Eve for in vitro efficacy in sensitive and resistant breast cancer cells. Nanoformulated Eve induced remarkable antiproliferative activity in vitro, making even resistant cell lines sensitive to Eve. Moreover, the antiproliferative activity of HEve is fully in accordance with cytotoxicity observed by cell death assay. Furthermore, the significant increase in anticancer efficacy displayed in HEve-treated samples is due to the improved drug accumulation, as demonstrated by UHPLC-MS/MS quantifications. Our findings suggest that optimizing Eve subcellular delivery, thanks to nanoformulation, determines its improved antitumor activity in a panel of Eve-sensitive or resistant breast cancer cell lines

Co-administration of H-ferritin-doxorubicin and Trastuzumab in neoadjuvant setting improves efficacy and prevents cardiotoxicity in HER2 + murine breast cancer model

Neoadjuvant chemotherapy has been established as the standard of care for HER2-positive breast cancer since it allows cancer down-staging, up to pathological complete response. The standard of care in the neoadjuvant setting for HER2-positive breast cancer is a combination of highly cytotoxic drugs such as anthracyclines and the anti-HER2 monoclonal antibody. Despite this cocktail allows a pathological complete response in up to 50%, their co-administration is strongly limited by intrinsic cardiotoxicity. Therefore, only a sequential administration of anthracyclines and the anti-HER2 treatment is allowed. Here, we propose the anthracycline formulation in H-Ferritin nanocages as promising candidate to solve this unmet clinical need, thanks to its capability to increase anthracyclines efficacy while reducing their cardiotoxicity. Treating a murine model of HER2-positive breast cancer with co-administration of Trastuzumab and H-Ferritin anthracycline nanoformulation, we demonstrate an improved tumor penetration of drugs, leading to increased anticancer efficacy and reduced of cardiotoxicity

Cardiac Involvement in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic disease of unknown etiology characterized by a chronic inflammatory process mainly leading to destruction of synovial membrane of small and major diarthrodial joints. The prevalence of RA within the general adult population is about 1% and female subjects in fertile age result mostly involved. It's an invalidating disease, associated with changes in life quality and a reduced life expectancy. Moreover, we can observe an increased mortality rate in this population early after the onset of the disease. The mortality excess can be partially due to infective, gastrointestinal, renal or pulmonary complications and malignancy (mainly lung cancer and non- Hodgkin lymphoma). Among extra-articular complications, cardiovascular (CV) involvement represents one of the leading causes of morbidity and mortality. Every cardiac structure can be affected by different pathogenic pathways: heart valves, conduction system, myocardium, endocardium, pericardium and coronary arteries. Consequently, different clinical manifestations can be detected, including: pericarditis, myocarditis, myocardial fibrosis, arrhythmias, alterations of conduction system, coronaropathies and ischemic cardiopathy, valvular disease, pulmonary hypertension and heart failure. Considering that early cardiac involvement negatively affects the prognosis, it is mandatory to identify high CV risk RA patients to better define long-term management of this population

Cardiovascular involvement in psoriatic arthritis

Psoriasis is a chronic, genetically determined and immunomediated inflammatory skin disease that affects 2-3% of the Caucasian population. A considerable proportion of these patients develop a form of inflammatory arthritis known as psoriatic arthritis (PsA), although the prevalence of this has not been well defined. Patients with PsA have a higher mortality rate than the general population and the risk of mortality is related to disease severity at the time of presentation. Endothelial dysfunction and early atherosclerosis have been found in patients with PsA without any cardiovascular disease (CVD) risk factors, and experts believe that CVD is one of the leading causes of death, as it is in patients with rheumatoid arthritis (RA). Various disease-related mechanisms may be involved in the development of premature vascular damage in both cases, including an increased synthesis of proinflammatory mediators (such as cytokines, chemokines and adhesion molecules), autoantibodies against endothelial cell components, perturbations in T-cell subsets, genetic polymorphisms, hyperhomocysteinemia, oxidative stress, abnormal vascular repair, and iatrogenic factors. In a recent study of 22 patients with PsA without any signs of CVD, we found that the plasma concentration of asymmetric dimethylarginine (ADMA) levels were significantly high and coronary flow reserve (CFR) was significantly reduced. Moreover, there was a significant correlation between CFR and plasma ADMA levels in the PsA group. The significant correlation between the reduced CRF and increased ADMA levels suggests that, like patients with early RA, PsA patients suffer from endothelial dysfunction and impaired coronary microcirculation. Active PsA is a risk factor for CVD, and so PsA patients should be screened for subclinical forms of the disease and its risk factors, and an early treatment approach should be adopted

