Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models
Despite the use of intensive multimodality therapy, the majority of high-risk neuroblastoma (NB) patients do not survive. Without significant improvements in delivery strategies, anticancer agents used as a first-line treatment for high-risk tumors often fail to provide clinically meaningful results...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/3/1752 |
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| author | Ivan S. Alferiev David T. Guerrero Danielle Soberman Peng Guan Ferro Nguyen Venkatadri Kolla Ilia Fishbein Blake B. Pressly Garrett M. Brodeur Michael Chorny |
| author_facet | Ivan S. Alferiev David T. Guerrero Danielle Soberman Peng Guan Ferro Nguyen Venkatadri Kolla Ilia Fishbein Blake B. Pressly Garrett M. Brodeur Michael Chorny |
| author_sort | Ivan S. Alferiev |
| collection | DOAJ |
| description | Despite the use of intensive multimodality therapy, the majority of high-risk neuroblastoma (NB) patients do not survive. Without significant improvements in delivery strategies, anticancer agents used as a first-line treatment for high-risk tumors often fail to provide clinically meaningful results in the settings of disseminated, recurrent, or refractory disease. By enhancing pharmacological selectivity, favorably shifting biodistribution, strengthening tumor cell killing potency, and overcoming drug resistance, nanocarrier-mediated delivery of topoisomerase I inhibitors of the camptothecin family has the potential to dramatically improve treatment efficacy and minimize side effects. In this study, a structurally enhanced camptothecin analog, SN22, reversibly coupled with a redox-silent tocol derivative (tocopheryl oxamate) to allow its optimally stable encapsulation and controlled release from PEGylated sub-100 nm nanoparticles (NP), exhibited strong NB cell growth inhibitory activity, translating into rapid regression and durably suppressed regrowth of orthotopic, <i>MYCN</i>-amplified NB tumors. The robust antitumor effects and markedly extended survival achieved in preclinical models recapitulating different phases of high-risk disease (at diagnosis vs. at relapse with an acquired loss of p53 function after intensive multiagent chemotherapy) demonstrate remarkable potential of SN22 delivered in the form of a hydrolytically cleavable superhydrophobic prodrug encapsulated in biodegradable nanocarriers as an experimental strategy for treating refractory solid tumors in high-risk cancer patients. |
| first_indexed | 2024-03-09T23:45:03Z |
| format | Article |
| id | doaj.art-b0dba32dcace496b87a25d04add398a4 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:45:03Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b0dba32dcace496b87a25d04add398a42023-11-23T16:46:00ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-02-01233175210.3390/ijms23031752Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma ModelsIvan S. Alferiev0David T. Guerrero1Danielle Soberman2Peng Guan3Ferro Nguyen4Venkatadri Kolla5Ilia Fishbein6Blake B. Pressly7Garrett M. Brodeur8Michael Chorny9Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USADespite the use of intensive multimodality therapy, the majority of high-risk neuroblastoma (NB) patients do not survive. Without significant improvements in delivery strategies, anticancer agents used as a first-line treatment for high-risk tumors often fail to provide clinically meaningful results in the settings of disseminated, recurrent, or refractory disease. By enhancing pharmacological selectivity, favorably shifting biodistribution, strengthening tumor cell killing potency, and overcoming drug resistance, nanocarrier-mediated delivery of topoisomerase I inhibitors of the camptothecin family has the potential to dramatically improve treatment efficacy and minimize side effects. In this study, a structurally enhanced camptothecin analog, SN22, reversibly coupled with a redox-silent tocol derivative (tocopheryl oxamate) to allow its optimally stable encapsulation and controlled release from PEGylated sub-100 nm nanoparticles (NP), exhibited strong NB cell growth inhibitory activity, translating into rapid regression and durably suppressed regrowth of orthotopic, <i>MYCN</i>-amplified NB tumors. The robust antitumor effects and markedly extended survival achieved in preclinical models recapitulating different phases of high-risk disease (at diagnosis vs. at relapse with an acquired loss of p53 function after intensive multiagent chemotherapy) demonstrate remarkable potential of SN22 delivered in the form of a hydrolytically cleavable superhydrophobic prodrug encapsulated in biodegradable nanocarriers as an experimental strategy for treating refractory solid tumors in high-risk cancer patients.https://www.mdpi.com/1422-0067/23/3/1752neuroblastomadrug resistancetopoisomerase I inhibitorSN22high-risk diseasenanoparticle |
| spellingShingle | Ivan S. Alferiev David T. Guerrero Danielle Soberman Peng Guan Ferro Nguyen Venkatadri Kolla Ilia Fishbein Blake B. Pressly Garrett M. Brodeur Michael Chorny Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models International Journal of Molecular Sciences neuroblastoma drug resistance topoisomerase I inhibitor SN22 high-risk disease nanoparticle |
| title | Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models |
| title_full | Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models |
| title_fullStr | Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models |
| title_full_unstemmed | Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models |
| title_short | Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models |
| title_sort | nanocarrier based delivery of sn22 as a tocopheryl oxamate prodrug achieves rapid tumor regression and extends survival in high risk neuroblastoma models |
| topic | neuroblastoma drug resistance topoisomerase I inhibitor SN22 high-risk disease nanoparticle |
| url | https://www.mdpi.com/1422-0067/23/3/1752 |
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