Search

Despite the advent of numerous targeted therapies in clinical practice, anthracyclines, including doxorubicin (DOX), continue to play a pivotal role in breast cancer (BC) treatment. DOX directly disrupts DNA replication, demonstrating remarkable efficacy against BC cells. However, its non-specificity toward cancer cells leads to significant side effects, limiting its clinical utility. Interestingly, DOX can also enhance the antitumor immune response by promoting immunogenic cell death in BC cells, thereby facilitating the presentation of tumor antigens to the adaptive immune system. However, the generation of an adaptive immune response involves highly proliferative processes, which may be adversely affected by DOX-induced cytotoxicity. Therefore, understanding the impact of DOX on dividing T cells becomes crucial, to deepen our understanding and potentially devise strategies to shield anti-tumor immunity from DOX-induced toxicity. Our investigation focused on studying DOX uptake and its effects on human lymphocytes. We collected lymphocytes from healthy donors and BC patients undergoing neoadjuvant chemotherapy (NAC). Notably, patient-derived peripheral blood mononuclear cells (PBMC) promptly internalized DOX when incubated in vitro or isolated immediately after NAC. These DOX-treated PBMCs exhibited significant proliferative impairment compared to untreated cells or those isolated before treatment initiation. Intriguingly, among diverse lymphocyte sub-populations, CD8 + T cells exhibited the highest uptake of DOX. To address this concern, we explored a novel DOX formulation encapsulated in ferritin nanocages (FerOX). FerOX specifically targets tumors and effectively eradicates BC both in vitro and in vivo. Remarkably, only T cells treated with FerOX exhibited reduced DOX internalization, potentially minimizing cytotoxic effects on adaptive immunity. Our findings underscore the importance of optimizing DOX delivery to enhance its antitumor efficacy while minimizing

Brain metastasis (BM) represents a clinical challenge for patients with advanced HER2 + breast cancer (BC). The monoclonal anti-HER2 antibody trastuzumab (TZ) improves survival of BC patients, but it has low central nervous system penetrance, being ineffective in treating BM. Previous studies showed that ferritin nanoparticles (HFn) may cross the blood brain barrier (BBB) through binding to the transferrin receptor 1 (TfR1). However, whether this has efficacy in promoting the trans-BBB delivery of TZ and combating BC BM was not studied yet. Here, we investigated the potential of HFn to drive TZ brain delivery and promote a targeted antitumor response in a murine model of BC BM established by stereotaxic injection of engineered BC cells overexpressing human HER2. HFn were covalently conjugated with TZ to obtain a nanoconjugate endowed with HER2 and TfR1 targeting specificity (H-TZ). H-TZ efficiently achieved TZ brain delivery upon intraperitoneal injection and triggered stable targeting of cancer cells. Treatment with H-TZ plus docetaxel significantly reduced tumor growth and shaped a protective brain microenvironment by engaging macrophage activation toward cancer cells. H-TZ-based treatment also avoided TZ-associated cardiotoxicity by preventing drug accumulation in the heart and did not induce any other major side effects when combined with docetaxel. These results provided in vivo demonstration of the pharmacological potential of H-TZ, able to tackle BC BM in combination with docetaxel. Indeed, upon systemic administration, the nanoconjugate guides TZ brain accumulation, reduces BM growth and limits side effects in off-target organs, thus showing promise for the management of HER2 + BC metastatic to the brain.

Background: Bisdemethoxycurcumin (BDC) might be an inflammation inhibitor in Alzheimer's Disease (AD). However, BDC is almost insoluble in water, poorly absorbed by the organism, and degrades rapidly. We thus developed a new nanoformulation of BDC based on H-Ferritin nanocages (BDC-HFn). Methods: We tested the BDC-HFn solubility, stability, and ability to cross a blood-brain barrier (BBB) model. We tested the effect of BDC-HFn on AD and control (CTR) PBMCs to evaluate the transcriptomic profile by RNA-seq. Results: We developed a nanoformulation with a diameter of 12 nm to improve the solubility and stability. The comparison of the transcriptomics analyses between AD patients before and after BDC-HFn treatment showed a major number of DEG (2517). The pathway analysis showed that chemokines and macrophages activation differed between AD patients and controls after BDC-HFn treatment. BDC-HFn binds endothelial cells from the cerebral cortex and crosses through a BBB in vitro model. Conclusions: Our data showed how BDC-Hfn could improve the stability of BDC. Significant differences in genes associated with inflammation between the same patients before and after BDC-Hfn treatment have been found. Inflammatory genes that are upregulated between AD and CTR after BDC-HFn treatment are converted and downregulated, suggesting a possible therapeutic approach.

