Littérature scientifique sur le sujet « Targeted nanotherapy »

(a) Rapamycin nanotherapeutic pre-treatment improves tracheal allograft outcome after transplantation. (b) Nanotherapy reduces aortic allograft vasculopathy. (c) Dose dependency of the nanotherapy in aortic interposition allografts.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Despite advances in treatment, the prognosis remains poor, highlighting the need for novel therapeutic strategies. The present review explores the potential of targeted epidermal growth factor receptor (EGFR) nanotherapy as an alternative treatment for NSCLC, showing that EGFR-targeted nanoparticles are efficiently taken up by NSCLC cells, leading to a significant reduction in tumor growth in mouse models. Consequently, we suggest that targeted EGFR nanotherapy could be an innovative treatment strategy for NSCLC; however, further studies are needed to optimize the nanoparticles and evaluate their safety and efficacy in clinical settings and human trials.

Abstract Purpose This study investigated alpha 4 beta 1/ Very Late Antigen-4 (α4β1/ VLA-4)-integrin targeted nanotherapy approach to deliver a new lipase-labile prodrug. Experimental Design A phospholipid-based MYC-MAX inhibitor prodrug (MI1-PD) was synthesized, and its inherent anti-proliferate potency was compared to the lipid-free compound (MI1) using mouse multiple myeloma (MM) cell line (5TGM1). VLA-4-targeted perfluorocarbon (PFC) nanoparticles binding to 5TGM1 cells was measured and compared to biomarker expression assessed with flow cytometry using antibodies. The efficacy of MI1-PD incorporated into non-targeted and VLA-4-targeted PFC NP exposed to 5TGM1 cells was assessed with MTT assays, Annexin V and cell cycle analysis. Results MI1-PD was more potent by several orders of magnitude than its free drug counterpart in culture. Targeted NP binding correlated well with biomarker expression assessment by flow cytometry in 5TGM1 cells. Non-targeted NPs had no appreciable binding to 5TGM1 cells. High anti-MM potency of MI1-PD was noted in VLA-4-targeted NPs compared to the non-targeted NPs demonstrating that the efficacy was dependent on expression of the targeted biomarker to afford particle-to-cell drug delivery. Conclusions These results suggest the feasibility of an improved integrin VLA-4- targeted nanotherapy approach to deliver a lipase- labile prodrug construct, MI1-PD. Disclosures: No relevant conflicts of interest to declare.

Philosophiae Doctor - PhD
The prevalence of obesity amongst South Africans is alarming, with more than 29% of men and 56% of women considered to be obese. Angiogenesis, a process for development of new blood vessels play a major role in growth and survival of the adipose tissues. Pharmacological inhibitors of angiogenesis are therefore a sensible strategy to reduce excess body weight. Current anti-obesity drugs have limitations because of their lack of selectivity and specificity, which lead to undesirable side effects and reduced drug efficacy. Future anti-obesity therapeutic strategies should be target-specific, with minimal toxicity towards healthy tissues will be more appropriate for obesity treatment. Targeted nano-therapeutic agents are currently being developed to overcome the drawbacks associated with conventional drug therapies. The nano-based delivery vehicles that specifically target diseased cells are appealing as they could reduce drug toxicity towards healthy tissues and be more effective at lower dosages. The main aim of this study was to develop a receptor-mediated nanotherapy that specifically targets the white adipose tissue vasculature and trigger the death of these cells through apoptosis. The 14 nm gold nanoparticles (AuNPs) were synthesized using theTurkevich method following reduction of gold aurate by sodium citrate salt. Different chemistries were used to functionalise the AuNPs for biological application by conjugating with either vascular targeting peptide or pro-apoptotic peptide on their surface or both. The nanomaterials were characterised by UV-Vis, Zeta potential and transmission electron microscopy (TEM). The sensitivity and specificity of various AuNP conjugates were tested in vitro on colon and breast cancer cell lines. A human (Caco-2) cell line that expresses the receptor for the adipose homing peptide was chosen as an in vitro model system. Cellular toxicity and uptake of the nanoparticles was evaluated using the WST-1 assay, Inductively Coupled Plasma-Optical Emission Spectra (ICP-OES) and TEM. The induction of apoptosis following exposure to the nanoparticles was examined by Western blot and flow cytometric analysis. The anti-proliferative activity of the targeted therapeutic nanoparticles on the cells was more pronounced on the cells expressing the receptor for the adipose homing peptide. The uptake of unfunctionalised AuNPs was higher compared to functionalised nanoparticles, but this did not impair cell viability. The activity of the therapeutic peptide was retained and enhanced following conjugation to AuNPs as shown by Western blot and flow cytometric analysis. The nanotherapy under study demonstrated receptor mediated targeting, and enhanced activity on the cells expressing the receptor. However, the therapeutic and efficacy of the targeted nanotherapy still need to be tested in animal models of obesity to confirm the treatment specificity.

