Tumor integrin targeted theranostic iron oxide nanoparticles for delivery of caffeic acid phenethyl ester: preparation, characterization, and anti-myeloma activities
Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells preferentially in the bone marrow. Currently, emerging chemotherapy drugs with improved biosafety profiles, such as immunomodulatory agents and protease inhibitors, have been used in clinics to treat MM in both init...
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| Format: | Article |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1325196/full |
| _version_ | 1797271799154606080 |
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| author | Barkley Smith Yuancheng Li Yuancheng Li Travis Fields Michael Tucker Anna Staskiewicz Erica Wong Handong Ma Hui Mao Xinyu Wang |
| author_facet | Barkley Smith Yuancheng Li Yuancheng Li Travis Fields Michael Tucker Anna Staskiewicz Erica Wong Handong Ma Hui Mao Xinyu Wang |
| author_sort | Barkley Smith |
| collection | DOAJ |
| description | Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells preferentially in the bone marrow. Currently, emerging chemotherapy drugs with improved biosafety profiles, such as immunomodulatory agents and protease inhibitors, have been used in clinics to treat MM in both initial therapy or maintenance therapy post autologous hematopoietic stem cell transplantation (ASCT). We previously discovered that caffeic acid phenethyl ester (CAPE), a water-insoluble natural compound, inhibited the growth of MM cells by inducing oxidative stress. As part of our continuous effort to pursue a less toxic yet more effective therapeutic approach for MM, the objective of this study is to investigate the potential of CAPE for in vivo applications by using magnetic resonance imaging (MRI)-capable superparamagnetic iron oxide nanoparticles (IONP) as carriers. Cyclo (Arg-Gly-Asp-D-Phe-Cys) (RGD) is conjugated to IONP (RGD-IONP/CAPE) to target the overexpressed αvβ3 integrin on MM cells for receptor-mediated internalization and intracellular delivery of CAPE. A stable loading of CAPE on IONP can be achieved with a loading efficiency of 48.7% ± 3.3% (wt%). The drug-release studies indicate RGD-IONP/CAPE is stable at physiological (pH 7.4) and basic pH (pH 9.5) and subject to release of CAPE at acidic pH (pH 5.5) mimicking the tumor and lysosomal condition. RGD-IONP/CAPE causes cytotoxicity specific to human MM RPMI8226, U266, and NCI-H929 cells, but not to normal peripheral blood mononuclear cells (PBMCs), with IC50s of 7.97 ± 1.39, 16.75 ± 1.62, and 24.38 ± 1.71 μM after 72-h treatment, respectively. Apoptosis assays indicate RGD-IONP/CAPE induces apoptosis of RPMI8226 cells through a caspase-9 mediated intrinsic pathway, the same as applying CAPE alone. The apoptogenic effect of RGD-IONP/CAPE was also confirmed on the RPMI8226 cells co-cultured with human bone marrow stromal cells HS-5 in a Transwell model to mimic the MM microenvironment in the bone marrow. In conclusion, we demonstrate that water-insoluble CAPE can be loaded to RGD-IONP to greatly improve the biocompatibility and significantly inhibit the growth of MM cells in vitro through the induction of apoptosis. This study paves the way for investigating the MRI-trackable delivery of CAPE for MM treatment in animal models in the future. |
| first_indexed | 2024-03-07T14:15:25Z |
| format | Article |
| id | doaj.art-4110b99eb0224c3d955fe43981f0ba8c |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-07T14:15:25Z |
| publishDate | 2024-03-01 |
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| spelling | doaj.art-4110b99eb0224c3d955fe43981f0ba8c2024-03-06T12:46:19ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-03-011510.3389/fphar.2024.13251961325196Tumor integrin targeted theranostic iron oxide nanoparticles for delivery of caffeic acid phenethyl ester: preparation, characterization, and anti-myeloma activitiesBarkley Smith0Yuancheng Li1Yuancheng Li2Travis Fields3Michael Tucker4Anna Staskiewicz5Erica Wong6Handong Ma7Hui Mao8Xinyu Wang9Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, GA, United States5M Biomed, Limited Liability Company, Atlanta, GA, United StatesDepartment of Radiology and Imaging Sciences, Emory University, Atlanta, GA, United StatesDivision of Research, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, GA, United StatesDepartment of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, GA, United StatesDivision of Research, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, GA, United