{"id":13212,"date":"2024-07-16T15:38:28","date_gmt":"2024-07-16T13:38:28","guid":{"rendered":"https:\/\/www.cinam.univ-mrs.fr\/cinam\/?p=13212"},"modified":"2024-07-16T15:39:24","modified_gmt":"2024-07-16T13:39:24","slug":"self-assembling-dendrimer-nanosystems-for-specific-fluorine-magnetic-resonance-imaging-and-effective-theranostic-treatment-of-tumors","status":"publish","type":"post","link":"https:\/\/www.cinam.univ-mrs.fr\/cinam\/en\/2024\/07\/16\/self-assembling-dendrimer-nanosystems-for-specific-fluorine-magnetic-resonance-imaging-and-effective-theranostic-treatment-of-tumors\/","title":{"rendered":"Self-assembling dendrimer nanosystems for specific fluorine magnetic resonance imaging and effective theranostic treatment of tumors"},"content":{"rendered":"

Proc. Natl. Acad. Sci. U.S.A. <\/em>2024<\/strong>, 121<\/em>, e2322403121. DOI: 10.1073\/pnas.2322403121.<\/p>\n

Zhenbin LYU1,2,#<\/sup>, Brigino RALAHY1,#<\/sup>, Teodora-Adriana PERLES-BARBACARU3,#<\/sup>, Ling DING1,3,#<\/sup>, Yifan JIANG1<\/sup>, Baoping LIAN4<\/sup>, Tom ROUSSEL1<\/sup>, Xi LIU1,5<\/sup>, Christina GALANAKOU1<\/sup>, Erik LAURINI6<\/sup>, Aura TINTARU2<\/sup>, Suzanne GIORGIO1<\/sup>, Sabrina PRICL6,7<\/sup>, Xiaoxuan LIU4<\/sup>, Monique BERNARD3<\/sup>, Juan IOVANNA5<\/sup>, Ang\u00e8le VIOLA3<\/sup>, Ling PENG1<\/sup><\/p>\n

Fluorine magnetic resonance imaging (19<\/sup>F-MRI) is particularly promising for biomedical applications owing to the absence of fluorine in most biological systems. However, its use has been limited by the lack of safe and water-soluble imaging agents with high fluorine contents and suitable relaxation properties. Because agents with high fluorine contents are both hydrophobic and lipophobic, they tend to be heavily aggregated and poorly soluble in water, impeding the mobility of 19<\/sup>F nuclei and therefore attenuating the 19<\/sup>F-MRI signal.<\/p>\n

In this paper, the authors report innovative 19<\/sup>F-MRI agents based on dendrimer nanosystems formed by self-assembly of an amphiphilic dendrimer composed of a hydrophobic alkyl chain and a hydrophilic dendron (Figure 1A). This amphiphilic dendrimer 1c<\/strong> (Figure 1B) bears multiple negatively charged terminals with high fluorine content, which effectively prevented intra- and intermolecular aggregation of fluorinated entities via electrostatic repulsion. This permitted high mobility of fluorine nuclei alongside good water solubility with favorable relaxation properties for use in 19<\/sup>F-MRI. Importantly, the self-assembling 19<\/sup>F-MRI agent was able to encapsulate the near-infrared fluorescence (NIRF) agent and the anticancer drug for multimodal 19<\/sup>F-MRI and NIRF imaging and theranostic treatment of cancer, with efficacy largely outperforming the clinical anticancer drug.<\/p>\n

Specifically, the amphiphilic dendrimer 1c<\/strong> self-assembled spontaneously in water into small and uniform nanomicelles 1c<\/strong>@ (Figure 2A\/B).\u00a0 The formed nanomicelles 1c<\/strong>@ gave a very sharp and intense 19<\/sup>F-NMR peak in water (Figure 2C), highlighting the excellent the mobility of 19<\/sup>F nuclei. In addition, 1c<\/strong>@ had favorable relaxation time constants (Figure 2D) with effective in vitro 19<\/sup>F-MRI (Figure 2E) and specific cancer detection in tumor-bearing mice (Figure 2F\/G).<\/p>\n

