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In Vitro and In Vivo evaluation of a novel folate-targeted theranostic nanoemulsion of docetaxel for imaging and improved anticancer activity against ovarian cancers

3区 · 医学

Article

作者: Litwin, Samuel ; Candiloro, Katie M. ; Davis, Barbara ; Piroyan, Aleksandr ; Galati, Corin A. ; Ganta, Srinivas ; Patel, Niravkumar R. ; Morse, Allison B. ; Maglaty, Marisa A. ; Coleman, Timothy P. ; O'Brien, Shane W. ; Solon, April L. ; Bora, Collete ; Connolly, Denise C. ; Nack, Abbegail H.

Ovarian cancer ranks fifth in cancer related deaths for women in USA. The high mortality rate associated with ovarian cancer is due to diagnosis at later stages of disease and the high recurrence rate of 60-80%. Recurrent ovarian cancers are more likely to present as multidrug resistance (MDR) leading to unfavorable response from 2^nd and 3^rd line chemotherapy. Nanoemulsions (NEs) are emerging as an attractive drug delivery system to overcome MDR challenges. NEs can also minimize exposure of therapeutic cargo to normal tissues potentially reducing side effects. In >80% of ovarian cancers, Folate Receptor-α (FR-α) is expressed at 10- to 100-fold higher levels than on non-pathological tissues. Therefore, folate (FA) is being evaluated as an active targeting moiety for FR-α⁺ ovarian cancer. To improve therapeutic outcome with reduced toxicity, we developed NMI-500, a FA targeted gadolinium (Gd) annotated NE loaded with docetaxel (DTX). NMI-500 has been developed as theranostic agents as Gd will enable physician to acquire real time pharmacodynamics data on NE + DTX accumulation in target lesions. In present study, characterization for key translational metrics of NMI-500 showed size distribution in range of 120 to 150 nm and zeta potential around -45 mV. Active targeting of FA was evaluated against FR-α⁺ KB cells and results demonstrated significant improvement in cell association which was surface ligand density dependent. We found that NMI-500 was able to inhibit tumor growth in a spontaneous transgenic ovarian cancer model with improved safety profile and this growth inhibition could be longitudinally followed by MRI. These results indicate NMI-500 warrants advancement to clinical trials.

2016-03-23·Drug Delivery2区 · 医学

Formulation development of a novel targeted theranostic nanoemulsion of docetaxel to overcome multidrug resistance in ovarian cancer

2区 · 医学

ArticleOA

作者: Ganta, Srinivas ; Coleman, Timothy P. ; Singh, Amit ; Patel, Niravkumar R. ; Amiji, Mansoor M. ; Cacaccio, Joseph ; Rawal, Yashesh ; Kulkarni, Praveen ; Ferris, Craig F.

OBJECTIVEOvarian cancer is a highly lethal disease in which the majority of patients eventually demonstrate multidrug resistance. Develop a novel active targeted theranostic nanomedicine designed to overcome drug efflux mechanisms, using a Generally Regarded As Safe (GRAS) grade nanoemulsion (NE) as a clinically relevant platform.MATERIALS AND METHODSThe NEs surface-functionalized with folate and gadolinium, were made using GRAS grade excipients and a high-shear microfluidization process. Efficacy was evaluated in ovarian cancer cells, SKOV3 and SKOV3TR. The NE accumulation in tumors was evaluated in SKOV3 tumor-bearing mice by magnetic resonance imaging (MRI).RESULTS AND DISCUSSIONThe NE with particle size < 150 nm were stable in plasma and parenteral fluids for 24 h. Ovarian cancer cells in vitro efficiently took up the non-targeted and folate-targeted NEs; improved cytotoxicity was observed for the folate-targeted NEs showing a 270-fold drop in the IC50 in SKOV3TR cells as compared to docetaxel alone. The addition of gadolinium did not affect cell viability in vitro, but showed relaxation times comparable to Magnevist®. Folate-targeted NEs accumulated in tumors for prolonged period of time compared to Magnevist® and showed enhanced contrast compared to non-targeted NEs with MRI in SKOV3 tumor-bearing mice suggesting active targeting of NEs due to folate modification.CONCLUSIONSA folate-targeted, theranostic NE delivers docetaxel by receptor mediated endocytosis that shows enhanced cytotoxicity capable of overcoming ABC transporter mediated taxane resistance. The diagnostic capability of the targeted nanomedicine showed enhanced contrast in tumors compared to clinically relevant MRI contrast agent Magnevist®.

2015-04-01·Therapeutic Delivery

Cancer Cell Spheroids for Screening of Chemotherapeutics and drug-delivery Systems

Review

作者: Patel, Niravkumar R ; Torchilin, Vladimir P ; Aryasomayajula, Bhawani ; Abouzeid, Abraham H

Over the last few decades, the most popular platform to perform high-throughput screening for viable anti-neoplastic compounds has been monolayer cell culture. However, cells in monolayer culture lose many of their in vivo characteristics. As a result, this platform provides a limited predictive value in determining the clinical outcome of the compounds of interest. Using a technique known as 3D spheroid culture, may be the answer to this conundrum. Spheroids have been shown to mimic the tissue-like properties of tumors necessary for the proper evaluation of compounds. In this review, production of cancer cell spheroids, utilization of these spheroids in understanding various therapeutic mechanisms and the potential for their use in high-throughput screening of drugs and drug-delivery systems are discussed in detail.

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药物(靶点)	适应症	全球最高研发状态

NMI-900 ( Aurora B x Aurora C )	费城染色体阳性慢性粒细胞白血病更多	无进展
NMI-2100	肿瘤更多	无进展
NMI-3100	肿瘤更多	无进展
NMI-500 ( FOLR1 )	卵巢癌更多	无进展
NMI-350 ( FOLR1 )	卵巢癌更多	无进展