Chemotherapy-Eluting Intraperitoneal Implants for Advanced Stage Ovarian Cancer Treatment
The objective of this work was to develop an implant for sustained abdominal chemotherapy delivery, intraperitoneal (IP) chemotherapy. IP chemotherapy has improved survival in ovarian cancer (OC) patients, but its adoption has suffered due to resource requirements and dose-limiting toxicities. We pr...
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| Format: | Thesis |
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Massachusetts Institute of Technology
2022
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| Online Access: | https://hdl.handle.net/1721.1/139892 |
| _version_ | 1811068517164777472 |
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| author | Subramanyam, Kriti S. |
| author2 | Cima, Michael J. |
| author_facet | Cima, Michael J. Subramanyam, Kriti S. |
| author_sort | Subramanyam, Kriti S. |
| collection | MIT |
| description | The objective of this work was to develop an implant for sustained abdominal chemotherapy delivery, intraperitoneal (IP) chemotherapy. IP chemotherapy has improved survival in ovarian cancer (OC) patients, but its adoption has suffered due to resource requirements and dose-limiting toxicities. We previously showed that an IP device that delivers sustained low-dose chemotherapy over time is equally effective in treating OC in mice and less toxic than intermittent high-dose injections.
To translate that work to a clinically relevant delivery system, a biocompatible composite implant was developed from medical-grade materials containing microparticulate cisplatin, a widely used drug in OC treatment. The material was designed to match mechanical properties of human abdominal organs for safe long-term IP placement. Sheets fabricated from the composite material were evaluated in vitro for sustained cisplatin release and for bioactivity against OC cell lines. Three-dimensional implant geometries were designed and prototyped to facilitate deployment by minimally invasive laparoscopic surgery.
Sustained low-dose chemotherapy may also potentiate tumor antigen-specific immune responses, but the impact of drug selection and dosing on this response is not well characterized. Multiple anticancer drugs were screened in this work and evaluated for their ability to induce immunogenic cell death-associated gene expression to inform future dose selection for the implant. The impact of sustained chemotherapy delivery is anticipated to be greatest against microscopic tumors left behind following debulking surgery, which precedes chemotherapy treatment in OC patients. Most OC animal models fail to replicate this disease pattern and, therefore, do not reflect the expected clinical treatment response. To address this shortcoming, a novel OC mouse model with disperse microscopic abdominal tumors was developed and characterized to provide a clinically translatable model to study the efficacy of the IP implant.
An implant that enhances efficacy and accessibility of IP chemotherapy will have greater impact in resource-limited settings. Design reviews and surveys of practicing physicians in India revealed eagerness for new technology adoption and potential for an IP implant to supplement and integrate into existing treatment regimens. The implant developed in this work serves as a sustained IP drug delivery platform to improve patient compliance and physician adoption globally. |
| first_indexed | 2024-09-23T07:57:08Z |
| format | Thesis |
| id | mit-1721.1/139892 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T07:57:08Z |
| publishDate | 2022 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1398922022-02-08T04:09:07Z Chemotherapy-Eluting Intraperitoneal Implants for Advanced Stage Ovarian Cancer Treatment Subramanyam, Kriti S. Cima, Michael J. Harvard-MIT Program in Health Sciences and Technology The objective of this work was to develop an implant for sustained abdominal chemotherapy delivery, intraperitoneal (IP) chemotherapy. IP chemotherapy has improved survival in ovarian cancer (OC) patients, but its adoption has suffered due to resource requirements and dose-limiting toxicities. We previously showed that an IP device that delivers sustained low-dose chemotherapy over time is equally effective in treating OC in mice and less toxic than intermittent high-dose injections. To translate that work to a clinically relevant delivery system, a biocompatible composite implant was developed from medical-grade materials containing microparticulate cisplatin, a widely used drug in OC treatment. The material was designed to match mechanical properties of human abdominal organs for safe long-term IP placement. Sheets fabricated from the composite material were evaluated in vitro for sustained cisplatin release and for bioactivity against OC cell lines. Three-dimensional implant geometries were designed and prototyped to facilitate deployment by minimally invasive laparoscopic surgery. Sustained low-dose chemotherapy may also potentiate tumor antigen-specific immune responses, but the impact of drug selection and dosing on this response is not well characterized. Multiple anticancer drugs were screened in this work and evaluated for their ability to induce immunogenic cell death-associated gene expression to inform future dose selection for the implant. The impact of sustained chemotherapy delivery is anticipated to be greatest against microscopic tumors left behind following debulking surgery, which precedes chemotherapy treatment in OC patients. Most OC animal models fail to replicate this disease pattern and, therefore, do not reflect the expected clinical treatment response. To address this shortcoming, a novel OC mouse model with disperse microscopic abdominal tumors was developed and characterized to provide a clinically translatable model to study the efficacy of the IP implant. An implant that enhances efficacy and accessibility of IP chemotherapy will have greater impact in resource-limited settings. Design reviews and surveys of practicing physicians in India revealed eagerness for new technology adoption and potential for an IP implant to supplement and integrate into existing treatment regimens. The implant developed in this work serves as a sustained IP drug delivery platform to improve patient compliance and physician adoption globally. Ph.D. 2022-02-07T15:11:10Z 2022-02-07T15:11:10Z 2021-09 2021-09-21T18:42:07.656Z Thesis https://hdl.handle.net/1721.1/139892 0000-0002-8715-4795 In Copyright - Educational Use Permitted Copyright MIT http://rightsstatements.org/page/InC-EDU/1.0/ application/pdf Massachusetts Institute of Technology |
| spellingShingle | Subramanyam, Kriti S. Chemotherapy-Eluting Intraperitoneal Implants for Advanced Stage Ovarian Cancer Treatment |
| title | Chemotherapy-Eluting Intraperitoneal Implants for Advanced Stage Ovarian Cancer Treatment |
| title_full | Chemotherapy-Eluting Intraperitoneal Implants for Advanced Stage Ovarian Cancer Treatment |
| title_fullStr | Chemotherapy-Eluting Intraperitoneal Implants for Advanced Stage Ovarian Cancer Treatment |
| title_full_unstemmed | Chemotherapy-Eluting Intraperitoneal Implants for Advanced Stage Ovarian Cancer Treatment |
| title_short | Chemotherapy-Eluting Intraperitoneal Implants for Advanced Stage Ovarian Cancer Treatment |
| title_sort | chemotherapy eluting intraperitoneal implants for advanced stage ovarian cancer treatment |
| url | https://hdl.handle.net/1721.1/139892 |
| work_keys_str_mv | AT subramanyamkritis chemotherapyelutingintraperitonealimplantsforadvancedstageovariancancertreatment |