Savla Ronak, Garbuzenko Olga B, Chen Suzie, Rodriguez-Rodriguez Lorna, Minko Tamara
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA.
Pharm Res. 2014 Dec;31(12):3487-502. doi: 10.1007/s11095-014-1436-x. Epub 2014 Jun 13.
Design and synthesis of a tumor responsive nanoparticle-based system for imaging and treatment of various cancers.
Manganese oxide nanoparticles (Mn3O4 NPs) were synthesized and modified with LHRH targeting peptide or anti-melanoma antibodies (cancer targeting moieties) and a MMP2 cleavable peptide (a possible chemotactic factor). Nanostructured lipid carriers (NLCs) were used to entrap the BRAF inhibitor, vemurafenib, and enhance cytotoxicity of the drug. Size distribution, stability, drug entrapment, cytotoxicity and genotoxicity of synthesized nanoparticles were studied in vitro. Enhancement of MRI signal by nanoparticles and their body distribution were examined in vivo on mouse models of melanoma, ovarian and lung cancers.
Uniform, stable cancer-targeted nanoparticles (PEGylated water-soluble Mn3O4 NPs and NLCs) were synthesized. No signs of cyto-,genotoxicity and DNA damage were detected for nanoparticles that do not contain an anticancer drug. Entrapment of vemurafenib into nanoparticles significantly enhanced drug toxicity in cancer cells with targeted V600E mutation. The developed nanoparticles containing LHRH and MMP2 peptides showed preferential accumulation in primary and metastatic tumors increasing the MRI signal in mice with melanoma, lung and ovarian cancers.
The proposed nanoparticle-based systems provide the foundation for building an integrated MRI diagnostic and therapeutic approach for various types of cancer.
设计并合成一种基于纳米颗粒的系统，用于多种癌症的成像和治疗。
合成氧化锰纳米颗粒（Mn3O4 NPs），并用促黄体生成素释放激素（LHRH）靶向肽或抗黑色素瘤抗体（癌症靶向部分）以及基质金属蛋白酶2（MMP2）可裂解肽（一种可能的趋化因子）进行修饰。使用纳米结构脂质载体（NLCs）包裹BRAF抑制剂维莫非尼，并增强药物的细胞毒性。在体外研究了合成纳米颗粒的尺寸分布、稳定性、药物包裹率、细胞毒性和遗传毒性。在黑色素瘤、卵巢癌和肺癌小鼠模型上，体内检测了纳米颗粒对磁共振成像（MRI）信号的增强作用及其体内分布。
合成了均匀、稳定的癌症靶向纳米颗粒（聚乙二醇化水溶性Mn3O4 NPs和NLCs）。对于不含抗癌药物的纳米颗粒，未检测到细胞毒性、遗传毒性和DNA损伤的迹象。维莫非尼包裹在纳米颗粒中显著增强了对具有靶向V600E突变的癌细胞的药物毒性。含有LHRH和MMP2肽的纳米颗粒在原发性和转移性肿瘤中显示出优先积累，增加了黑色素瘤、肺癌和卵巢癌小鼠的MRI信号。
所提出的基于纳米颗粒的系统为构建针对各种类型癌症的集成MRI诊断和治疗方法奠定了基础。