The design and development of contrast agents (CAs) for magnetic resonance imaging (MRI) in clinical analysis is expected to improve the image spatial resolution and to increase the detection sensitivity, especially regarding neurological disorders and cancer disease. In particular, advanced CAs for T1-weighted images are investigated to achieve the sensitive detection of early-stage primary tumors or brain metastases. In this study, we present a strategy toward diagnostic T1 CAs for MRI, based on polymer-modified MnO nanoparticles (NPs). Two different nanosystems were synthesized, consisting of (1) colloidal MnO nanocrystals wrapped by a multidentate amphiphilic polymer and (2) MnO nanocrystals embedded within poly(lactic-co-glycolic acid) (PLGA) NPs. These nanosystems were compared in terms of their MRI contrast power and biological safety. The latter system combines the excellent biocompatibility of PLGA with the unique magnetic properties of MnO NPs and allows sustained contrast enhancement over time. Longitudinal relaxivities of both MnO composite nanomaterials proved to be higher than those of commercial Gd-based CAs and Teslascan, both in phosphate-buffered saline and in plasma, also exhibiting low cytotoxicity. The high relaxation rates achieved with these contrast enhancers are promising toward future application in in vivo imaging.

Purpose: Assessment of inflammatory bowel disease (IBD) currently relies on aspecific clinical signs of bowel inflammation. Specific imaging of the diseased bowel regions is still lacking. Here, we investigate mucosal addressin cell adhesion molecule 1 (MAdCAM-1) as a reliable and specific endothelial target for engineered nanoparticles delivering imaging agents to obtain an exact mapping of diseased bowel foci. Materials and Methods: We generated a nanodevice composed of PLGA-PEG coupled with anti-MAdCAM-1 antibody half-chains and loaded with quantum dots (P@QD-MdC NPs). Bowel localization and systemic biodistribution of the nanoconjugate were analyzed upon injection in a murine model of chronic IBD obtained through repeated administration of dextran sulfate sodium salt. Specificity for diseased bowel regions was also assessed ex vivo in human specimens from patients with IBD. Potential for development as contrast agent in magnetic resonance imaging was assessed by preliminary study on animal model. Results: Synthesized nanoparticles revealed good stability and monodispersity. Molecular targeting properties were analyzed in vitro in a cell culture model. Upon intravenous injection, P@QD-MdC NPs were localized in the bowel of colitic mice, with enhanced accumulation at 24 h post-injection compared to untargeted nanoparticles (p<0.05). Nanoparticles injection did not induce histologic lesions in non-target organs. Ex vivo exposure of human bowel specimens to P@QD-MdC NPs revealed specific recognition of the diseased regions vs uninvolved tracts (p<0.0001). After loading with appropriate contrast agent, the nanoparticles enabled localized contrast enhancement of bowel mucosa in the rectum of treated mice. Conclusion: P@QD-MdC NPs efficiently detected bowel inflammation foci, accurately following the expression pattern of MAdCAM-1. Fine-tuning of this nanoconjugate with appropriate imaging agents offers a promising non-invasive tool for specific IBD diagnosis.

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.

Vascular surgery patients have multiple comorbidities and are at high risk for perioperative complications. Aortic repair surgery has greatly evolved in recent years, with an increasing predominance of endovascular techniques (EVAR). The incidence of cardiac complications is significantly reduced with endovascular repair, but high-risk patients require postoperative ST-segment monitoring. Open aortic repair may portend a prohibitive risk of respiratory complications that could be a contraindication for surgery. This risk is greatly reduced in the case of an endovascular approach, and general anesthesia should be avoided whenever possible in the case of endovascular repair. Preoperative renal function and postoperative kidney injury are powerful determinants of short- and long-term outcome, so that preoperative risk stratification and secondary prevention are critical tasks. Intraoperative renal protection with selective renal and distal aortic perfusion is essential during open repair. EVAR has lower rates of postoperative renal failure compared to open repair, with approximately half the risk for acute kidney injury (AKI) and one-third of the risk of hemodialysis requirement. Spinal cord ischemia used to be the most distinctive and feared complication of aortic repair. The risk has significantly decreased since the beginning of aortic surgery, with advances in surgical technique and spinal protection protocols, and is lower with endovascular repair. Endovascular repair avoids extensive aortic dissection and aortic cross-clamping and is generally associated with reduced blood loss and less coagulopathy. The intensive care physician must be aware that aortic repair surgery has an impact on every organ system, and the importance of early recognition of organ failure cannot be overemphasized.