In addition, the authors encapsulated the hydrophobic NIRF dye DiR and the anticancer drug paclitaxene (PTX) within the nanomicelles 1c<\/strong>@ for multimodality imaging and theranostic treatment of pancreatic cancer in a patient-derived pancreatic cancer model. The obtained PTX\/DiR\/1c<\/strong>@ nanomieclles had high drug loading (23%), and similar size and morphology as 1c<\/strong>@ (Figure 3A). Also, PTX\/DiR\/1c<\/strong>@ displayed similar NIRF as the fluorescent DiR (Figure 3B), and its 19<\/sup>F-MRI properties resembled those of 1c<\/strong>@ with relaxation time constants allowing similar 19<\/sup>F-MRI detectability (Figure 3C). Both NIRF imaging (Figure 3D) and 19<\/sup>F-MRI (Figure 3E) showed the presence of PTX\/DiR\/1c<\/strong>@ in the tumors, confirming the performance of PTX\/DiR\/1c<\/strong>@ as a dual 19<\/sup>F-MRI and NIRF imaging agent.<\/p>\n

Furthermore, mice treated with PTX\/DiR\/1c<\/strong>@ showed markedly inhibited tumor growth, compared to a non-significant inhibition in those treated with the equivalent dose of non-encapsulated PTX (Figure 3F). Effective anticancer activity was further confirmed using PTX\/1c<\/strong>@ at an even lower PTX dose of 3.0 mg\/kg (Figure 3G). The superior anticancer activities of both PTX\/1c<\/strong>@ and PTX\/DiR\/1c<\/strong>@ over the free drug PTX can be ascribed to the EPR-based passive tumor targeting obtained by encapsulation of the drug within the nanoparticles. The resulting increase in the accumulation and local concentration of the drug within the tumor significantly improves treatment efficiency.<\/p>\n

In summary, the innovative self-assembling fluorinated dendrimer nanosystems are effective for 19<\/sup>F-MRI, 19<\/sup>F-MRI-based multimodal imaging and theranostic treatment of tumors. In personalized medicine, this approach can be adapted to the construction of modular nanosystems for the required multimodal imaging and theranostics, enabling targeted delivery of patient-specific pharmaceutical agents and image-based monitoring of their efficacy. This concept of modular nanosystems issued from self-assembling supramolecular dendrimers is an innovative approach providing a platform for the encapsulation of imaging agents and therapeutics for 19<\/sup>F-MRI-based multimodal theranostics for improved treatment efficiency and monitoring.<\/p>\n

Fig. 1 <\/strong>Schematic illustration of self-assembling supramolecular dendrimer nanosystems for fluorine magnetic resonance imaging (19<\/sup>F-MRI), 19<\/sup>F-MRI-based multimodal imaging and theranostics. (A) Self-assembly of a fluorinated amphiphilic dendrimer into nanomicelles in the absence and\/or presence of the NIRF probe DiR and the anticancer drug paclitaxel (PTX) within the supramolecular dendrimer core for 19<\/sup>F-MRI, bimodal 19<\/sup>F-MRI and NIRF imaging as well as 19<\/sup>F-MRI-based theranostics for cancer detection and treatment. (B) Chemical structures of the amphiphilic dendrimer 1c <\/strong>designed and studied for 19<\/sup>F-MRI.<\/p>\n

