Targeted Delivery of Secretory Promelittin via Novel Poly(lactone‐co‐β‐amino ester) Nanoparticles for Treatment of Breast Cancer Brain Metastases
Abstract Breast cancer brain metastases (BCBM) is a devastating disease with dismal prognosis. Although chemotherapy is widely used for clinical management of most tumors, it is often ineffective for BCBM. Therefore, alternative approaches for improved treatment of BCBM are in great demand. Here, an...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-03-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.201901866 |
| _version_ | 1818383406528987136 |
|---|---|
| author | Yu Zhou Shenqi Zhang Zeming Chen Youmei Bao Ann T. Chen Wendy C. Sheu Fuyao Liu Zhaozhong Jiang Jiangbing Zhou |
| author_facet | Yu Zhou Shenqi Zhang Zeming Chen Youmei Bao Ann T. Chen Wendy C. Sheu Fuyao Liu Zhaozhong Jiang Jiangbing Zhou |
| author_sort | Yu Zhou |
| collection | DOAJ |
| description | Abstract Breast cancer brain metastases (BCBM) is a devastating disease with dismal prognosis. Although chemotherapy is widely used for clinical management of most tumors, it is often ineffective for BCBM. Therefore, alternative approaches for improved treatment of BCBM are in great demand. Here, an innovative gene therapy regimen is reported that is designed for effective treatment of BCBM. First, poly(lactone‐co‐β‐amino ester) nanoparticles that are capable of efficient gene delivery are synthesized and are engineered for targeted delivery to BCBM through surface conjugation of AMD3100, which interacts with CXCR4 enriched in the tumor microenvironment. Next, an artificial gene, proMel, is designed for the expression of secretory promelittin protein, which has limited toxicity on its own but releases cytolytic melittin after activation by MMP‐2 accumulated in tumors. It is demonstrated that delivery of the proMel via the AMD3100‐conjugated nanoparticles effectively inhibits tumor progression in a BCBM mouse model. This study suggests a new direction to treat BCBM through targeted delivery of promelittin‐mediated gene therapy. |
| first_indexed | 2024-12-14T03:05:52Z |
| format | Article |
| id | doaj.art-bd229033568541c4bdd7941c6835f812 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-12-14T03:05:52Z |
| publishDate | 2020-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-bd229033568541c4bdd7941c6835f8122022-12-21T23:19:24ZengWileyAdvanced Science2198-38442020-03-0175n/an/a10.1002/advs.201901866Targeted Delivery of Secretory Promelittin via Novel Poly(lactone‐co‐β‐amino ester) Nanoparticles for Treatment of Breast Cancer Brain MetastasesYu Zhou0Shenqi Zhang1Zeming Chen2Youmei Bao3Ann T. Chen4Wendy C. Sheu5Fuyao Liu6Zhaozhong Jiang7Jiangbing Zhou8Department of Neurosurgery Yale University New Haven CT 06511 USADepartment of Neurosurgery Yale University New Haven CT 06511 USADepartment of Neurosurgery Yale University New Haven CT 06511 USADepartment of Neurosurgery Yale University New Haven CT 06511 USADepartment of Biomedical Engineering Yale University New Haven CT 06511 USADepartment of Biomedical Engineering Yale University New Haven CT 06511 USADepartment of Neurosurgery Yale University New Haven CT 06511 USADepartment of Biomedical Engineering Yale University New Haven CT 06511 USADepartment of Neurosurgery Yale University New Haven CT 06511 USAAbstract Breast cancer brain metastases (BCBM) is a devastating disease with dismal prognosis. Although chemotherapy is widely used for clinical management of most tumors, it is often ineffective for BCBM. Therefore, alternative approaches for improved treatment of BCBM are in great demand. Here, an innovative gene therapy regimen is reported that is