The efficient targeting of cancer cells depends on the success of obtaining the active targeting of overexpressed receptors. A very accurate design of nanoconjugates should be done via the selection of the conjugation strategy to achieve effective targeted nanoconjugates. Here, we present a detailed study of cetuximab-conjugated nonspherical gold nanocages for the active targeting of triple-negative breast cancer cells, including MDA-MB-231 and MDA-MB-468. A few different general strategies were selected for monoclonal antibody conjugation to the nanoparticle surface. By varying the bioconjugation conditions, including antibody orientation or the presence of a polymeric spacer or recombinant protein biolinker, we demonstrate the importance of a rational design of nanoconjugates. A quantitative study of gold content via ICP-AES allowed us to compare the effectiveness of cellular uptake as a function of the conjugation strategy and confirmed the active nature of nanoparticle internalization in cancer cells via epidermal growth factor receptor recognition, corroborating the importance of the rational design of nanomaterials for nanomedicine.

Monoclonal antibodies (mAbs) have been developed to improve the treatment of cancer patients. They are able to target certain cancer antigens and possess multiple relevant mechanisms of action (i) modifying the host response to the malignant cells, (ii) delivering cytotoxic moieties, (iii) redirecting T cells towards the cancer to reduce cancer progression inducing an anti-tumour immune response [1, 2]. The research of different formats of antibody fragments, such as single chain variable fragment (scFv), Fab, nanobody, bispecific antibody, bifunctional antibody and half-chain antibodies (HC-mAbs) has been focused on the discovery of valuable alternatives to the nanoconjugation of entire mAbs, which could be able to maintain their functional potential [3]. Many monoclonal antibodies approved for therapeutic purposes or are under clinical investigation. Among them, Cetuximab (CTX): a recombinant human/mouse chimeric monoclonal antibody which binds to the tyrosine-kinase Epidermal Growth Factor Receptor (EGFR). It acts by blocking the dimerization of EGFR thus inhibiting downstream signalling pathways. CTX-based treatments suffer of several limitations: inadequate pharmacokinetics, short circulation half-life, low tumour penetration and activation of the autoimmune response [4]. In this context, the rise of nanotechnology has offered new opportunities of treatment with mAbs, exploiting new strategies of conjugation to nanoparticles (NPs) or of incorporation within nanocarriers in order to overcome the major limitations of the mAbs-based conventional therapy [5]. Here, we investigated the effect of a CTX-nanoconjugate on triple negative breast cancer (TNBC). TNBC is a particularly aggressive subtype of breast cancer characterized by high heterogeneity and different molecular expression profiles, which make even more difficult the establishment of targeted therapy to control tumour growth [6]. The majority of TNBCs cell lines are characterized by the overexpression of E

Brain cancers are a group of neoplasms that can be either primary, such as glioblastoma multiforme (GBM), or metastatic, such as the HER2+ breast cancer brain metastasis. The brain represents a sanctuary for cancer cells thanks to the presence of the blood brain barrier (BBB) that controls trafficking of molecules, protecting the brain from toxic substances including drugs. Considering that GBM and HER2+ breast cancer brain metastases are characterized by EGFR and HER2 over-expression respectively, CTX- and TZ-based treatment could be effective. Several studies show that these monoclonal antibodies (mAbs) exert both a cytostatic activity interfering with the transduction pathways of EGFR family and a cytotoxic activity mainly through the immune system activation via the antibody dependent cell-mediated cytotoxicity (ADCC). Since the major limitation to therapeutic mAbs application is the presence of the BBB, here we use a recombinant form of human apoferritin (HFn) as a nanovector to promote the delivery of mAbs to the brain for the activation of the ADCC response. Using a transwell model of the BBB we proved the crossing ability of HFn-mAb. Cellular uptake of HFn-mAb by human cerebral microvascular endothelial cells (hCMEC/D3) was demonstrated by confocal microscopy. Moreover, after crossing the endothelial monolayer, HFn-conjugated mAbs retain their biological activity against targets, as assessed by MTS and ADCC assays. Our data support the use of HFn as efficient carrier to enhance the BBB crossing of mAbs, without affecting their antitumoral activity.

