Antitumor bioactivity and gut microbiota modulation of polyhydroxybutyrate (PHB) in a rat animal model for colorectal cancer

Polyhydroxybutyrate (PHB) is a non-toxic polyhydroxyalkanoate polymer produced by several microorganisms, widely used as a biological substitute for plastics derived from fossil hydrocarbons. In this work, PHB polymer has been tested in an animal model for colorectal cancer. In the animal model, PHB has been able to reduce the number of polyps by 48,1%, and the tumoral extension area by 58,1%. Also, PHB induces a selective increase in beneficial gut bacterial taxons in this animal model, and a selective reduction in pro-inflammatory taxons, demonstrating its value as a nutraceutical compound. This antitumor effect is caused by gut production of 3hydroxybutyrate and butyrate. In this animal model, 3-hydroxybutyrate is also observed in plasma and in brain tissue, after PHB consumption, making PHB supplementation interesting as a bioactive compound in other extraintestinal conditions, as 3-hydroxybutyrate has been reported to enhance brain and cognitive function, cardiac performance, appetite suppression and diabetes. Therefore, PHB could be postulated as an interesting non-polysaccharide antitumor prebiotic, paving the way towards its future use in functional foods

Immobilization of Monolayer Protected Lipophilic Gold Nanorods on a Glass Surface

We present a novel process of immobilization of gold nanorods (GNRs) on a glass surface. Wedemonstrate that by exploiting monolayer protection of the GNRs, their unusual opticalproperties can be completely preserved. UV–visible spectroscopy and atomic forcemicroscopy analysis are used to reveal the optical and morphological properties of monolayerprotected immobilized lipophilic GNRs, and molecular dynamics simulations are used toelucidate their surface molecule arrangements

Correction: Phosphorescent bio-based resin for digital light processing (DLP) 3D-printing

Correction for 'Phosphorescent bio-based resin for digital light processing (DLP) 3D-printing' by Mirko Maturi et al., Green Chem., 2020, 22, 6212–6224, DOI: 10.1039/D0GC01983F

Itaconic-Acid-Based Sustainable Poly(ester amide) Resin for Stereolithography

Material science is recognized as a frontrunner in achieving a sustainable future, owing to its primary reliance upon petroleum-based chemical raw materials. Several efforts are made to implement common renewable feedstocks as an alternative to common fossil resources. For this purpose, additive manufacturing (AM) represents promising and effective know-how for the replacement of high energy- and resource-demanding processes with more environmentally friendly practices. This work presents a novel biobased ink for stereolithography, which has been formulated by mixing a photocurable poly(ester amide) (PEA) obtained from renewable resources with citrate and itaconate cross-linkers and appropriate photopolymerization initiators, terminators, and dyes. The mechanical features and the relative biocompatibility of 3D-printed objects have been carefully studied to evaluate the possible resin implementation in the field of the textile fashion industry.9 página

In vivo anticancer evaluation of the hyperthermic efficacy of anti-human epidermal growth factor receptor-targeted PEG-based nanocarrier containing magnetic nanoparticles

Polymeric nanoparticles with targeting moieties containing magnetic nanoparticles as theranostic agents have considerable potential for the treatment of cancer. Here we report the chemical synthesis and characterization of a poly(D,L-lactide-co-glycolide)-b-poly(ethylene glycol)-based nanocarrier containing iron oxide nanoparticles and human epithelial growth factor receptor on the outer shell. The nanocarrier was also radiolabeled with (99m)Tc and tested as a theranostic nanomedicine, ie, it was investigated for both its diagnostic ability in vivo and its therapeutic hyperthermic effects in a standard A431 human tumor cell line. Following radiolabeling with (99m)Tc, the biodistribution and therapeutic hyperthermic effects of the nanosystem were studied noninvasively in vivo in tumor-bearing mice. A substantial decrease in tumor size correlated with an increase in both nanoparticle concentration and local temperature was achieved, confirming the possibility of using this multifunctional nanosystem as a therapeutic tool for epidermoid carcinoma

MRE11 inhibition highlights a replication stress-dependent vulnerability of MYCN-driven tumors

MRE11 is a component of the MRE11/RAD50/NBS1 (MRN) complex, whose activity is essential to control faithful DNA replication and to prevent accumulation of deleterious DNA double-strand breaks. In humans, hypomorphic mutations in these genes lead to DNA damage response (DDR)-defective and cancer-prone syndromes. Moreover, MRN complex dysfunction dramatically affects the nervous system, where MRE11 is required to restrain MYCN-dependent replication stress, during the rapid expansion of progenitor cells. MYCN activation, often due to genetic amplification, represents the driving oncogenic event for a number of human tumors, conferring bad prognosis and predicting very poor responses even to the most aggressive therapeutic protocols. This is prototypically exemplified by neuroblastoma, where MYCN amplification occurs in about 25% of the cases. Intriguingly, MRE11 is highly expressed and predicts bad prognosis in MYCN-amplified neuroblastoma. Due to the lack of direct means to target MYCN, we explored the possibility to trigger intolerable levels of replication stress-dependent DNA damage, by inhibiting MRE11 in MYCN-amplified preclinical models. Indeed, either MRE11 knockdown or its pharmacological inhibitor mirin induce accumulation of replication stress and DNA damage biomarkers in MYCN-amplified cells. The consequent DDR recruits p53 and promotes a p53-dependent cell death, as indicated by p53 loss- and gain-of-function experiments. Encapsulation of mirin in nanoparticles allowed its use on MYCN-amplified neuroblastoma xenografts in vivo, which resulted in a sharp impairment of tumor growth, associated with DDR activation, p53 accumulation, and cell death. Therefore, we propose that MRE11 inhibition might be an effective strategy to treat MYCN-amplified and p53 wild-type neuroblastoma, and suggest that targeting replication stress with appropriate tools should be further exploited to tackle MYCN-driven tumors

