Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma
Patients with high-risk non-metastatic renal cell carcinoma (RCC) are at risk of metastatic relapse following nephrectomy. Cabozantinib (CZ), a potent multitarget tyrosine kinase inhibitor, interferes with angiogenesis and immunosuppression associated with surgery-induced metastasis. Here, we explor...
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| Format: | Article |
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MDPI AG
2022-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/20/12634 |
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| author | Hye Won Lee Hee Seung Seo Seon-Yong Yeom Se-Na Kim Cho Rim Kim Dae-Hwan Park Wooram Park Young Bin Choy Chun Gwon Park Seong Il Seo |
| author_facet | Hye Won Lee Hee Seung Seo Seon-Yong Yeom Se-Na Kim Cho Rim Kim Dae-Hwan Park Wooram Park Young Bin Choy Chun Gwon Park Seong Il Seo |
| author_sort | Hye Won Lee |
| collection | DOAJ |
| description | Patients with high-risk non-metastatic renal cell carcinoma (RCC) are at risk of metastatic relapse following nephrectomy. Cabozantinib (CZ), a potent multitarget tyrosine kinase inhibitor, interferes with angiogenesis and immunosuppression associated with surgery-induced metastasis. Here, we explored the therapeutic potential of CZ-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CZ-PLGA-NPs) as an adjuvant strategy for targeting post-nephrectomy metastasis. A clinically relevant subline recapitulating post-nephrectomy lung metastasis of high-risk human RCC, namely Renca-SRLu5-Luc, was established through in vivo serial selection of luciferase-expressing murine RCC Renca-Luc cells. CZ was encapsulated into PLGA-NPs via the conventional single emulsion technique. The multifaceted preclinical antimetastatic efficacy of CZ-PLGA-NPs was assessed in Renca-SRLu5-Luc cells. CZ-PLGA-NPs with a smooth surface displayed desirable physicochemical properties, good CZ encapsulation efficiency, as well as controlled and sustained CZ release. CZ-PLGA-NPs exhibited remarkable dose-dependent toxicity against Renca-SRLu5-Luc cells by inducing G2/M cell cycle arrest and apoptosis. CZ-PLGA-NPs attenuated in vitro colony formation, migration, and invasion by abrogating AKT and ERK1/2 activation. An intravenous injection of CZ-PLGA-NPs markedly reduced lung metastatic burden and prolonged lifespan with favorable safety in the Renca-SRLu5-Luc experimental lung metastasis model. The novel CZ-PLGA-NPs system with multifaceted antimetastatic effects and alleviating off-target toxicity potential is a promising adjunctive agent for patients with surgically resected high-risk RCC. |
| first_indexed | 2024-03-09T20:05:03Z |
| format | Article |
| id | doaj.art-a7f65aeee7db4e239052b1542e102686 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T20:05:03Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a7f65aeee7db4e239052b1542e1026862023-11-24T00:34:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123201263410.3390/ijms232012634Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell CarcinomaHye Won Lee0Hee Seung Seo1Seon-Yong Yeom2Se-Na Kim3Cho Rim Kim4Dae-Hwan Park5Wooram Park6Young Bin Choy7Chun Gwon Park8Seong Il Seo9Department of Urology, Center for Urologic Cancer, National Cancer Center, Goyang 10408, KoreaDepartment of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University, Suwon 16419, KoreaDepartment of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, KoreaInstitute of Medical & Biological Engineering, Medical Research Center, Seoul National University, Seoul 03080, KoreaInterdisciplinary Program in Bioengineering, College of Engineering, Seoul National University, Seoul 08826, KoreaDepartment of Engineering Chemistry, College of Engineering, Chungbuk National University, Cheongju 28644, KoreaDepartment of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon 16419, KoreaInstitute of Medical & Biological Engineering, Medical Research Center, Seoul National University, Seoul 03080, KoreaDepartment of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University, Suwon 16419, KoreaDepartment of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, KoreaPatients with high-risk non-metastatic renal cell carcinoma (RCC) are at risk of metastatic relapse following nephrectomy. Cabozantinib (CZ), a potent multitarget tyrosine kinase inhibitor, interferes with angiogenesis and immunosuppression associated with surgery-induced metastasis. Here, we explored the therapeutic potential of CZ-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CZ-PLGA-NPs) as an adjuvant strategy for targeting post-nephrectomy metastasis. A clinically relevant subline recapitulating post-nephrectomy lung metastasis of high-risk human RCC, namely Renca-SRLu5-Luc, was established through in vivo serial selection of luciferase-expressing murine RCC Renca-Luc cells. CZ was encapsulated into PLGA-NPs via the conventional single emulsion technique. The multifaceted preclinical antimetastatic efficacy of CZ-PLGA-NPs was assessed in Renca-SRLu5-Luc cells. CZ-PLGA-NPs with a smooth surface displayed desirable physicochemical properties, good CZ encapsulation efficiency, as well as controlled and sustained CZ release. CZ-PLGA-NPs exhibited remarkable dose-dependent toxicity against Renca-SRLu5-Luc cells by inducing G2/M cell cycle arrest and apoptosis. CZ-PLGA-NPs attenuated in vitro colony formation, migration, and invasion by abrogating AKT and ERK1/2 activation. An intravenous injection of CZ-PLGA-NPs markedly reduced lung metastatic burden and prolonged lifespan with favorable safety in the Renca-SRLu5-Luc experimental lung metastasis model. The novel CZ-PLGA-NPs system with multifaceted antimetastatic effects and alleviating off-target toxicity potential is a promising adjunctive agent for patients with surgically resected high-risk RCC.https://www.mdpi.com/1422-0067/23/20/12634adjuvantcabozantinibdrug deliveryenhanced permeability retentionnanoparticlepoly(lactic-co-glycolic acid) |
| spellingShingle | Hye Won Lee Hee Seung Seo Seon-Yong Yeom Se-Na Kim Cho Rim Kim Dae-Hwan Park Wooram Park Young Bin Choy Chun Gwon Park Seong Il Seo Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma International Journal of Molecular Sciences adjuvant cabozantinib drug delivery enhanced permeability retention nanoparticle poly(lactic-co-glycolic acid) |
| title | Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma |
| title_full | Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma |
| title_fullStr | Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma |
| title_full_unstemmed | Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma |
| title_short | Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma |
| title_sort | cabozantinib loaded plga nanoparticles a potential adjuvant strategy for surgically resected high risk non metastatic renal cell carcinoma |
| topic | adjuvant cabozantinib drug delivery enhanced permeability retention nanoparticle poly(lactic-co-glycolic acid) |
| url | https://www.mdpi.com/1422-0067/23/20/12634 |
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