designed for effective treatment of BCBM. First, poly(lactone‐co‐β‐amino ester) nanoparticles that are capable of efficient gene delivery are synthesized and are engineered for targeted delivery to BCBM through surface conjugation of AMD3100, which interacts with CXCR4 enriched in the tumor microenvironment. Next, an artificial gene, proMel, is designed for the expression of secretory promelittin protein, which has limited toxicity on its own but releases cytolytic melittin after activation by MMP‐2 accumulated in tumors. It is demonstrated that delivery of the proMel via the AMD3100‐conjugated nanoparticles effectively inhibits tumor progression in a BCBM mouse model. This study suggests a new direction to treat BCBM through targeted delivery of promelittin‐mediated gene therapy.https://doi.org/10.1002/advs.201901866brain metastasisbreast cancergene therapymelittinpoly(lactone‐co‐β‐amino ester) |
| spellingShingle | Yu Zhou Shenqi Zhang Zeming Chen Youmei Bao Ann T. Chen Wendy C. Sheu Fuyao Liu Zhaozhong Jiang Jiangbing Zhou Targeted Delivery of Secretory Promelittin via Novel Poly(lactone‐co‐β‐amino ester) Nanoparticles for Treatment of Breast Cancer Brain Metastases Advanced Science brain metastasis breast cancer gene therapy melittin poly(lactone‐co‐β‐amino ester) |
| title | Targeted Delivery of Secretory Promelittin via Novel Poly(lactone‐co‐β‐amino ester) Nanoparticles for Treatment of Breast Cancer Brain Metastases |
| title_full | Targeted Delivery of Secretory Promelittin via Novel Poly(lactone‐co‐β‐amino ester) Nanoparticles for Treatment of Breast Cancer Brain Metastases |
| title_fullStr | Targeted Delivery of Secretory Promelittin via Novel Poly(lactone‐co‐β‐amino ester) Nanoparticles for Treatment of Breast Cancer Brain Metastases |
| title_full_unstemmed | Targeted Delivery of Secretory Promelittin via Novel Poly(lactone‐co‐β‐amino ester) Nanoparticles for Treatment of Breast Cancer Brain Metastases |
| title_short | Targeted Delivery of Secretory Promelittin via Novel Poly(lactone‐co‐β‐amino ester) Nanoparticles for Treatment of Breast Cancer Brain Metastases |
| title_sort | targeted delivery of secretory promelittin via novel poly lactone co β amino ester nanoparticles for treatment of breast cancer brain metastases |
| topic | brain metastasis breast cancer gene therapy melittin poly(lactone‐co‐β‐amino ester) |
| url | https://doi.org/10.1002/advs.201901866 |
| work_keys_str_mv | AT yuzhou targeteddeliveryofsecretorypromelittinvianovelpolylactonecobaminoesternanoparticlesfortreatmentofbreastcancerbrainmetastases AT shenqizhang targeteddeliveryofsecretorypromelittinvianovelpolylactonecobaminoesternanoparticlesfortreatmentofbreastcancerbrainmetastases AT zemingchen targeteddeliveryofsecretorypromelittinvianovelpolylactonecobaminoesternanoparticlesfortreatmentofbreastcancerbrainmetastases AT youmeibao targeteddeliveryofsecretorypromelittinvianovelpolylactonecobaminoesternanoparticlesfortreatmentofbreastcancerbrainmetastases AT anntchen targeteddeliveryofsecretorypromelittinvianovelpolylactonecobaminoesternanoparticlesfortreatmentofbreastcancerbrainmetastases AT wendycsheu targeteddeliveryofsecretorypromelittinvianovelpolylactonecobaminoesternanoparticlesfortreatmentofbreastcancerbrainmetastases AT fuyaoliu targeteddeliveryofsecretorypromelittinvianovelpolylactonecobaminoesternanoparticlesfortreatmentofbreastcancerbrainmetastases AT zhaozhongjiang targeteddeliveryofsecretorypromelittinvianovelpolylactonecobaminoesternanoparticlesfortreatmentofbreastcancerbrainmetastases AT jiangbingzhou targeteddeliveryofsecretorypromelittinvianovelpolylactonecobaminoesternanoparticlesfortreatmentofbreastcancerbrainmetastases |