Cancer-associated fibroblasts (CAFs) are key actors in regulating cancer progression. They promote tumor growth, metastasis formation, and induce drug resistance. For these reasons, they are emerging as potential therapeutic targets. Here, with the aim of developing CAF-targeted drug delivery agents, we functionalized H-ferritin (HFn) nanocages with fibroblast activation protein (FAP) antibody fragments. Functionalized nanocages (HFn-FAP) have significantly higher binding with FAP+ CAFs than with FAP cancer cells. We loaded HFn-FAP with navitoclax (Nav), an experimental Bcl-2 inhibitor pro-apoptotic drug, whose clinical development is limited by its strong hydrophobicity and toxicity. We showed that Nav is efficiently loaded into HFn (HNav), maintaining its mechanism of action. Incubating Nav-loaded functionalized nanocages (HNav-FAP) with FAP+ cells, we found significantly higher cytotoxicity as compared to non-functionalized HNav. This was correlated with a significantly higher drug release only in FAP+ cells, confirming the specific targeting ability of functionalized HFn. Finally, we showed that HFn-FAP is able to reach the tumor and to target CAFs in a mouse syngeneic model of triple negative breast cancer after intravenous administration. Our data show that HNav-FAP could be a promising tool to enhance specific drug delivery into CAFs, thus opening new therapeutic possibilities focused on tumor microenvironment.

Motivated by the empirical evidence of high-frequency lead-lag effects and cross-asset linkages, we introduce a multi-asset price formation model which generalizes standard univariate microstructure models of lagged price adjustment. Econometric inference on such model provides: (i) a unified statistical test for the presence of lead-lag correlations in the latent price process and for the existence of a multi-asset price formation mechanism; (ii) separate estimation of contemporaneous and lagged dependencies; (iii) an unbiased estimator of the integrated covariance of the efficient martingale price process that is robust to microstructure noise, asynchronous trading, and lead-lag dependencies. Through an extensive simulation study, we compare the proposed estimator to alternative approaches and show its advantages in recovering the true lead-lag structure of the latent price process. Our application to a set of NYSE stocks provides empirical evidence for the existence of a multi-asset price formation mechanism and sheds light on its market microstructure determinants. Supplementary materials for this article are available online.

This is a case report in which the Anesthetic Management of Patients Undergoing Aortic Dissection Repair With Suspected Severe Acute Respiratory Syndrome Coronavirus Disease 2019 (COVID-19) Infection is reported

Poly(ADP-ribose) polymerase (PARP) inhibitors are a novel promising strategy toward triple-negative breast cancer (TNBC). TNBC is a breast cancer subtype that represents one of the main clinical challenges in cancer treatment due to its heterogeneity, biological behavior, invasiveness and poor prognosis. Moreover, it often shows genomic instability and/or BRCA mutations. However, clinical results obtained with PARP inhibitors are controversial, and no benefits were demonstrated in case of wild type BRCA, possibly due to poor bioavailability and inadequate nuclear delivery [1-4]. Nanotechnology could overcome these major limitations with the development of nanocaged-drugs. Among these, the most promising is represented by H-ferritin (HFn): natural protein-based nanoparticles with native capability of targeting tumor cells thanks to its specific interaction with the TfR1, which is overexpressed in tumor cells. HFn are constituted of self-assembling human H-ferritin monomers arranged in a hollow structure. HFn also possess some other unique features very appealing from the clinical point of view: i) uniform cage architecture, which allows the precise control of the amount of encapsulated drugs; ii) negligible toxicity and immunogenicity; iii) stability in physiological environment as a result of their protein nature, which increases circulation time, protects the cargo molecule from degradation and improves bioavailability[5-7]. The aim of this study was to assess the anticancer efficacy of H-Ferritin nanoformulated Olaparib (HOla) vs. free Olaparib (Ola) on BRCA-mutated and non mutated TNBC cells exploiting both the natural targeting of H-ferritin toward the transferrin receptor-1 and also its physiological tropism toward the nuclear compartment. BRCA-mutated HCC1937 cells and BRCA-wild type MDA MB-231 and MDA MB-468 cells were treated with HOla or Ola in vitro. All TNBC cell lines over-expressed TfR-1 and were succesfully recognized by H-Ferritin, displaying a fast i

