ICAM-1 Targeted Drug Combination Nanoparticles Enhanced Gemcitabine-Paclitaxel Exposure and Breast Cancer Suppression in Mouse Models
Despite the availability of molecularly targeted treatments such as antibodies and small molecules for human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and programmed death-ligand 1 (PD-L1), limited treatment options are available for advanced metastatic breast cancer (MBC), w...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/1/89 |
| _version_ | 1797491146962763776 |
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| author | Linxi Zhu Qingxin Mu Jesse Yu James I. Griffin Xiaolin Xu Rodney J. Y. Ho |
| author_facet | Linxi Zhu Qingxin Mu Jesse Yu James I. Griffin Xiaolin Xu Rodney J. Y. Ho |
| author_sort | Linxi Zhu |
| collection | DOAJ |
| description | Despite the availability of molecularly targeted treatments such as antibodies and small molecules for human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and programmed death-ligand 1 (PD-L1), limited treatment options are available for advanced metastatic breast cancer (MBC), which constitutes ~90% mortality. Many of these monotherapies often lead to drug resistance. Novel MBC-targeted drug-combination therapeutic approaches that may reduce resistance are urgently needed. We investigated intercellular adhesion molecule-1 (ICAM-1), which is abundant in MBC, as a potential target to co-localize two current drug combinations, gemcitabine (G) and paclitaxel (T), assembled in a novel drug-combination nanoparticle (GT DcNP) form. With an ICAM-1-binding peptide (referred to as LFA1-P) coated on GT DcNPs, we evaluated the role of the LFA1-P density in breast cancer cell localization in vitro and in vivo. We found that 1–2% LFA1-P peptide incorporated on GT DcNPs provided optimal cancer cell binding in vitro with ~4× enhancement compared to non-peptide GT DcNPs. The in vivo probing of GT DcNPs labeled with a near-infrared marker, indocyanine green, in mice by bio-imaging and G and T analyses indicated LFA1-P enhanced drug and GT DcNP localization in breast cancer cells. The target/healthy tissue (lung/gastrointestinal (GI)) ratio of particles increased by ~60× compared to the non-ligand control. Collectively, these data indicated that LFA1 on GT DcNPs may provide ICAM-1-targeted G and T drug combination delivery to advancing MBC cells found in lung tissues. As ICAM-1 is generally expressed even in breast cancers that are triple-negative phenotypes, which are unresponsive to inhibitors of nuclear receptors or HER2/estrogen receptor (ER) agents, ICAM-1-targeted LFA1-P-coated GT DcNPs should be considered for clinical development to improve therapeutic outcomes of MBCs. |
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| id | doaj.art-8c29b1dad6914e5893c0a991bad61a30 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T00:43:17Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-8c29b1dad6914e5893c0a991bad61a302023-11-23T15:03:40ZengMDPI AGPharmaceutics1999-49232021-12-011418910.3390/pharmaceutics14010089ICAM-1 Targeted Drug Combination Nanoparticles Enhanced Gemcitabine-Paclitaxel Exposure and Breast Cancer Suppression in Mouse ModelsLinxi Zhu0Qingxin Mu1Jesse Yu2James I. Griffin3Xiaolin Xu4Rodney J. Y. Ho5Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USADepartment of Pharmaceutics, University of Washington, Seattle, WA 98195, USADepartment of Pharmaceutics, University of Washington, Seattle, WA 98195, USADepartment of Pharmaceutics, University of Washington, Seattle, WA 98195, USADepartment of Pharmaceutics, University of Washington, Seattle, WA 98195, USADepartment of Pharmaceutics, University of Washington, Seattle, WA 98195, USADespite the availability of molecularly targeted treatments such as antibodies and small molecules for human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and programmed death-ligand 1 (PD-L1), limited treatment options are available for advanced metastatic breast cancer (MBC), which constitutes ~90% mortality. Many of these monotherapies often lead to drug resistance. Novel MBC-targeted drug-combination therapeutic approaches that may reduce resistance are urgently needed. We investigated intercellular adhesion molecule-1 (ICAM-1), which is abundant in MBC, as a potential target to co-localize two current drug combinations, gemcitabine (G) and paclitaxel (T), assembled in a novel drug-combination nanoparticle (GT DcNP) form. With an ICAM-1-binding peptide (referred to as LFA1-P) coated on GT DcNPs, we evaluated the role of the LFA1-P density in breast cancer cell localization in vitro and in vivo. We found that 1–2% LFA1-P peptide incorporated on GT DcNPs provided optimal cancer cell binding in vitro with ~4× enhancement compared to non-peptide GT DcNPs. The in vivo probing of GT DcNPs labeled with a near-infrared marker, indocyanine green, in mice by bio-imaging and G and T analyses indicated LFA1-P enhanced drug and GT DcNP localization in breast cancer cells. The target/healthy tissue (lung/gastrointestinal (GI)) ratio of particles increased by ~60× compared to the non-ligand control. Collectively, these data indicated that LFA1 on GT DcNPs may provide ICAM-1-targeted G and T drug combination delivery to advancing MBC cells found in lung tissues. As ICAM-1 is generally expressed even in breast cancers that are triple-negative phenotypes, which are unresponsive to inhibitors of nuclear receptors or HER2/estrogen receptor (ER) agents, ICAM-1-targeted LFA1-P-coated GT DcNPs should be considered for clinical development to improve therapeutic outcomes of MBCs.https://www.mdpi.com/1999-4923/14/1/89metastatic breast cancernanoparticlesICAM-1targetingcombination therapy |
| spellingShingle | Linxi Zhu Qingxin Mu Jesse Yu James I. Griffin Xiaolin Xu Rodney J. Y. Ho ICAM-1 Targeted Drug Combination Nanoparticles Enhanced Gemcitabine-Paclitaxel Exposure and Breast Cancer Suppression in Mouse Models Pharmaceutics metastatic breast cancer nanoparticles ICAM-1 targeting combination therapy |
| title | ICAM-1 Targeted Drug Combination Nanoparticles Enhanced Gemcitabine-Paclitaxel Exposure and Breast Cancer Suppression in Mouse Models |
| title_full | ICAM-1 Targeted Drug Combination Nanoparticles Enhanced Gemcitabine-Paclitaxel Exposure and Breast Cancer Suppression in Mouse Models |
| title_fullStr | ICAM-1 Targeted Drug Combination Nanoparticles Enhanced Gemcitabine-Paclitaxel Exposure and Breast Cancer Suppression in Mouse Models |
| title_full_unstemmed | ICAM-1 Targeted Drug Combination Nanoparticles Enhanced Gemcitabine-Paclitaxel Exposure and Breast Cancer Suppression in Mouse Models |
| title_short | ICAM-1 Targeted Drug Combination Nanoparticles Enhanced Gemcitabine-Paclitaxel Exposure and Breast Cancer Suppression in Mouse Models |
| title_sort | icam 1 targeted drug combination nanoparticles enhanced gemcitabine paclitaxel exposure and breast cancer suppression in mouse models |
| topic | metastatic breast cancer nanoparticles ICAM-1 targeting combination therapy |
| url | https://www.mdpi.com/1999-4923/14/1/89 |
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