Decoration of Anti-CD38 on Nanoparticles Carrying a STAT3 Inhibitor Can Improve the Therapeutic Efficacy Against Myeloma
STAT3 is an oncoprotein which has been shown to contribute to drug resistance in multiple myeloma (MM). Nonetheless, the clinical utility of STAT3 inhibitors in treating MM has been limited, partly related to some of their pharmacologic properties. To overcome these challenges, our group had previou...
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MDPI AG
2019-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/2/248 |
| _version_ | 1797763674712047616 |
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| author | Yung-Hsing Huang Mohammad Reza Vakili Ommoleila Molavi Yuen Morrissey Chengsheng Wu Igor Paiva Amir Hasan Soleimani Forugh Sanaee Afsaneh Lavasanifar Raymond Lai |
| author_facet | Yung-Hsing Huang Mohammad Reza Vakili Ommoleila Molavi Yuen Morrissey Chengsheng Wu Igor Paiva Amir Hasan Soleimani Forugh Sanaee Afsaneh Lavasanifar Raymond Lai |
| author_sort | Yung-Hsing Huang |
| collection | DOAJ |
| description | STAT3 is an oncoprotein which has been shown to contribute to drug resistance in multiple myeloma (MM). Nonetheless, the clinical utility of STAT3 inhibitors in treating MM has been limited, partly related to some of their pharmacologic properties. To overcome these challenges, our group had previously packaged STAT3 inhibitors using a novel formulation of nanoparticles (NP) and found encouraging results. In this study, we aimed to further improve the pharmacologic properties of these NP by decorating them with monoclonal anti-CD38 antibodies. NP loaded with S3I-1757 (a STAT3 inhibitor), labeled as S3I-NP, were generated. S3I-NP decorated with anti-CD38 (labeled as CD38-S3I-NP) were found to have a similar nanoparticular size, drug encapsulation, and loading as S3I-NP. The release of S3I-1757 at 24 h was also similar between the two formulations. Using Cy5.5 labeling of the NP, we found that the decoration of anti-CD38 on these NP significantly increased the cellular uptake by two MM cell lines (<i>p</i> < 0.001). Accordingly, CD38-S3I-NP showed a significantly lower inhibitory concentration at 50% (IC50) compared to S3I-NP in two IL6-stimulated MM cell lines (<i>p</i> < 0.001). In a xenograft mouse model, CD38-S3I-NP significantly reduced the tumor size by 4-fold compared to S3I-NP on day 12 after drug administration (<i>p</i> = 0.006). The efficacy of CD38-S3I-NP in suppressing STAT3 phosphorylation in the xenografts was confirmed by using immunocytochemistry and Western blot analysis. In conclusion, our study suggests that the decoration of anti-CD38 on NP loaded with STAT3 inhibitors can further improve their therapeutic effects against MM. |
| first_indexed | 2024-03-12T19:44:47Z |
| format | Article |
| id | doaj.art-f30164702de74221b3ce31da3ee1ec28 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T19:44:47Z |
| publishDate | 2019-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-f30164702de74221b3ce31da3ee1ec282023-08-02T03:36:28ZengMDPI AGCancers2072-66942019-02-0111224810.3390/cancers11020248cancers11020248Decoration of Anti-CD38 on Nanoparticles Carrying a STAT3 Inhibitor Can Improve the Therapeutic Efficacy Against MyelomaYung-Hsing Huang0Mohammad Reza Vakili1Ommoleila Molavi2Yuen Morrissey3Chengsheng Wu4Igor Paiva5Amir Hasan Soleimani6Forugh Sanaee7Afsaneh Lavasanifar8Raymond Lai9Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, CanadaFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2H7, CanadaDepartment of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, CanadaDepartment of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, CanadaDepartment of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, CanadaFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2H7, CanadaFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2H7, CanadaFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2H7, CanadaFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2H7, CanadaDepartment of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, CanadaSTAT3 is an oncoprotein which has been shown to contribute to drug resistance in multiple myeloma (MM). Nonetheless, the clinical utility of STAT3 inhibitors in treating MM has been limited, partly related to some of their pharmacologic properties. To overcome these challenges, our group had previously packaged STAT3 inhibitors using a novel formulation of nanoparticles (NP) and found encouraging results. In this study, we aimed to further improve the pharmacologic properties of these NP by decorating them with monoclonal anti-CD38 antibodies. NP loaded with S3I-1757 (a STAT3 inhibitor), labeled as S3I-NP, were generated. S3I-NP decorated with anti-CD38 (labeled as CD38-S3I-NP) were found to have a similar nanoparticular size, drug encapsulation, and loading as S3I-NP. The release of S3I-1757 at 24 h was also similar between the two formulations. Using Cy5.5 labeling of the NP, we found that the decoration of anti-CD38 on these NP significantly increased the cellular uptake by two MM cell lines (<i>p</i> < 0.001). Accordingly, CD38-S3I-NP showed a significantly lower inhibitory concentration at 50% (IC50) compared to S3I-NP in two IL6-stimulated MM cell lines (<i>p</i> < 0.001). In a xenograft mouse model, CD38-S3I-NP significantly reduced the tumor size by 4-fold compared to S3I-NP on day 12 after drug administration (<i>p</i> = 0.006). The efficacy of CD38-S3I-NP in suppressing STAT3 phosphorylation in the xenografts was confirmed by using immunocytochemistry and Western blot analysis. In conclusion, our study suggests that the decoration of anti-CD38 on NP loaded with STAT3 inhibitors can further improve their therapeutic effects against MM.https://www.mdpi.com/2072-6694/11/2/248multiple myelomaSTAT3S3I-1757nanoparticleCD38 |
| spellingShingle | Yung-Hsing Huang Mohammad Reza Vakili Ommoleila Molavi Yuen Morrissey Chengsheng Wu Igor Paiva Amir Hasan Soleimani Forugh Sanaee Afsaneh Lavasanifar Raymond Lai Decoration of Anti-CD38 on Nanoparticles Carrying a STAT3 Inhibitor Can Improve the Therapeutic Efficacy Against Myeloma Cancers multiple myeloma STAT3 S3I-1757 nanoparticle CD38 |
| title | Decoration of Anti-CD38 on Nanoparticles Carrying a STAT3 Inhibitor Can Improve the Therapeutic Efficacy Against Myeloma |
| title_full | Decoration of Anti-CD38 on Nanoparticles Carrying a STAT3 Inhibitor Can Improve the Therapeutic Efficacy Against Myeloma |
| title_fullStr | Decoration of Anti-CD38 on Nanoparticles Carrying a STAT3 Inhibitor Can Improve the Therapeutic Efficacy Against Myeloma |
| title_full_unstemmed | Decoration of Anti-CD38 on Nanoparticles Carrying a STAT3 Inhibitor Can Improve the Therapeutic Efficacy Against Myeloma |
| title_short | Decoration of Anti-CD38 on Nanoparticles Carrying a STAT3 Inhibitor Can Improve the Therapeutic Efficacy Against Myeloma |
| title_sort | decoration of anti cd38 on nanoparticles carrying a stat3 inhibitor can improve the therapeutic efficacy against myeloma |
| topic | multiple myeloma STAT3 S3I-1757 nanoparticle CD38 |
| url | https://www.mdpi.com/2072-6694/11/2/248 |
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