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Published on: June 22, 2021
Implantable Microdevices for In Vivo Assessment of Chemotherapy Response in Patient Derived Organoid Orthotopic
Oliver J Standring1,2, Julien T Hohenleitner1,2, Lyudmyla Demyan1,2
1Lustgarten Foundation Pancreatic Cancer Research Laboratory at Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
Objective:
To investigate the feasibility of using implantable microdevices (IMDs) in pancreatic ductal adenocarcinoma (PDAC).
Background:
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited treatment options. IMDs permit localized delivery of multiple therapies with simultaneous in vivo assessment of tumor response. Although IMDs have previously been evaluated in multiple malignancies, their application in PDAC has not been reported.
Methods:
Xenograft tumors were generated by injecting PDAC patient-derived organoids (PDO) into mouse pancreata. IMDs loaded with standard-of-care chemotherapeutic drugs including gemcitabine, paclitaxel, SN38 (irinotecan metabolite), oxaliplatin, and 5-fluorouracil were then inserted into the tumor during laparotomy. Mice were sacrificed at 4 or 24 hours after insertion. Immunofluorescence was performed to assess biomarkers of DNA damage (γH2AX), apoptosis (cleaved caspase-3; CC3), and proliferation (Ki67).
Results:
Fourteen mice underwent IMD placement with successful device retrieval and analysis. CC3 and γH2AX analyses revealed treatment specific biologic response, with the most pronounced response at 24 hours. Ki67 analysis demonstrated reduction of the proliferation within treated regions at both 4 and 24 hours compared to controls. Overall, the IMD enabled localized chemotherapy delivery and concurrent assessment of responses to multiple chemotherapeutic agents in an in vivo setting.
Conclusion:
Intra-pancreatic IMD deployment in orthotopic PDAC organoid tumors presents a feasible approach to assess chemotherapy sensitivities. Changes in proliferation revealed drug specific response at all timepoints, while apoptotic markers required longer incubation. These data support further investigation into the intra-operative or endoscopic deployment of IMDs as a platform for precision medicine.
Insights
Implantable microdevices (IMDs) show feasibility for localized chemotherapy delivery and response assessment in pancreatic ductal adenocarcinoma (PDAC) models. This approach enables precise evaluation of drug effectiveness in vivo.
Area of Science:
- Oncology
- Biomedical Engineering
- Surgical Innovation
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with limited therapeutic options.
- Implantable microdevices (IMDs) offer localized drug delivery and in vivo tumor response monitoring.
- Previous IMD applications have not been reported for PDAC.
Purpose of the Study:
- To assess the feasibility of using IMDs for pancreatic ductal adenocarcinoma (PDAC).
- To evaluate localized chemotherapy delivery and in vivo response assessment in PDAC models.
- To explore IMDs as a platform for precision medicine in PDAC.
Main Methods:
- Generated PDAC xenograft tumors using patient-derived organoids (PDO) in mice.
- Loaded IMDs with gemcitabine, paclitaxel, SN38, oxaliplatin, and 5-fluorouracil for localized delivery.
- Assessed tumor response via immunofluorescence for DNA damage (γH2AX), apoptosis (CC3), and proliferation (Ki67).
Main Results:
- Successful IMD placement and retrieval in fourteen mice.
- Treatment-specific biologic responses (DNA damage, apoptosis) observed, most pronounced at 24 hours.
- Reduced proliferation within treated regions at 4 and 24 hours compared to controls.
Conclusions:
- Intra-pancreatic IMD deployment is feasible for assessing chemotherapy sensitivities in PDAC.
- IMDs enable localized drug delivery and in vivo assessment of treatment response.
- IMDs represent a promising platform for precision medicine in PDAC, supporting further investigation.
