Granulocyte-Colony Stimulating Factor Nanocarriers for Stimulation of the Immune System (Part II): Dose-Dependent Biodistribution and In Vivo Antitumor Efficacy in Combination with Rituximab,Bioconjugate Chemistry

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Granulocyte-Colony Stimulating Factor Nanocarriers for Stimulation of the Immune System (Part II): Dose-Dependent Biodistribution and In Vivo Antitumor Efficacy in Combination with Rituximab
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-12-28 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00606
David Kryza _{1,

2} , Gabriel De Crozals ₃ , Doriane Mathe ₄ , Jacqueline Taleb Sidi-Boumedine ₁ , Marc Janier _{1,

2} , Carole Chaix ₃ , Charles Dumontet _{2,

4}

Affiliation

The purpose of immuno-modulation is to increase or restore the action of immunocompetent cells against tumors with or without the use of monoclonal antibodies. The innate immune system is a key player in various pathological situations, but cells of this system appear to be inhibited or insufficiently active in malignancy or severe infectious diseases. The present study was designed to investigate therapeutic value of nanoparticles (NPs) coupled with bioactive hematopoietic growth factors acting on the innate immune system. The use of nanoparticles (NPs) allowing multimodal detection and multifunctional grafting are currently of great interest for theranostic purposes. In the present work, we have evaluated the impact of the number of granulocyte-colony stimulating factor (G-CSF) grafted on the surface on the NPs on the biodistribution in mice thanks to indium 111 radiolabeling. Furthermore, we have investigated whether grafted G-CSF NPs could stimulate the immune innate system and enhance the therapeutic efficacy of the monoclonal antibody rituximab in mice bearing human lymphoma xenografts. Following intravenous (i.v.) administration of NP-DTPA and NP-DTPA/G-CSF-X high levels of radioactivity were observed in the liver. Furthermore, spleen uptake was correlated with the number of G-CSF molecules grafted on the surface of the NPs. Combining NP-DTPA/G-CSF-34 with rituximab strongly reduced RL tumor growth compared to rituximab alone or in combination with conventional G-CSF + rituximab. The use of highly loaded G-CSF NPs as immune adjuvants could enhance the antitumor activity of therapeutic monoclonal antibodies by amplifying tumor cell destruction by innate immune cells.

中文翻译：

刺激免疫系统的粒细胞集落刺激因子纳米载体（第二部分）：剂量依赖性生物分布和利妥昔单抗联合体内抗肿瘤功效

免疫调节的目的是在使用或不使用单克隆抗体的情况下增加或恢复免疫活性细胞对肿瘤的作用。先天性免疫系统是各种病理情况的关键因素，但该系统的细胞在恶性肿瘤或严重的传染病中似乎被抑制或活性不足。本研究旨在调查纳米粒子（NPs）结合对先天免疫系统起作用的生物活性造血生长因子的治疗价值。目前，出于治疗诊断的目的，使用允许进行多峰检测和多功能接枝的纳米颗粒（NPs）引起了人们的极大兴趣。在目前的工作中，由于铟111放射性标记，我们评估了NPs表面嫁接的粒细胞集落刺激因子（G-CSF）数量对小鼠生物分布的影响。此外，我们已经研究了移植的G-CSF NP是否可以刺激免疫先天系统并增强单克隆抗体利妥昔单抗在携带人淋巴瘤异种移植物的小鼠中的治疗效果。静脉内（iv）施用NP-DTPA和NP-DTPA / G-CSF-X后，在肝脏中观察到高水平的放射性。此外，脾脏摄取与嫁接在NP表面上的G-CSF分子数量有关。与单独使用利妥昔单抗或与常规G-CSF +利妥昔单抗联用相比，将NP-DTPA / G-CSF-34与利妥昔单抗联合使用可大大降低RL肿瘤的生长。

更新日期：2017-12-28

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