Biology subjects

Josserand, V.

Publications and source records attributed to Josserand, V..

9 recordsLinked to original sources

bioRxiv2025

Radiotherapy Enhancement by Gold Nanocluster-functionalized Nanoliposomes Using Polychromatic Orthovoltage X-ray Irradiation

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, as the most effective chemoradiation therapies achieve unsatisfactory outcomes while associated with high toxicity. Nanoliposomal drug delivery systems are widely used to improve chemotherapy safety, yet passive release of amphiphilic drugs may still associate with adverse toxicity. To address this, we previously developed nanoliposomes functionalized with hydrophobic gold nanoclusters, demonstrating radiocatalytic activity and enhanced chemoradiotherapy effects in 3D PDAC microtumors under synchrotron irradiation. In this study, gold nanocluster-functionalized nanoliposomes (AuLPs) were optimized and evaluated under 220 kVp orthovoltage X-ray irradiation, widely used in preclinical irradiation systems. AuLPs containing 0.2 mol% gold nanoclusters produced 1.5-fold more reactive oxygen species than unloaded liposomes. However, higher molar ratios were necessary to improve radiotherapy outcomes in 3D PDAC microtumor models following 4 and 8 Gy irradiation. Pharmacokinetics and biodistribution evaluations showed a modest increase in tumor gold content 24 hours post-injection in orthotopic PDAC models. Altogether, these results underscore the potential of gold-radiotherapy-responsive liposomes while highlighting critical formulation challenges, which must be resolved for full therapeutic potential.

bioengineering↗

bioRxiv2025

The delivery of nano-formulated drugs to solid tumours is selectively increased by co-application of the vascular disrupting agent CA4P

Improving the efficacy of existing cytotoxic chemotherapeutics requires increasing drug delivery to tumours while minimising systemic toxicity. Formulating these drugs as nanoparticles can reduce their exposure to healthy tissues, but broadly applicable strategies to enhance tumoral accumulation are lacking. Here, we show that co-administering small molecule vascular disrupting agents together with nanoparticle formulations (e.g. diagnostic reporters, or clinical drugs irinotecan and doxorubicin) increases their tumoral uptake by up to threefold, without raising systemic exposure. In a syngeneic mouse model of triple-negative breast cancer, this enhancement diminished when co-treatments were repeated, limiting its therapeutic benefit. However, since most solid tumour types are susceptible to vascular disrupting agents, this approach may be a broadly applicable strategy to improve the selectivity of drug delivery: with particular relevance for single dose use in diagnostic or research settings. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/669501v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@a5b07corg.highwire.dtl.DTLVardef@1e5dcd2org.highwire.dtl.DTLVardef@49134org.highwire.dtl.DTLVardef@1d90aae_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Lipid nanoemulsion incorporating DOTAP reverse micelles as clinically translatable carriers of ALDH inhibitors for lung cancer therapy

Lung cancer remains the most prevalent malignancy worldwide and the leading cause of cancer-related deaths. In this study, we designed and optimized a lipid nanosystem incorporating the cationic lipid DOTAP by utilizing reverse micelle structures to enhance pulmonary tropism. Fluorescence quenching assays confirmed the incorporation of reverse micelles into the oily core, thus validating the structural integrity of the system. This nanosystem was tailored for the encapsulation of ABD0171, a potent inhibitor of ALDH1A3, an enzyme strongly associated with chemoresistance in lung cancer. Physicochemical characterization revealed robust colloidal properties with a particle diameter of 60 nm, a surface charge of +45 mV, and a drug encapsulation yield of 99%. In vitro, formulations with/without DOTAP demonstrated high efficacy against epithelial-like H358 cells derived from human bronchioalveolar carcinoma, with IC50 values < 5 {micro}M. Chicken ChorioAllantoic Membrane (CAM) evaluations demonstrated good tolerability of the DOTAP-containing formulation and significant H358 tumor reduction by 28% compared with the untreated control, while maintaining a favorable safety profile. By combining industrially feasible methods with FDA-approved components, this study demonstrated the potential of DOTAP-containing lipid nanosystems as scalable platforms for the delivery of ALDH inhibitors for lung cancer treatment. These findings provide a pathway for future applications in cancer therapy, bridging the gap between nanosystem innovation and clinical translation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/659868v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@dbc8org.highwire.dtl.DTLVardef@5d5187org.highwire.dtl.DTLVardef@9391f3org.highwire.dtl.DTLVardef@52fd54_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

bioengineering↗

bioRxiv2025

Preventing neuropathy and improving anti-cancer chemotherapy with a carbazole-based compound

Advances in cancer treatment have led to a steady increase in the rate of disease remission. However, while many treatment-related adverse effects gradually resolve after therapy, chemotherapy-induced peripheral neuropathy (CIPN) often persists, with no means of prevention or direct treatment available. Herein, we present Carba1, a novel bi-functional carbazole that mitigates neuropathy through two distinct mechanisms. First, by interacting with tubulin, Carba1 reduces the required dose of taxanes, widely used chemotherapy drugs notorious for their toxic side effects, including CIPN. Second, Carba1 activates nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway, triggering a metabolic rewiring that enhances the resilience of neurons and Schwann cells against chemotherapy-induced toxicity. We demonstrate the neuroprotective efficacy of Carba1 both in vitro, against neurotoxicity induced by paclitaxel (PTX), cisplatin, and bortezomib, and in vivo in a rat model of PTX-induced neuropathy. Importantly, we establish that Carba1 does not compromise the therapeutic efficacy of PTX nor promotes tumor growth. Comparative analyses of Carba1 derivatives further suggest the potential of designing compounds with either dual synergistic and neuroprotective activity or exclusive neuroprotective properties. Altogether, our findings position Carba1 as a promising therapeutic candidate for preventing CIPN, with the potential, if successfully translated to clinical settings, to improve both the quality of life and treatment outcome for cancer patients.

