Combined Docetaxel/Pictilisib-Loaded mPEGylated Nanocarriers with Dual HER2 Targeting Antibodies for Synergistic Chemotherapy of Breast Cancer
Wei-Jie Cheng,1,* Shyr-Yi Lin,2,3,* Kuo-Hsiang Chuang,4,5,* Michael Chen,4 Hsiu-O Ho,1 Ling-Chun Chen,6 Chien-Ming Hsieh,1 Ming-Thau Sheu1 1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; 2Division of Gastroenterology, Department of Interna...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2022-11-01
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| Series: | International Journal of Nanomedicine |
| Subjects: | |
| Online Access: | https://www.dovepress.com/combined-docetaxelpictilisib-loaded-mpegylated-nanocarriers-with-dual--peer-reviewed-fulltext-article-IJN |
| _version_ | 1797963001472483328 |
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| author | Cheng WJ Lin SY Chuang KH Chen M Ho HO Chen LC Hsieh CM Sheu MT |
| author_facet | Cheng WJ Lin SY Chuang KH Chen M Ho HO Chen LC Hsieh CM Sheu MT |
| author_sort | Cheng WJ |
| collection | DOAJ |
| description | Wei-Jie Cheng,1,* Shyr-Yi Lin,2,3,* Kuo-Hsiang Chuang,4,5,* Michael Chen,4 Hsiu-O Ho,1 Ling-Chun Chen,6 Chien-Ming Hsieh,1 Ming-Thau Sheu1 1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; 2Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 3Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 4Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan; 5PhD Program in Clinical Drug Development of Chinese Herbal Medicine, Taipei Medical University, Taipei, Taiwan; 6Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu, Taiwan*These authors contributed equally to this workCorrespondence: Chien-Ming Hsieh; Ming-Thau Sheu, Email cmhsieh@tmu.edu.tw; mingsheu@tmu.edu.twIntroduction: Approximately 15%~30% of breast cancers have gene amplification or overexpression of the human epidermal growth factor receptor 2 (HER2), resulting in the chemotherapy resistance, a more-aggressive phenotype and poor prognosis.Methods: We propose a strategy of nanocarriers co-loaded with docetaxel (DTX) and pictilisib (PIC) at a synergistic ratio and non-covalently bound with dual anti-HER2 epitopes bispecific antibodies (BsAbs: anti-HER2-IV/methoxy-polyethylene glycol (mPEG) and anti-HER2-II/methoxy-PEG) for synergistic targeting to overcome the therapeutic dilemmas of the resistance for HER2-targetable chemodrugs. DTX/PIC-loaded nanocarriers (D/P_NCs) were prepared with single emulsion methods and characterized using dynamic light scattering analysis, and the drug content was assayed by high-performance liquid chromatographic method. The integrity and function of BsABs were evaluated using sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and enzyme-linked immunosorbent assay (ELISA). The in vitro cell studies and in vivo breast tumor-bearing mice model were used to evaluate the anti-cancer effect and biosafety of formulations.Results: D/P_NCs optimally prepared exhibited a spherical morphology with small particle sizes (~140 nm), high drug loading (~5.5%), and good colloidal stability. The synergistic tumor cytotoxicity of loading DTX and PIC at 2:1 ratio in D/P_NCs was discovered. The BsAbs are successfully decorated on mPEGylated DTX/PIC-loaded nanocarriers via anti-mPEG moiety. In vitro studies revealed that non-covalent decoration with dual BsAbs on D_P-NCs significantly and synergistically increased cellular uptake, while with loading DTX and PIC at a synergistic ratio of 2:1 in D/P_NCs further resulted in synergistic cytotoxicity. In vivo tumor inhibition studies showed the comparable results for synergistic antitumor efficacy while minimizing systemic toxicity of chemodrugs.Conclusion: Non-covalent modification with dual distinct epitopes BsAbs on the nanocarriers loaded with dual chemodrugs at a synergistic ratio was expected to be a promising therapeutic platform to overcome the chemoresistance of various cancers and warrants further development for future therapy in the clinical.Graphical Abstract: Keywords: docetaxel, pictilisib, nanocarriers, bispecific antibodies, dual epitopes, HER2-positive breast cancer |
| first_indexed | 2024-04-11T01:21:29Z |
| format | Article |
| id | doaj.art-41f605d5b23c4342b63aeeef628ed45a |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-04-11T01:21:29Z |
| publishDate | 2022-11-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nanomedicine |
