Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, via Olgettina 58, 20132, Milan, Italy.
Università Vita-Salute San Raffaele, Milan, Italy.
J Nanobiotechnology. 2021 May 5;19(1):128. doi: 10.1186/s12951-021-00871-y.
Gold nanospheres tagged with peptides containing isoDGR (isoAsp-Gly-Arg), an αvβ3 integrin binding motif, represent efficient carriers for delivering pro-inflammatory cytokines to the tumor vasculature. We prepared bi- or trifunctional nanoparticles bearing tumor necrosis factor-α (TNF) and/or interleukin-12 (IL12) plus a peptide containing isoDGR, and we tested their anti-cancer effects, alone or in combination with doxorubicin, in tumor-bearing mice.
In vitro biochemical studies showed that both nanodrugs were monodispersed and functional in terms of binding to TNF and IL12 receptors and to αvβ3. In vivo studies performed in a murine model of fibrosarcoma showed that low doses of bifunctional nanoparticles bearing isoDGR and TNF (corresponding to few nanoparticles per cell) delayed tumor growth and increased the efficacy of doxorubicin without worsening its toxicity. Similar effects were obtained using trifunctional nanoparticles loaded with isoDGR, TNF and IL12. Mechanistic studies showed that nanoparticles bearing isoDGR and TNF could increase doxorubicin penetration in tumors a few hours after injection and caused vascular damage at later time points.
IsoDGR-coated gold nanospheres can be exploited as a versatile platform for single- or multi-cytokine delivery to cells of the tumor vasculature. Extremely low doses of isoDGR-coated nanodrugs functionalized with TNF or TNF plus IL12 can enhance doxorubicin anti-tumor activity.
肽标记的金纳米球含有 isoDGR（异天冬氨酸-甘氨酸-精氨酸），这是一种 αvβ3 整合素结合基序，代表了将促炎细胞因子递送至肿瘤血管的有效载体。我们制备了携带肿瘤坏死因子-α（TNF）和/或白细胞介素-12（IL12）以及含有 isoDGR 的肽的双功能或三功能纳米颗粒，并在荷瘤小鼠中测试了它们的抗癌效果，单独使用或与多柔比星联合使用。
体外生化研究表明，两种纳米药物均为单分散的，并且在结合 TNF 和 IL12 受体以及 αvβ3 方面具有功能。在纤维肉瘤的小鼠模型中进行的体内研究表明，携带 isoDGR 和 TNF 的双功能纳米颗粒（相当于每个细胞几个纳米颗粒）的低剂量可延迟肿瘤生长，并提高多柔比星的疗效，而不会增加其毒性。使用负载有 isoDGR、TNF 和 IL12 的三功能纳米颗粒也获得了类似的效果。机制研究表明，携带 isoDGR 和 TNF 的纳米颗粒可在注射后数小时内增加多柔比星在肿瘤中的渗透，并在稍后的时间点引起血管损伤。
isoDGR 涂层的金纳米球可被开发为用于向肿瘤血管细胞递送单一或多种细胞因子的多功能平台。携带 TNF 或 TNF 加 IL12 的 isoDGR 涂层纳米药物的极低剂量可增强多柔比星的抗肿瘤活性。
