Luong Duy, Sau Samaresh, Kesharwani Prashant, Iyer Arun K
Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , 259 Mack Avenue, Detroit, Michigan 48201, United States.
Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
Biomacromolecules. 2017 Apr 10;18(4):1197-1209. doi: 10.1021/acs.biomac.6b01885. Epub 2017 Mar 9.
The low therapeutic index of conventional chemotherapy and poor prognosis of patients diagnosed with metastatic cancers are prompting clinicians to adopt newer strategies to simultaneously detect cancer lesions at an early stage and to precisely deliver anticancer drugs to tumor sites. In this study, we employed a novel strategy to engineer a polyvalent theranostic nanocarrier consisting of superparamagnetic iron oxide nanoparticle core (SPIONs) decorated with folic acid-polyamidoamine dendrimers surface (FA-PAMAM). In addition, a highly potent hydrophobic anticancer agent 3,4-difluorobenzylidene-curcumin (CDF) was coloaded in the FA-PAMAM dendrimer to increase its solubility and assess its therapeutic potentials. The resulting targeted nanoparticles (SPIONs@FA-PAMAM-CDF) exhibited high MR contrast. When tested on folate receptor overexpressing ovarian (SKOV3) and cervical (HeLa) cancer cells, the CDF loaded targeted nanoformulations showed higher accumulation with a better anticancer activity as compared to the nontargeted counterparts, possibly due to multivalent folate receptor binding interaction with cells overexpressing the target. The results were corroborated by observation of a larger population of cells undergoing apoptosis due to upregulation of tumor suppressor phosphatase and tensis homologue (PTEN), caspase 3, and inhibition of NF-κB in groups treated with the targeted formulations, which further confirmed the ability of the multivalent theranostic nanoparticles for simultaneous imaging and therapy of cancers.
传统化疗的治疗指数较低，且转移性癌症患者的预后较差，这促使临床医生采用更新的策略，以便在早期同时检测癌症病灶，并将抗癌药物精确地输送到肿瘤部位。在本研究中，我们采用了一种新策略，构建了一种多价诊疗纳米载体，其由超顺磁性氧化铁纳米颗粒核心（SPIONs）和表面修饰有叶酸-聚酰胺胺树枝状大分子（FA-PAMAM）组成。此外，一种高效的疏水性抗癌剂3,4-二氟亚苄基姜黄素（CDF）被共负载于FA-PAMAM树枝状大分子中，以提高其溶解度并评估其治疗潜力。所得的靶向纳米颗粒（SPIONs@FA-PAMAM-CDF）表现出高磁共振对比度。当在叶酸受体过表达的卵巢癌细胞（SKOV3）和宫颈癌细胞（HeLa）上进行测试时，与非靶向对应物相比，负载CDF的靶向纳米制剂显示出更高的蓄积和更好的抗癌活性，这可能是由于多价叶酸受体与过表达靶点的细胞发生结合相互作用。在用靶向制剂处理的组中观察到更多细胞因肿瘤抑制因子磷酸酶和张力蛋白同源物（PTEN）、半胱天冬酶3上调以及NF-κB受到抑制而发生凋亡，这证实了上述结果，进一步证实了多价诊疗纳米颗粒同时进行癌症成像和治疗的能力。