| spelling | doaj.art-41f605d5b23c4342b63aeeef628ed45a2023-01-03T11:15:21ZengDove Medical PressInternational Journal of Nanomedicine1178-20132022-11-01Volume 175353537479723Combined Docetaxel/Pictilisib-Loaded mPEGylated Nanocarriers with Dual HER2 Targeting Antibodies for Synergistic Chemotherapy of Breast CancerCheng WJLin SYChuang KHChen MHo HOChen LCHsieh CMSheu MTWei-Jie Cheng,1,* Shyr-Yi Lin,2,3,* Kuo-Hsiang Chuang,4,5,* Michael Chen,4 Hsiu-O Ho,1 Ling-Chun Chen,6 Chien-Ming Hsieh,1 Ming-Thau Sheu1 1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; 2Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 3Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 4Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan; 5PhD Program in Clinical Drug Development of Chinese Herbal Medicine, Taipei Medical University, Taipei, Taiwan; 6Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu, Taiwan*These authors contributed equally to this workCorrespondence: Chien-Ming Hsieh; Ming-Thau Sheu, Email cmhsieh@tmu.edu.tw; mingsheu@tmu.edu.twIntroduction: Approximately 15%~30% of breast cancers have gene amplification or overexpression of the human epidermal growth factor receptor 2 (HER2), resulting in the chemotherapy resistance, a more-aggressive phenotype and poor prognosis.Methods: We propose a strategy of nanocarriers co-loaded with docetaxel (DTX) and pictilisib (PIC) at a synergistic ratio and non-covalently bound with dual anti-HER2 epitopes bispecific antibodies (BsAbs: anti-HER2-IV/methoxy-polyethylene glycol (mPEG) and anti-HER2-II/methoxy-PEG) for synergistic targeting to overcome the therapeutic dilemmas of the resistance for HER2-targetable chemodrugs. DTX/PIC-loaded nanocarriers (D/P_NCs) were prepared with single emulsion methods and characterized using dynamic light scattering analysis, and the drug content was assayed by high-performance liquid chromatographic method. The integrity and function of BsABs were evaluated using sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and enzyme-linked immunosorbent assay (ELISA). The in vitro cell studies and in vivo breast tumor-bearing mice model were used to evaluate the anti-cancer effect and biosafety of formulations.Results: D/P_NCs optimally prepared exhibited a spherical morphology with small particle sizes (~140 nm), high drug loading (~5.5%), and good colloidal stability. The synergistic tumor cytotoxicity of loading DTX and PIC at 2:1 ratio in D/P_NCs was discovered. The BsAbs are successfully decorated on mPEGylated DTX/PIC-loaded nanocarriers via anti-mPEG moiety. In vitro studies revealed that non-covalent decoration with dual BsAbs on D_P-NCs significantly and synergistically increased cellular uptake, while with loading DTX and PIC at a synergistic ratio of 2:1 in D/P_NCs further resulted in synergistic cytotoxicity. In vivo tumor inhibition studies showed the comparable results for synergistic antitumor efficacy while minimizing systemic toxicity of chemodrugs.Conclusion: Non-covalent modification with dual distinct epitopes BsAbs on the nanocarriers loaded with dual chemodrugs at a synergistic ratio was expected to be a promising therapeutic platform to overcome the chemoresistance of various cancers and warrants further development for future therapy in the clinical.Graphical Abstract: Keywords: docetaxel, pictilisib, nanocarriers, bispecific antibodies, dual epitopes, HER2-positive breast cancerhttps://www.dovepress.com/combined-docetaxelpictilisib-loaded-mpegylated-nanocarriers-with-dual--peer-reviewed-fulltext-article-IJNdocetaxelpictilisibnanocarriersbispecific antibodiesdual epitopesher2-positive breast cancer |
| spellingShingle | Cheng WJ Lin SY Chuang KH Chen M Ho HO Chen LC Hsieh CM Sheu MT Combined Docetaxel/Pictilisib-Loaded mPEGylated Nanocarriers with Dual HER2 Targeting Antibodies for Synergistic Chemotherapy of Breast Cancer International Journal of Nanomedicine docetaxel pictilisib nanocarriers bispecific antibodies dual epitopes her2-positive breast cancer |
| title | Combined Docetaxel/Pictilisib-Loaded mPEGylated Nanocarriers with Dual HER2 Targeting Antibodies for Synergistic Chemotherapy of Breast Cancer |
| title_full | Combined Docetaxel/Pictilisib-Loaded mPEGylated Nanocarriers with Dual HER2 Targeting Antibodies for Synergistic Chemotherapy of Breast Cancer |
| title_fullStr | Combined Docetaxel/Pictilisib-Loaded mPEGylated Nanocarriers with Dual HER2 Targeting Antibodies for Synergistic Chemotherapy of Breast Cancer |
| title_full_unstemmed | Combined Docetaxel/Pictilisib-Loaded mPEGylated Nanocarriers with Dual HER2 Targeting Antibodies for Synergistic Chemotherapy of Breast Cancer |
| title_short | Combined Docetaxel/Pictilisib-Loaded mPEGylated Nanocarriers with Dual HER2 Targeting Antibodies for Synergistic Chemotherapy of Breast Cancer |
| title_sort | combined docetaxel pictilisib loaded mpegylated nanocarriers with dual her2 targeting antibodies for synergistic chemotherapy of breast cancer |
| topic | docetaxel pictilisib nanocarriers bispecific antibodies dual epitopes her2-positive breast cancer |
| url | https://www.dovepress.com/combined-docetaxelpictilisib-loaded-mpegylated-nanocarriers-with-dual--peer-reviewed-fulltext-article-IJN |
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