Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, 715 Sumter St., Columbia, SC 29208, United States.
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, 715 Sumter St., Columbia, SC 29208, United States.
Acta Biomater. 2019 Jan 15;84:378-390. doi: 10.1016/j.actbio.2018.12.010. Epub 2018 Dec 5.
Suramin (SM), a drug for African sleeping sickness and river blindness therapy, has been investigated in various clinical trials for cancer therapy. However, SM was eventually withdrawn from the market because of its narrow therapeutic window and the side effects associated with multiple targets. In this work, we developed a simple but effective system based on a nontoxic dose of SM combined with a chemotherapeutic agent for the treatment of metastatic triple-negative breast cancer (TNBC). SM and glycol chitosan (GCS) formed nanogels because of the electrostatic effect, whereas doxorubicin (DOX) was incorporated into the system through the hydrophilic and hydrophobic interactions between DOX and GCS as well as the ionic interactions between DOX and SM to yield GCS-SM/DOX nanoparticles (NPs). GCS-SM/DOX NPs have a size of approximately 186 nm and a spherical morphology. In vitro experiments showed that GCS-SM NPs could effectively inhibit cancer cell migration and invasion, as well as angiogenesis. Furthermore, in a TNBC lung metastasis animal model, GCS-SM/DOX NPs significantly reduced tumor burden and extended the lifespan of animals, while not inducing cardio and renal toxicities associated with the DOX and SM, respectively. As all the components used in this system are biocompatible and easy for large-scale fabrication, the GCS-SM/DOX system is highly translatable for the metastatic breast cancer treatment. STATEMENT OF SIGNIFICANCE: The doxorubicin-loaded glycol chitosan-suramin nanoparticle (GCS-SM/DOX) is novel in the following aspects: SM acts as not only a gelator for the first time in the preparation of the nanoparticle but also an active pharmaceutical agent in the dosage form. GCS-SM/DOX NP significantly reduced tumor burden and extended the lifespan of animals with triple-negative breast cancer lung metastasis. GCS-SM/DOX NPs attenuate cardio and renal toxicities associated with the DOX and SM. The GCS-SM/DOX system is highly translatable because of its simple, one-pot, and easy-to-scale-up preparation protocol.
苏拉明（SM）是一种用于治疗非洲昏睡病和河盲症的药物，已在各种临床试验中被研究用于癌症治疗。然而，由于其治疗窗口狭窄和与多个靶点相关的副作用，SM 最终被撤出市场。在这项工作中，我们开发了一种简单但有效的系统，该系统基于低毒性剂量的 SM 与化疗药物结合，用于治疗转移性三阴性乳腺癌（TNBC）。SM 和乙二醇壳聚糖（GCS）由于静电作用而形成纳米凝胶，而阿霉素（DOX）则通过 DOX 和 GCS 之间的亲水性和疏水性相互作用以及 DOX 和 SM 之间的离子相互作用被掺入系统中，从而产生 GCS-SM/DOX 纳米颗粒（NPs）。GCS-SM/DOX NPs 的大小约为 186nm，呈球形形态。体外实验表明，GCS-SM NPs 能够有效抑制癌细胞迁移和侵袭以及血管生成。此外，在 TNBC 肺转移动物模型中，GCS-SM/DOX NPs 显著降低了肿瘤负担并延长了动物的寿命，同时没有分别诱导与 DOX 和 SM 相关的心脏和肾脏毒性。由于该系统中使用的所有成分都是生物相容的，并且易于大规模制造，因此 GCS-SM/DOX 系统非常适合转移性乳腺癌的治疗。 意义声明：载有阿霉素的乙二醇壳聚糖-苏拉明纳米颗粒（GCS-SM/DOX）在以下几个方面具有新颖性：SM 首次作为凝胶剂用于制备纳米颗粒，并且在剂型中作为活性药物成分。GCS-SM/DOX NP 显著降低了具有三阴性乳腺癌肺转移的动物的肿瘤负担并延长了其寿命。GCS-SM/DOX NPs 减轻了与 DOX 和 SM 相关的心脏和肾脏毒性。由于其简单、一锅法和易于放大的制备方案，GCS-SM/DOX 系统具有很高的可转化性。