\"\"<\/p>\n

Fig. 2<\/strong> Self-assembling of the amphiphilic dendrimer 1c<\/strong> into nanomicelles 1c<\/strong>@ for use as an imaging agent for fluorine magnetic resonance imaging (19<\/sup>F-MRI). (A) Dynamic light scattering results and (B) transmission electron microscopy image of the self-assembled 1c<\/strong>@ nanomicelles. (C) 19<\/sup>F-NMR spectrum of 1c<\/strong>@ in D2<\/sub>O. (D) 19<\/sup>F magnetic resonance relaxation time constants (T1<\/sub> and T2<\/sub>) for 1c<\/strong>@ at a magnetic field strength of 7 T and 20\u00b0C. (E) In vitro<\/em> 19<\/sup>F-MR images of 1c<\/strong>@ at four different concentrations. (F, G) In vivo <\/em>1<\/sup>H-MR anatomical images (top), 19<\/sup>F-MR images (middle), and overlay of 1<\/sup>H-MR and 19<\/sup>F-MR images (bottom) of tumors in pancreatic cancer xenograft mice 24 h after intravenous injection of 1c<\/strong>@ at 1c <\/strong>concentrations of (F) 0.208 mmol\/kg and (G) 0.104 mmol\/kg (corresponding to fluorine concentrations of 5.00 and 2.50 mmol\/kg, respectively). MR images were acquired in the sagittal plane with respect to the mouse.<\/p>\n

\"\"<\/p>\n

Fig. 3 <\/strong>The anticancer drug paclitaxel (PTX) and the near-infrared fluorescence (NIRF) dye DiR encapsulated within 1c<\/strong>@ for 19<\/sup>F-MRI-based multimodal imaging and theranostic treatment of tumor in pancreatic cancer xenograft mice. (A) Transmission electron microscopy image of PTX\/DiR\/1c<\/strong>@. (B) Normalized fluorescence emission spectrum of PTX\/DiR\/1c<\/strong>@. (C) In vitro<\/em> 19<\/sup>F-MR images of PTX\/DiR\/1c<\/strong>@. (D) In vivo<\/em> NIRF imaging of pancreatic cancer xenograft mice 48 h after injection of PTX\/DiR\/1c<\/strong>@. (E) 19<\/sup>F-MRI superimposed on anatomic 1<\/sup>H-MRI of tumors in pancreatic cancer xenograft mice 48 h after accomplished treatment with of PTX\/DiR\/1c<\/strong>@. MR images were acquired in the sagittal plane with respect to the mouse. (F, G) Tumor growth inhibition in tumor-xenograft mice following intravenous injection of (F) PTX\/DiR\/1c<\/strong>@ at a PTX concentration of 7.5 mg\/kg or (G) PTX\/1c<\/strong>@ at a PTX concentration of 3.0 mg\/kg twice per week for 2 weeks. Statistical differences were assessed using two-way ANOVA with Tukey\u2019s multiple comparison test.<\/p>\n

\"\"<\/p>\n","protected":false},"excerpt":{"rendered":"

A new publication in IMMF Department<\/p>\n","protected":false},"author":16,"featured_media":13200,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[31],"tags":[],"aioseo_notices":[],"_links":{"self":[{"href":"https:\/\/www.cinam.univ-mrs.fr\/cinam\/en\/wp-json\/wp\/v2\/posts\/13212"}],"collection":[{"href":"https:\/\/www.cinam.univ-mrs.fr\/cinam\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.cinam.univ-mrs.fr\/cinam\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.cinam.univ-mrs.fr\/cinam\/en\/wp-json\/wp\/v2\/users\/16"}],"replies":[{"embeddable":true,"href":"https:\/\/www.cinam.univ-mrs.fr\/cinam\/en\/wp-json\/wp\/v2\/comments?post=13212"}],"version-history":[{"count":2,"href":"https:\/\/www.cinam.univ-mrs.fr\/cinam\/en\/wp-json\/wp\/v2\/posts\/13212\/revisions"}],"predecessor-version":[{"id":13220,"href":"https:\/\/www.cinam.univ-mrs.fr\/cinam\/en\/wp-json\/wp\/v2\/posts\/13212\/revisions\/13220"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.cinam.univ-mrs.fr\/cinam\/en\/wp-json\/wp\/v2\/media\/13200"}],"wp:attachment":[{"href":"https:\/\/www.cinam.univ-mrs.fr\/cinam\/en\/wp-json\/wp\/v2\/media?parent=13212"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.cinam.univ-mrs.fr\/cinam\/en\/wp-json\/wp\/v2\/categories?post=13212"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.cinam.univ-mrs.fr\/cinam\/en\/wp-json\/wp\/v2\/tags?post=13212"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}