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Anne Rodallec,1 Jean-Michel Brunel,2 Sarah Giacometti,1 Helene Maccario,3 Florian Correard,3 Eric Mas,3 Caroline Orneto,4 Ariel Savina,5 Fanny Bouquet,5 Bruno Lacarelle,1 Joseph Ciccolini,1 Raphaelle Fanciullino11SMARTc Unit, Pharmacokinetics Laboratory, CRCM UMR U1068 CNRS UMR 7258 Aix Marseille Université, Marseille, France; 2CRCM CNRS UMR 7258 Aix Marseille Université, Marseille, France; 3CRO2 UMR S_911 Aix Marseille Université, Marseille, France; 4Biopharmacy Laboratory, Aix Marseille Université, Marseille, France; 5Institut Roche, Boulogne Billancourt Cedex, FranceBackground: Trastuzumab plus docetaxel is a mainstay to treat HER2-positive breast cancers. However, developing nanoparticles could help to improve the efficacy/toxicity balance of this doublet by improving drug trafficking and delivery to tumors. This project aimed to develop an immunoliposome in breast cancer, combining docetaxel encapsulated in a stealth liposome engrafted with trastuzumab, and comparing its performances on human breast cancer cell lines with standard combination of docetaxel plus trastuzumab.Methods: Several strategies to engraft trastuzumab to pegylated liposomes were tested. Immunoliposomes made of natural (antibody nanoconjugate-1 [ANC-1]) and synthetic lipids (ANC-2) were synthesized using standard thin film method and compared in size, morphology, docetaxel encapsulation, trastuzumab engraftment rates and stability. Antiproliferative activity was tested on human breast cancer models ranging from almost negative (MDA-MB-231), positive (MDA-MB-453) to overexpressing (SKBR3) HER2. Finally, cell uptake of ANC-1 was studied by electronic microscopy.Results: ANC-1 showed a greater docetaxel encapsulation rate (73%±6% vs 53%±4%) and longer stability (up to 1 week) as compared with ANC-2. Both ANC presented particle size ≤150 nm and showed similar or higher in vitro antiproliferative activities than standard treatment, ANC-1 performing better than ANC-2. The IC50s for docetaxel combined to free trastuzumab were 8.7±4, 2±0.7 and 6±2 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. The IC50s for ANC-1 were 2.5±1, 1.8±0.6 and 3.4±0.8 nM and for ANC-2 were 1.8±0.3 nM, 2.8±0.8 nM and 6.8±1.8 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. Cellular uptake appeared to depend on HER2 expression, the higher the expression, the higher the uptake.Conclusion: In vitro results suggest that higher antiproliferative efficacy and efficient drug delivery can be achieved in breast cancer models using nanoparticles.Keywords: immunoliposomes, biopharmaceutical development, breast cancer, docetaxel, trastuzumab, HER2

Background/Objective: Little information is available on the stability and quality controls of compounded 40% dextrose gel required to ensure its safe use in the treatment and prevention of neonatal hypoglycemia. Whether its efficacy relies on buccal absorption also remains uncertain. This study investigates the stability, microbiological safety, rheological properties and dextrose diffusion of a compounded 40% oral dextrose gel, ensuring it can be widely compounded and stored for clinical use. Methods: A 40% dextrose gel compounded with anhydrous dextrose, carboxymethylcellulose, citric acid, sorbic acid and sterile water was subjected to quality control measures including a dextrose content assay, degradation product analysis, microbiological testing and preservative efficacy. Stability studies were conducted at refrigerated (4-8 °C) and ambient temperatures for 7 days and 3 months, respectively. Rheological properties were assessed, and dextrose permeation was measured through an artificial membrane model that mimics a biological membrane. Results: The compounded gel demonstrated stability for up to 7 days at ambient temperature and 90 days when refrigerated. The dextrose content remained within the acceptable range (90-110%) and microbiological tests confirmed compliance with safety standards. The gel exhibited the consistent rheological properties and shear-thinning behavior appropriate for oral mucosal administration. In vitro permeation studies showed no evidence of dextrose diffusion with a long lag time followed by a low steady-state permeation flux. Conclusions: This study validates the compounding process of a stable 40% oral dextrose gel formulation for neonatal hypoglycemia management, which meets quality control criteria and can be safely administered in clinical practice, offering a cost-effective and safe alternative for neonatal care.

Pyomelanin is a brown-black phenolic polymer and results from the oxidation of homogentisic acid (HGA) in the L-tyrosine pathway. As part of the research for natural and active ingredients issued from realistic bioprocesses, this work re-evaluates the HGA pigment and makes an updated inventory of its syntheses, microbial pathways, and properties, with tracks and recent advances for its large-scale production. The mechanism of the HGA polymerization is also well documented. In alkaptonuria, pyomelanin formation leads to connective tissue damage and arthritis, most probably due to the ROS issued from HGA oxidation. While UV radiation on human melanin may generate degradation products, pyomelanin is not photodegradable, is hyperthermostable, and has other properties better than L-Dopa melanin. This review aims to raise awareness about the potential of this pigment for various applications, not only for skin coloring and protection but also for other cells, materials, and as a promising (semi)conductor for bioelectronics and energy., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society of Industrial Microbiology and Biotechnology.)