Loco-regional treatment with temozolomide-loaded thermogels prevents glioblastoma recurrences in orthotopic human xenograft models

Glioblastoma multiforme (GBM) is the most aggressive primary tumor of the central nervous system and the diagnosis is often dismal. GBM pharmacological treatment is strongly limited by its intracranial location beyond the blood–brain barrier (BBB). While Temozolomide (TMZ) exhibits the best clinical performance, still less than 20% crosses the BBB, therefore requiring administration of very high doses with resulting unnecessary systemic side efects. Here, we aimed at designing new negative temperature‐responsive gel formulations able to locally release TMZ beyond the BBB. The biocompatibility of a chitosan‐β‐glycerophosphate‐based thermogel (THG)‐containing mesoporous SiO2 nanoparticles (THG@SiO2) or polycaprolactone microparticles (THG@PCL) was ascertained in vitro and in vivo by cell counting and histological examination. Next, we loaded TMZ into such matrices (THG@SiO2‐TMZ and THG@PCL‐TMZ) and tested their therapeutic potential both in vitro and in vivo, in a glioblastoma resection and recurrence mouse model based on orthotopic growth of human cancer cells. The two newly designed anticancer formulations, consisting in TMZ‐silica (SiO2@TMZ) dispersed in the thermogel matrix (THG@SiO2‐TMZ) and TMZ, spray‐dried on PLC and incorporated into the thermogel (THG@PCL‐TMZ), induced cell death in vitro. When applied intracranially to a resected U87‐MG‐Red‐FLuc human GBM model, THG@SiO2‐TMZ and THG@PCL‐ TMZ caused a signifcant reduction in the growth of tumor recurrences, when compared to untreated controls. THG@SiO2‐TMZ and THG@PCL‐TMZ are therefore new promising gel‐based local therapy candidates for the treatment of GBM

Early diagnosis of bladder cancer by photoacoustic imaging of tumor-targeted gold nanorods

Detection and removal of bladder cancer lesions at an early stage is crucial for preventing tumor relapse and progression. This study aimed to develop a new technological platform for the visualization of small and flat urothelial lesions of high-grade bladder carcinoma in situ (CIS). We found that the integrin alpha 581, overexpressed in bladder cancer cell lines, murine orthotopic bladder cancer and human bladder CIS, can be exploited as a receptor for targeted delivery of GNRs functionalized with the cyclic CphgisoDGRG peptide (Iso4). The GNRs@Chit-Iso4 was stable in urine and selectively recognized alpha 581 positive neoplastic urothelium, while low frequency ultrasound-assisted shaking of intravesically instilled GNRs@Chit-Iso4 allowed the distribution of nanoparticles across the entire volume of the bladder. Photoacoustic imaging of GNRs@Chit-Iso4 bound to tumor cells allowed for the detection of neoplastic lesions smaller than 0.5 mm that were undetectable by ultrasound imaging and bioluminescence

Synthesis and functionalization of protease-activated nanoparticles with tissue plasminogen activator peptides as targeting moiety and diagnostic tool for pancreatic cancer

Background: Functionalized nanoparticles (NPs) are one promising tool for detecting specific molecular targets and combine molecular biology and nanotechnology aiming at modern imaging. We aimed at ligand-directed delivery with a suitable target-biomarker to detect early pancreatic ductal adenocarcinoma (PDAC). Promising targets are galectins (Gal), due to their strong expression in and on PDAC-cells and occurrence at early stages in cancer precursor lesions, but not in adjacent normal tissues. Results: Molecular probes (10-29 AA long peptides) derived from human tissue plasminogen activator (t-PA) were selected as binding partners to galectins. Affinity constants between the synthesized t-PA peptides and Gal were determined by microscale thermophoresis. The 29 AA-long t-PA-peptide-1 with a lactose-functionalized serine revealed the strongest binding properties to Gal-1 which was 25-fold higher in comparison with the native t-PA protein and showed additional strong binding to Gal-3 and Gal-4, both also over-expressed in PDAC. t-PA-peptide-1 was selected as vector moiety and linked covalently onto the surface of biodegradable iron oxide nanoparticles (NPs). In particular, CAN-doped maghemite NPs (CAN-Mag), promising as contrast agent for magnetic resonance imaging (MRI), were selected as magnetic core and coated with different biocompatible polymers, such as chitosan (CAN-Mag-Chitosan NPs) or polylactic co glycolic acid (PLGA) obtaining polymeric nanoparticles (CAN-Mag@PNPs), already approved for drug delivery applications. The binding efficacy of t-PA-vectorized NPs determined by exposure to different pancreatic cell lines was up to 90%, as assessed by flow cytometry. The in vivo targeting and imaging efficacy of the vectorized NPs were evaluated by applying murine pancreatic tumor models and assessed by 1.5 T magnetic resonance imaging (MRI). The t-PA-vectorized NPs as well as the protease-activated NPs with outer shell decoration (CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1Lac) showed clearly detectable drop of subcutaneous and orthotopic tumor staining-intensity indicating a considerable uptake of the injected NPs. Post mortem NP deposition in tumors and organs was confirmed by Fe staining of histopathology tissue sections. Conclusions: The targeted NPs indicate a fast and enhanced deposition of NPs in the murine tumor models. The CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1Lac interlocking steps strategy of NPs delivery and deposition in pancreatic tumor is promising