De La Fuente Adriana, Zilio Serena, Caroli Jimmy, Van Simaeys Dimitri, Mazza Emilia M C, Ince Tan A, Bronte Vincenzo, Bicciato Silvio, Weed Donald T, Serafini Paolo
Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
Department of Life Sciences, University of Modena and Reggio Emilia, Modena 41100, Italy.
Sci Transl Med. 2020 Jun 17;12(548). doi: 10.1126/scitranslmed.aav9760.
Local delivery of anticancer agents has the potential to maximize treatment efficacy and minimize the acute and long-term systemic toxicities. Here, we used unsupervised systematic evolution of ligands by exponential enrichment to identify four RNA aptamers that specifically recognized mouse and human myeloid cells infiltrating tumors but not their peripheral or circulating counterparts in multiple mouse models and from patients with head and neck squamous cell carcinoma (HNSCC). The use of these aptamers conjugated to doxorubicin enhanced the accumulation and bystander release of the chemotherapeutic drug in both primary and metastatic tumor sites in breast and fibrosarcoma mouse models. In the 4T1 mammary carcinoma model, these doxorubicin-conjugated aptamers outperformed Doxil, the first clinically approved highly optimized nanoparticle for targeted chemotherapy, promoting tumor regression after just three administrations with no detected changes in weight loss or blood chemistry. These RNA aptamers recognized tumor infiltrating myeloid cells in a variety of mouse tumors in vivo and from human HNSCC ex vivo. This work suggests the use of RNA aptamers for the detection of myeloid-derived suppressor cells in humans and for a targeted delivery of chemotherapy to the tumor microenvironment in multiple malignancies.
局部递送抗癌药物有可能使治疗效果最大化，并将急性和长期全身毒性降至最低。在此，我们利用指数富集的配体无监督系统进化技术，鉴定出四种RNA适配体，它们能特异性识别浸润肿瘤的小鼠和人类髓样细胞，但在多个小鼠模型以及头颈部鳞状细胞癌（HNSCC）患者中，不识别其外周或循环中的对应细胞。将这些适配体与阿霉素偶联使用，可增强化疗药物在乳腺癌和纤维肉瘤小鼠模型的原发和转移肿瘤部位的蓄积及旁观者释放。在4T1乳腺癌模型中，这些与阿霉素偶联的适配体优于Doxil（首个临床批准的用于靶向化疗的高度优化纳米颗粒），仅给药三次后就能促进肿瘤消退，且未检测到体重减轻或血液生化指标的变化。这些RNA适配体在体内多种小鼠肿瘤以及体外人类HNSCC中均能识别肿瘤浸润髓样细胞。这项研究表明，RNA适配体可用于检测人类髓源性抑制细胞，并用于将化疗靶向递送至多种恶性肿瘤的肿瘤微环境。