Kupffer Cells Hasten Resolution of Liver Immunopathology in Mouse Models of Viral Hepatitis

Kupffer cells (KCs) are widely considered important contributors to liver injury during viral hepatitis due to their pro-inflammatory activity. Herein we utilized hepatitis B virus (HBV)-replication competent transgenic mice and wild-type mice infected with a hepatotropic adenovirus to demonstrate that KCs do not directly induce hepatocellular injury nor do they affect the pathogenic potential of virus-specific CD8 T cells. Instead, KCs limit the severity of liver immunopathology. Mechanistically, our results are most compatible with the hypothesis that KCs contain liver immunopathology by removing apoptotic hepatocytes in a manner largely dependent on scavenger receptors. Apoptotic hepatocytes not readily removed by KCs become secondarily necrotic and release high-mobility group box 1 (HMGB-1) protein, promoting organ infiltration by inflammatory cells, particularly neutrophils. Overall, these results indicate that KCs resolve rather than worsen liver immunopathology

Role of Selenof as a Gatekeeper of Secreted Disulfide-Rich Glycoproteins

Selenof (15-kDa selenoprotein; Sep15) is an endoplasmic reticulum (ER)-resident thioredoxin-like oxidoreductase that occurs in a complex with UDPglucose: glycoprotein glucosyltransferase. We found that Selenof deficiency in mice leads to elevated levels of non-functional circulating plasma immunoglobulins and increased secretion of IgM during in vitro splenic B cell differentiation. However, Selenof knockout animals show neither enhanced bacterial killing capacity nor antigen-induced systemic IgM activity, suggesting that excess immunoglobulins are not functional. In addition, ER-to-Golgi transport of a target glycoprotein was delayed in Selenof knockout embryonic fibroblasts, and proteomic analyses revealed that Selenof deficiency is primarily associated with antigen presentation and ER-to-Golgi transport. Together, the data suggest that Selenof functions as a gatekeeper of immunoglobulins and, likely, other client proteins that exit the ER, thereby supporting redox quality control of these proteins

Hyperthermia Induces the ER Stress Pathway

The ER chaperone GRP78/BiP is a homolog of the Hsp70 family of heat shock proteins, yet GRP78/BiP is not induced by heat shock but instead by ER stress. However, previous studies had not considered more physiologically relevant temperature elevation associated with febrile hyperthermia. In this report we examine the response of GRP78/BiP and other components of the ER stress pathway in cells exposed to 40°C.AD293 cells were exposed to 43°C heat shock to confirm inhibition of the ER stress response genes. Five mammalian cell types, including AD293 cells, were then exposed to 40°C hyperthermia for various time periods and induction of the ER stress pathway was assessed.The inhibition of the ER stress pathway by heat shock (43°C) was confirmed. In contrast cells subjected to more mild temperature elevation (40°C) showed either a partial or full ER stress pathway induction as determined by downstream targets of the three arms of the ER stress pathway as well as a heat shock response. Cells deficient for Perk or Gcn2 exhibit great sensitivity to ER stress induction by hyperthermia.The ER stress pathway is induced partially or fully as a consequence of hyperthermia in parallel with induction of Hsp70. These findings suggest that the ER and cytoplasm of cells contain parallel pathways to coordinately regulate adaptation to febrile hyperthermia associated with disease or infection