Nanoparticles have been utilised in a wide range of applications and they provide unique advantages as drug delivery carriers and imaging agents in biomedicine. In particular, nanoparticles have been employed as therapeutic systems in oncology to overcome the limitations of conventional chemotherapeutics. Melanoma is the cancer of pigment-producing cells in the basal layer of the epidermis. Once metastasised, melanoma is highly aggressive and notoriously difficult to treat with the currently available therapies. In order to improve the therapeutic options available for the treatment of melanoma, we developed iron oxide nanoparticles for use as a melanoma-specific drug delivery system. Iron oxide nanoparticles are useful tools in oncology as their superparamagnetic properties allow them to be used as a delivery system capable of acting as both an imaging contrast agent and a magnetic hyperthermia therapy agent. Here, we developed a targeted iron oxide nanoparticle that exploits the overexpression of melanocortin 1 receptor, which is upregulated on the cell surface of melanoma cells. Surface functionalisation of iron oxide nanoparticles with the melanocortin 1 receptor agonist, α-melanocytes stimulating hormone, increased internalisation of nanoparticles in melanoma cells compared to non-melanoma and melanocyte cell lines. Moreover, the cytotoxic drug paclitaxel, was successfully encapsulated into the outer shell of the nanosystem. Delivery of paclitaxel via melanoma targeted iron oxide nanoparticles led to dose dependent cytotoxicity in melanoma cells. A major limitation in the application of novel nanosystems in the clinic is the lack of an accurate and substantial toxicity assessment at the early stages of development. We addressed this issue by developing a hazard assessment protocol that combines cytotoxicity data with an embryonic vertebrate phenotypic assay to produce an overall toxicity index. Our iron oxide nanoparticle was assessed using this toxicity methodology to confirm they induced no toxic effects, and so were validated for further developed to be used as a therapeutic system.