Evaluation of acute colitis relies on invasive endoscopic examination to assess the presence and the severity of the disease, and on aspecific radiological signs of bowel inflammation, such as contrast enhancement of bowel wall thickening. Consequently, the current best clinical management only offers an approximation of the real clinical scenario, and has a negative impact on the quality of life of patients. An accurate stadiation of inflammatory bowel diseases for assessment of response to therapies or indication for surgery remains challenging. Here, mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) was investigated as a reliable and specific target of active bowel inflammation, to be exploited for site-specific nanotheranostics in a preclinical murine model of colitis. MAdCAM-1 is a cell adhesion molecule, which is upregulated on gut endothelium in case of inflammation at very early stages of the disease, and is responsible for T cells recruitment in involved bowel tracts. Moreover, it is finely related to activity of inflammatory bowel diseases and correlates with response to therapy. Anti-MAdCAM-1 antibodies were conjugated to the surface of smart and safe delivery nanoparticles, consisting of a manganese oxide core endowed with paramagnetic properties. The aim of the study was to assess the in vivo targeting efficacy and the accuracy of these innovative low-toxic MAdCAM-1-targeted nanoparticles, specifically designed to detect active bowel inflammation foci at early stages of the disease. Manganese oxide nanoparticles revealed good stability and polydispersity. Their negligible citotoxicity was demonstrated on endothelial cell cultures by analysis of viability and apoptosis, and on blood samples by hemolysis assay. Colitis was induced in mice by oral treatment with dextran sulfate sodium, and MAdCAM-1 overexpression was assessed on the intestinal vascular endothelium by immunohistochemistry and western blotting. Fluorescent anti-MAdCAM-1 nanoparticles wer

Curcumin’s pharmacological properties and its possible benefits for neurological diseases and dementia have been much debated. In vitro experiments show that curcumin modulates several key physiological pathways of importance for neurology. However, in vivo studies have not always matched expectations. Thus, improved formulations of curcumin are emerging as powerful tools in overcoming the bioavailability and stability limitations of curcumin. New studies in animal models and recent double-blinded, placebo-controlled clinical trials using some of these new formulations are finally beginning to show that curcumin could be used for the treatment of cognitive decline. Ultimately, this work could ease the burden caused by a group of diseases that are becoming a global emergency because of the unprecedented growth in the number of people aged 65 and over worldwide. In this review, we discuss curcumin’s main mechanisms of action and also data from in vivo experiments on the eects of curcumin on cognitive decline.

Systemic chemotherapy has not significantly reduced clinical demand for triple negative breast cancer (TNBC) treatments. To address the need for more effective therapy, the use of nonviral nanoparticles is explored to deliver suicide gene therapy as valuable alternative to protect nucleic acids in the bloodstream and improve their tumor uptake. Biocompatible cationic lipid nanoparticles are developed as a novel delivery system of a suicide plasmid gene encoding saporin. Active targeting is accomplished by taking advantage of nanoparticle functionalization with U11 peptide, designed to be directed toward urokinase plasminogen activator receptor, limiting off-target toxicity. The antitumor effect of U11-lipid-protamine-DNA (U11-LPD) nanoparticles are tested in TBNC cells, showing a strong prevalence of targeted versus nontargeted nanoparticles in terms of uptake kinetics and proliferation inhibition. Transfection of green fluorescent protein (GFP) plasmid in MDA-MB-231 cells is demonstrated. U11-LPD nanoparticles administered by retro bulbar injection exhibit excellent tumor tropism in TNBC orthotopic xenograft mice and effectively transfect TNBC cells with saporin plasmid resulting in tumor mass reduction. No systemic toxicity or organ damage is discovered after repeated treatments with nanoparticles. The findings suggest that systemic administration of targeted LPD nanoparticles to deliver saporin safely allows for active inhibition of cancer progression even in the absence of specific promoter gene sequences.