cancer biology↗

bioRxiv2024

Tumor-associated macrophages confer resistance to chemotherapy (Trifluridine/Tipiracil) in digestive cancers by overexpressing Thymidine Phosphorylase

Pyrimidine analogs are part of the first-line chemotherapy regimen for gastrointestinal cancers. Trifluridine combined with tipiracil, a specific thymidine phosphorylase inhibitor, in TAS-102 has recently emerged as a potential alternative in the face of primary or secondary chemoresistance to 5-fluorouracil. Despite its promise, in the current study, we report that macrophage-specific overexpression of thymidine phosphorylase results in macrophage-induced chemoresistance to TAS-102 that is insensitive to tipiracil inhibition. In addition, we demonstrate the human specificity of this mechanism, as mouse macrophages do not express significant levels of thymidine phosphorylase. To study the importance of macrophages in chemoresistance to trifluridine, we developed a humanized mouse model with tumor-implanted human macrophages and demonstrated their important role in treatment resistance to pyrimidine analogs. We also showed in human colorectal cancer that macrophages represent a major source of thymidine phosphorylase expression leading to chemoresistance. SignificanceThymidine phosphorylase overexpression in TAMs confers chemoresistance to TAS-102 in digestive cancers.

pathology↗

bioRxiv2023

Sperm motility restoration in mice suffering from oligo-astheno-teratozoospermia by in vivo injection and electroporation of naked mRNA

Oligo-astheno-teratozoospermia (OAT), a recurent cause of male infertility, is the most frequent disorder of spermatogenesis with a probable genetic cause. Patients and mice bearing mutations in the ARMC2 gene have a decreased sperm concentration, and individual sperm show multiple morphological defects and a lack of motility - a canonical OAT phenotype. Intracytoplasmic sperm injection (ICSI) is required to treat such a condition but it is associated with a small increase in birth defects in comparison to pregnancies not involving assisted conception. Consequently, new targeted treatments are needed to restore fertility. Here, a combination of in vivo injection and electroporation of capped and poly-A-tailed naked mRNA is tested as a strategy to treat ARMC2-related infertility in mouse. mRNAs coding for several reporter genes are tested and the efficiency and the kinetic of expression are assessed using in vivo and in vitro 2D and 3D imaging experiments. We show that mRNA-coded reporter proteins are detected for up to 3 weeks in germ cells, making the use of mRNA possible to treat infertility. We compare these results with those obtained with a non-integrative plasmid Enhanced Episomal Vector (EEV), which induces low and transient expression in spermatogenic cells. Consequently, injection and electroporation of naked mRNA-Armc2 into the testes of Armc2-deficient males were performed and we show the presence of normal and motile sperm in the epididymis. These motile sperm were able to produce embryos by IVF and ICSI. This study demonstrates, for the first time, that mRNA electroporation can restore sperm motility and partially fertilizing ability, providing a proof-of-concept for mRNA-based strategies to correct monogenic causes of male infertility and opening new avenues for male infertility treatment.

molecular biology↗

bioRxiv2022

3D-printed polymeric scaffolds with optimized architecture to repair a sheep metatarsal critical-size bone defect

The reconstruction of critical-size bone defects in long bones remains a challenge for clinicians. We developed a new bioactive medical device for long bone repair by combining a 3D-printed architectured cylindrical scaffold made of clinical-grade polylactic acid (PLA) with a polyelectrolyte film coating delivering the osteogenic bone morphogenetic protein 2 (BMP-2). This film-coated scaffold was used to repair a sheep metatarsal 25-mm long critical-size bone defect. In vitro and in vivo biocompatibility of the film-coated PLA material were proved according to ISO standards. Scaffold geometry was found to influence BMP-2 incorporation. Bone regeneration was followed using X-ray scans, {micro}CT scans, and histology. We showed that scaffold internal geometry, notably pore shape, influenced bone regeneration, which was homogenous longitudinally. Scaffolds with cubic pores of [~]870 {micro}m and a low BMP-2 dose of [~]120 {micro}g/cm3 induced the best bone regeneration without any adverse effects. The visual score given by clinicians during animal follow-up was found to be an easy way to predict bone regeneration. This work opens perspectives for a clinical application in personalized bone regeneration.

bioengineering↗

bioRxiv2020

Two antagonistic microtubule targeting drugs act synergistically to kill cancer cells

Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for drugs which could potentiate its therapeutic effect. We have screened a chemical library and selected Carba1, a carbazolone, which exerts synergistic cytotoxic effects on tumor cells grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. The Carba1-induced modulation of microtubule dynamics increases the accumulation of fluorescent paclitaxel inside microtubules, providing a mechanistic explanation of the observed synergy between Carba1 and paclitaxel. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring paclitaxel accumulation in microtubules can be transposed to in vivo mouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action.

cancer biology↗

bioRxiv2020

Non-invasive, Real-time Detection of Vascular Disorders in Mice using Bright SWIR-emitting Gold Nanoclusters and Monte Carlo Image Analysis

We present here a new approach for non-invasive high resolution whole-body vascular imaging in depth by combining water-soluble and bright SWIR-emitting gold nanoclusters revealing an anisotropic surface charge with Monte Carlo image processing of the images. We applied and validated this approach to quantify vessel complexity in transgenic mice presenting vascular disorders.

bioengineering↗