Codelivery of BCL2 and MCL1 Inhibitors Enabled by Phenylboronic Acid‐Functionalized Polypeptide Nanovehicles for Synergetic and Potent Therapy of Acute Myeloid Leukemia
Abstract Acute myeloid leukemia (AML) is the most refractory hematologic malignancy characterized by acute onset, rapid progression, and high recurrence rate. Here, codelivery of BCL2 (ABT199) and MCL1 (TW37) inhibitors using phenylboronic acid‐functionalized polypeptide nanovehicles to achieve syne...
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| Format: | Article |
| Language: | English |
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Wiley
2023-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202204866 |
| _version_ | 1797870210560032768 |
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| author | Jiguo Xie Xiaofei Zhao Peng Zhang Yueyue Zhang Ru Cheng Zhiyuan Zhong Chao Deng |
| author_facet | Jiguo Xie Xiaofei Zhao Peng Zhang Yueyue Zhang Ru Cheng Zhiyuan Zhong Chao Deng |
| author_sort | Jiguo Xie |
| collection | DOAJ |
| description | Abstract Acute myeloid leukemia (AML) is the most refractory hematologic malignancy characterized by acute onset, rapid progression, and high recurrence rate. Here, codelivery of BCL2 (ABT199) and MCL1 (TW37) inhibitors using phenylboronic acid‐functionalized polypeptide nanovehicles to achieve synergetic and potent treatment of AML is adopted. Leveraging the dynamic boronic ester bonds, BN coordination, and π–π stacking, the nanovehicles reveal remarkably efficient and robust drug coencapsulation. ABT199 can induce a series of pro‐apoptotic reactions by promoting the dissociation of the pro‐apoptotic protein Bim from BCL2, while the released Bim is often captured by MCL1 protein overexpressed in AML. TW37 has a strong inhibitory ability to MCL1, thereby can restrain the depletion of Bim protein. Dual inhibitor‐loaded nanoparticles (NPAT) reveal excellent stability, acid/enzyme/H2O2‐triggered drug release, and significant cytotoxicity toward MOLM‐13‐Luc and MV‐411 AML cells with low half maximal inhibitory concentrations of 1.15 and 7.45 ng mL−1, respectively. In mice bearing MOLM‐13‐Luc or MV‐411 AML cancer, NPAT reveal significant inhibition of tumor cell infiltration in bone marrow and main organs, potent suppression of tumor growth, and remarkably elevated mouse survival. With facile construction, varying drug combination, superior safety, synergetic efficacy, the phenylboronic acid‐functionalized smart nanodrugs hold remarkable potential for AML treatment. |
| first_indexed | 2024-04-10T00:24:49Z |
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| id | doaj.art-efd2c2a560bd4660814a3f02fbc37ac8 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-10T00:24:49Z |
| publishDate | 2023-03-01 |
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| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-efd2c2a560bd4660814a3f02fbc37ac82023-03-15T13:19:15ZengWileyAdvanced Science2198-38442023-03-01108n/an/a10.1002/advs.202204866Codelivery of BCL2 and MCL1 Inhibitors Enabled by Phenylboronic Acid‐Functionalized Polypeptide Nanovehicles for Synergetic and Potent Therapy of Acute Myeloid LeukemiaJiguo Xie0Xiaofei Zhao1Peng Zhang2Yueyue Zhang3Ru Cheng4Zhiyuan Zhong5Chao Deng6Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application College of Chemistry Chemical Engineering and Materials Science and State Key Laboratory of Radiation Medicine and Protection Soochow University Suzhou 215123 P. R. ChinaBiomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application College of Chemistry Chemical Engineering and Materials Science and State Key Laboratory of Radiation Medicine and Protection Soochow University Suzhou 215123 P. R. ChinaBiomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application College of Chemistry Chemical Engineering and Materials Science and State Key Laboratory of Radiation Medicine and Protection Soochow University Suzhou 215123 P. R. ChinaBiomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application College of Chemistry Chemical Engineering and Materials Science and State Key Laboratory of Radiation Medicine