StatesDepartment of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, GA, United StatesDivision of Research, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, GA, United StatesDepartment of Radiology and Imaging Sciences, Emory University, Atlanta, GA, United StatesDepartment of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine–Georgia Campus, Suwanee, GA, United StatesMultiple myeloma (MM) is characterized by the accumulation of malignant plasma cells preferentially in the bone marrow. Currently, emerging chemotherapy drugs with improved biosafety profiles, such as immunomodulatory agents and protease inhibitors, have been used in clinics to treat MM in both initial therapy or maintenance therapy post autologous hematopoietic stem cell transplantation (ASCT). We previously discovered that caffeic acid phenethyl ester (CAPE), a water-insoluble natural compound, inhibited the growth of MM cells by inducing oxidative stress. As part of our continuous effort to pursue a less toxic yet more effective therapeutic approach for MM, the objective of this study is to investigate the potential of CAPE for in vivo applications by using magnetic resonance imaging (MRI)-capable superparamagnetic iron oxide nanoparticles (IONP) as carriers. Cyclo (Arg-Gly-Asp-D-Phe-Cys) (RGD) is conjugated to IONP (RGD-IONP/CAPE) to target the overexpressed αvβ3 integrin on MM cells for receptor-mediated internalization and intracellular delivery of CAPE. A stable loading of CAPE on IONP can be achieved with a loading efficiency of 48.7% ± 3.3% (wt%). The drug-release studies indicate RGD-IONP/CAPE is stable at physiological (pH 7.4) and basic pH (pH 9.5) and subject to release of CAPE at acidic pH (pH 5.5) mimicking the tumor and lysosomal condition. RGD-IONP/CAPE causes cytotoxicity specific to human MM RPMI8226, U266, and NCI-H929 cells, but not to normal peripheral blood mononuclear cells (PBMCs), with IC50s of 7.97 ± 1.39, 16.75 ± 1.62, and 24.38 ± 1.71 μM after 72-h treatment, respectively. Apoptosis assays indicate RGD-IONP/CAPE induces apoptosis of RPMI8226 cells through a caspase-9 mediated intrinsic pathway, the same as applying CAPE alone. The apoptogenic effect of RGD-IONP/CAPE was also confirmed on the RPMI8226 cells co-cultured with human bone marrow stromal cells HS-5 in a Transwell model to mimic the MM microenvironment in the bone marrow. In conclusion, we demonstrate that water-insoluble CAPE can be loaded to RGD-IONP to greatly improve the biocompatibility and significantly inhibit the growth of MM cells in vitro through the induction of apoptosis. This study paves the way for investigating the MRI-trackable delivery of CAPE for MM treatment in animal models in the future.https://www.frontiersin.org/articles/10.3389/fphar.2024.1325196/fullmultiple myelomaCAPERGDIONPapoptosistumor microenvironment |
| spellingShingle | Barkley Smith Yuancheng Li Yuancheng Li Travis Fields Michael Tucker Anna Staskiewicz Erica Wong Handong Ma Hui Mao Xinyu Wang Tumor integrin targeted theranostic iron oxide nanoparticles for delivery of caffeic acid phenethyl ester: preparation, characterization, and anti-myeloma activities Frontiers in Pharmacology multiple myeloma CAPE RGD IONP apoptosis tumor microenvironment |
| title | Tumor integrin targeted theranostic iron oxide nanoparticles for delivery of caffeic acid phenethyl ester: preparation, characterization, and anti-myeloma activities |
| title_full | Tumor integrin targeted theranostic iron oxide nanoparticles for delivery of caffeic acid phenethyl ester: preparation, characterization, and anti-myeloma activities |
| title_fullStr | Tumor integrin targeted theranostic iron oxide nanoparticles for delivery of caffeic acid phenethyl ester: preparation, characterization, and anti-myeloma activities |
| title_full_unstemmed | Tumor integrin targeted theranostic iron oxide nanoparticles for delivery of caffeic acid phenethyl ester: preparation, characterization, and anti-myeloma activities |
| title_short | Tumor integrin targeted theranostic iron oxide nanoparticles for delivery of caffeic acid phenethyl ester: preparation, characterization, and anti-myeloma activities |
| title_sort | tumor integrin targeted theranostic iron oxide nanoparticles for delivery of caffeic acid phenethyl ester preparation characterization and anti myeloma activities |
| topic | multiple myeloma CAPE RGD IONP apoptosis tumor microenvironment |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1325196/full |
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