Grâce à leurs propriétés physico-chimiques et leur biocompatibilité les nanoparticules magnétiques d'oxyde de fer (SPION) offrent de nombreux avantages. Elles répondent à l'application de champs magnétiques en libérant de l'énergie thermique en réponse à l'application d'un champ magnétique alternatif à haute fréquence (AMF), ou générant des forces mécaniques exposées à des champs magnétiques rotatifs à basse fréquence (RMF). Des essais cliniques utilisant le principe de l'hyperthermie magnétique ont été menés sur le glioblastome et le cancer de la prostate en association avec de la radiothérapie. Néanmoins, le bénéfice était négligeable en raison d'effets indésirables sur les tissus sains adjacents. Or, notre équipe a précédemment montré qu'il était possible d'induire spécifiquement la mort de cellules grâce à de faibles concentrations de SPION vectorisées qui s'accumulent spécifiquement dans les lysosomes de cellules ciblées. L'application d'AMF va induire la mort des cellules-cibles par hyperthermie magnétique intra-lysosomale ciblée MILH via la production de ROS dans le lysosome selon la réaction de Fenton qui nécessite des ions Fe et peut être catalysée par un pH acide et une augmentation de la température. Cependant, l'origine des ions Fe impliqués dans la réaction de Fenton n'a pas été élucidée. Une autre stratégie a également été établie dans l'équipe ; elle repose sur l'application de champs RMF qui vont générer des forces mécaniques à partir des SPION et induire la mort des cellules par ablation mécanique intra-lysosomale ciblée. Nous avons choisi comme modèle, l'adénocarcinome pancréatique particulièrement résistant aux thérapies conventionnelles et caractérisé par la présence d'un microenvironnement important et dense. Dans ce microenvionnement, les CAF (Cancer Associated Fibroblast) jouent un rôle clef, notamment par la sécrétion de matrice extracellulaire et de molécules solubles, limitant la pénétration et l'efficacité des traitements et contribuant à l'acquisition de résistance. Les cellules cancéreuses et les CAF peuvent surexprimer le récepteur de type 2 de la cholécystokinine (RCCK2). Ce récepteur membranaire présente la propriété de s'internaliser après fixation de son agoniste spécifique : la gastrine. Afin de cibler spécifiquement ces cellules, l'équipe a développé, des SPION, fonctionnalisées, à haut pouvoir chauffant et vectorisées avec de la gastrine (NF@Gastrine). Ces nanoparticules reconnaissent spécifiquement les cellules pancréatiques humaines MiaPaca2 et de CAF exprimant le récepteur CCK2 et s'accumulent dans leurs lysosomes. L'application d'AMF (275 kHz, 30mT) ou de RMF (1 Hz, 40 mT) induit spécifiquement la mort de ces cellules par MILH ou ablation mécanique intra-lysosomale ciblée. Nous avons comparé les effets de l'hyperthermie magnétique intra-lysosomale induits par des NF@Gastrine à ceux induits par les mêmes nanoparticules recouvertes d'une coque de silice hermétique (NF@SiO2@Gastrine), empêchant la libération de fer sous l'AMF, en présence ou non de Ferristatin-II, un inhibiteur de la capture de fer par la cellule. Cette étude a permis de mettre en évidence que le fer impliqué dans la réaction de Fenton à l'origine de la production de ROS par MILH provenait du pool endogène de la cellule et non de la libération de fer par les SPION soumises à l'AMF. Nous avons ensuite mis en évidence que l'hyperthermie magnétique et l'ablation mécanique intra-lysosomales augmentent l'expression de motifs moléculaires associés aux dégâts (DAMPs) à la surface des cellules MiaPaca2 et des CAF ayant internalisées les NF@Gastrine et stimulent leur phagocytose par des macrophages. Ces deux approches, pourraient donc être deux nouvelles stratégies capables de rétablir une immunité anti tumorale dans l'adénocarcinome pancréatique. Enfin, ces deux stratégies peuvent également modifier le phénotype pro-tumoral des CAF, en inhibant leur migration, diminuant leur sécrétion de collagène
Due to their physico-chemical properties, magnetic iron oxide nanoparticles (SPION) offer many advantages. They are biocompatible and functionalizable and therefore have already been used as a contrast agent for MRI diagnosis. They can respond to the application of magnetic fields: release thermal energy in response to the application of a high frequency alternating magnetic field (AMF), or generate mechanical forces when they are exposed to low frequency rotating magnetic fields (RMF). Clinical trials using magnetic hyperthermia mediated by SPION and AMF fields have been carried out on glioblastoma and prostate cancer in association with radiotherapy. Nevertheless, the benefit on life expectancy was negligible and adverse effects were noted on adjacent healthy tissues. But our team has previously shown that it is possible to specifically induce tumor cells and microenvironment cells death through the use of low concentrations of targeted magnetic nanoparticle that specifically accumulate in the lysosomes of the targeted cells. Then AMF fields specifically induce the death of target cells by targeted intra-lysosomal magnetic hyperthermia MILH. The mechanisms leading to the death of these cells have been characterized and show that it is initiated in the lysosomes by the generation of ROS according to the Fenton reaction which requires Fe ions and can be catalyzed by an acid pH and an increase of temperature (optimal at 40°C). However, the origin of the Fe ions involved in the Fenton reaction has not been elucidated. Another strategy was also established in the team; it is based on the application of RMF fields which will generate mechanical forces from the SPIONs and induce cell death by targeted intra-lysosomal mechanical ablation. We have chosen as a model, the pancreatic adenocarcinoma particularly resistant to conventional therapies and characterized by the presence of a large and dense microenvironment. In this microenvironment, CAFs (Cancer Associated Fibroblasts) play a key role, in particular through the secretion of extracellular matrix and soluble molecules, limiting the penetration and effectiveness of treatments and contributing to the acquisition of resistance. Cancer cells as well as CAF can overexpress the cholecystokinin receptor type 2 (RCCK2). This membrane receptor has the property of internalizing after binding of its specific agonist: the gastrin. The team has developed functionalized nanoparticles with high heating power vectorized with gastrin peptides (NF@Gastrin). These nanoparticles specifically recognize human pancreatic MiaPaca2 cells and CAFs expressing the CCK2 receptor and accumulate in their lysosomes. The application of AMF (275 kHz, 30 mT) or RMF (1 Hz, 40 mT) fields specifically induces the death of these cells by MILH or targeted intra-lysosomal mechanical ablation. First, we compared the effects of MILH induced by NF@Gastrin to those induced by the same nanoparticles covered with a hermetic silica shell (NF@SiO2@Gastrin), preventing the release of iron under the application of AMF field, in the presence or absence of Ferristatin-II, an inhibitor of iron uptake by the cell. This study demonstrate that the iron involved in the Fenton reaction at the origin of ROS production by MILH came from the endogenous pool of the cell and not from the release of iron by the iron oxide nanoparticles submitted to AMF. Then, we demonstrate that MILH and mechanical ablation increase the expression of damage-associated molecular patterns (DAMPs) on the surface of MiaPaca2 cells and CAFs having specifically internalized NF@Gastrin and stimulate their phagocytosis by macrophages. These two approaches, magnetic hyperthermia and mechanical ablation, could therefore be two new strategies to restore anti-tumor immunity in pancreatic adenocarcinoma. Finally, these two strategies can also modify the pro-tumoral phenotype of CAFs, by inhibiting their migration, decreasing their collagen secretion

Diabetes mellitus is a chronic metabolic disorder characterized by impaired glucose regulation, which leads to various complications affecting multiple organs and systems. This chapter discusses various types of nanomaterials, such as liposomes, polymeric nanoparticles, dendrimers, and carbon-based nanomaterials, and their potential for encapsulating and delivering therapeutic agents to specific sites affected by diabetic complications. The advantages of nanomaterial-based drug delivery, including enhanced drug stability, prolonged circulation time, and improved targeting efficiency, are highlighted. The challenges and considerations associated with targeted nanotherapy development, including biocompatibility, toxicity, and regulatory aspects, are also discussed. The chapter serves as a valuable resource for researchers, clinicians, and healthcare professionals involved in the development and translation of targeted nano therapies, ultimately contributing to the advancement of diabetic complication management.