and Protection Soochow University Suzhou 215123 P. R. ChinaBiomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application College of Chemistry Chemical Engineering and Materials Science and State Key Laboratory of Radiation Medicine and Protection Soochow University Suzhou 215123 P. R. ChinaBiomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application College of Chemistry Chemical Engineering and Materials Science and State Key Laboratory of Radiation Medicine and Protection Soochow University Suzhou 215123 P. R. ChinaBiomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application College of Chemistry Chemical Engineering and Materials Science and State Key Laboratory of Radiation Medicine and Protection Soochow University Suzhou 215123 P. R. ChinaAbstract Acute myeloid leukemia (AML) is the most refractory hematologic malignancy characterized by acute onset, rapid progression, and high recurrence rate. Here, codelivery of BCL2 (ABT199) and MCL1 (TW37) inhibitors using phenylboronic acid‐functionalized polypeptide nanovehicles to achieve synergetic and potent treatment of AML is adopted. Leveraging the dynamic boronic ester bonds, BN coordination, and π–π stacking, the nanovehicles reveal remarkably efficient and robust drug coencapsulation. ABT199 can induce a series of pro‐apoptotic reactions by promoting the dissociation of the pro‐apoptotic protein Bim from BCL2, while the released Bim is often captured by MCL1 protein overexpressed in AML. TW37 has a strong inhibitory ability to MCL1, thereby can restrain the depletion of Bim protein. Dual inhibitor‐loaded nanoparticles (NPAT) reveal excellent stability, acid/enzyme/H2O2‐triggered drug release, and significant cytotoxicity toward MOLM‐13‐Luc and MV‐411 AML cells with low half maximal inhibitory concentrations of 1.15 and 7.45 ng mL−1, respectively. In mice bearing MOLM‐13‐Luc or MV‐411 AML cancer, NPAT reveal significant inhibition of tumor cell infiltration in bone marrow and main organs, potent suppression of tumor growth, and remarkably elevated mouse survival. With facile construction, varying drug combination, superior safety, synergetic efficacy, the phenylboronic acid‐functionalized smart nanodrugs hold remarkable potential for AML treatment.https://doi.org/10.1002/advs.202204866acute myeloid leukemiaBCL2 inhibitorBN coordinationboronic ester bondMCL1 inhibitorsynergetic therapy |
| spellingShingle | Jiguo Xie Xiaofei Zhao Peng Zhang Yueyue Zhang Ru Cheng Zhiyuan Zhong Chao Deng Codelivery of BCL2 and MCL1 Inhibitors Enabled by Phenylboronic Acid‐Functionalized Polypeptide Nanovehicles for Synergetic and Potent Therapy of Acute Myeloid Leukemia Advanced Science acute myeloid leukemia BCL2 inhibitor BN coordination boronic ester bond MCL1 inhibitor synergetic therapy |
| title | Codelivery of BCL2 and MCL1 Inhibitors Enabled by Phenylboronic Acid‐Functionalized Polypeptide Nanovehicles for Synergetic and Potent Therapy of Acute Myeloid Leukemia |
| title_full | Codelivery of BCL2 and MCL1 Inhibitors Enabled by Phenylboronic Acid‐Functionalized Polypeptide Nanovehicles for Synergetic and Potent Therapy of Acute Myeloid Leukemia |
| title_fullStr | Codelivery of BCL2 and MCL1 Inhibitors Enabled by Phenylboronic Acid‐Functionalized Polypeptide Nanovehicles for Synergetic and Potent Therapy of Acute Myeloid Leukemia |
| title_full_unstemmed | Codelivery of BCL2 and MCL1 Inhibitors Enabled by Phenylboronic Acid‐Functionalized Polypeptide Nanovehicles for Synergetic and Potent Therapy of Acute Myeloid Leukemia |
| title_short | Codelivery of BCL2 and MCL1 Inhibitors Enabled by Phenylboronic Acid‐Functionalized Polypeptide Nanovehicles for Synergetic and Potent Therapy of Acute Myeloid Leukemia |
| title_sort | codelivery of bcl2 and mcl1 inhibitors enabled by phenylboronic acid functionalized polypeptide nanovehicles for synergetic and potent therapy of acute myeloid leukemia |
| topic | acute myeloid leukemia BCL2 inhibitor BN coordination boronic ester bond MCL1 inhibitor synergetic therapy |
| url | https://doi.org/10.1002/advs.202204866 |
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