(F-201) Local Drug Delivery of Doxorubicin Achieves Complete Response in a Preclinical Pediatric Brain Tumor Model

Introduction:: According to a report from the St. Jude Lifetime Cohort Study, 99.9% of patients treated for childhood cancer develop chronic health conditions from the chemotherapy used to treat their initial malignancy. Central Nervous System tumors are the leading cause of death in pediatric cancer patients, and survivors have the highest risk of developing late effects. Despite the widespread use and benefit of chemotherapy in clinical practice, challenges with the use of chemotherapy in treating pediatric brain tumors remain. Major factors limiting treatment success include appropriate dosages of conventional chemotherapies for treatment in pediatric neuro-oncology, risk of future malignancies from drug toxicity, and systemic and local drug barriers preventing complete drug penetration of traditional drug delivery routes of administration¹.



Our strategy is to develop a novel, biodegradable starch hydrogel, Amygel, as a vehicle for sustained drug release. Specifically, in mouse xenograft models bearing pediatric brain tumors, we will test the use of Amygel to locally deliver chemotherapy directly to the tumor microenvironment.


Materials and Methods:: The goal of this project is to effectively treat pediatric brain tumors while preventing the debilitating side effects of systemic chemotherapy. To test the hypothesis that localized, Amygel-mediated, intratumoral delivery of chemotherapy in vivo will provide more efficacious tumor killing as compared to other routes, our study focused on developing Amygel as a vehicle for sustained release of doxorubicin. Our Amygel/Doxorubicin formulations were optimized to be directly injected into medulloblastoma tumors to eliminate the tumor mass and minimize systemic exposure to the chemotherapy agent. Our data shows that utilizing the free base structure of doxorubicin, not the salt form, and formulating it in the Amygel system using dimethyl sulfoxide achieves greater than 10 mm of diffusion of the doxorubicin from the injection site. Subcutaneous xenografts of medulloblastoma were established in a nude mouse model using the DAOY cell line. Each mouse received one tumor in each thigh to serve as its own control, one tumor was treated with doxorubicin-loaded hydrogel and the other with an empty vehicle. Tumors were treated with a single intratumoral injection, and ultrasound was used to monitor tumor response in vivo. At the end of the study, the tumor site as well as major organs including the heart, liver, and kidneys were analyzed histologically.


Results, Conclusions, and Discussions:: Results and Discussion: Our Amygel/Doxorubicin strategy is designed to achieve improved tissue penetration of the chemotherapy agent by utilizing dimethyl sulfoxide in the formulation. Our data shows that utilizing the free base structure of doxorubicin, not the salt form, and formulating it in the Amygel system using dimethyl sulfoxide achieved complete elimination of the tumor without any histologic evidence of drug distribution beyond the tumor site. Histologic analysis shows no drug distribution outside the treatment site and no evidence of toxicity or even the presence of the drug in non-target tissues or organs.



Conclusions: Amygel delivery of chemotherapeutic agents directly to tumor sites has great advantages over traditional and emerging drug delivery technologies. Local delivery of compounds using Amygel increases drug concentration at the target site, decreases drug effects on non-target tissues, and improves drug penetration in the tumor tissue. For these reasons, local chemotherapy delivery using Amygel may prove to be a more effective way to treat pediatric solid tumor malignancies and improve long-term patient outcomes.


Acknowledgements (Optional): : I would like to recognize and thank Dr. Elizabeth D. Barker and Dr. Jenny Patel for their mentorship throughout the experiments and beyond.




References (Optional): : [1] Patel, J., A Local Drug Delivery Approach for Enhancing Tissue Penetration of Chemotherapy to Improve Treatment Outcomes of Pediatric Brain Tumors. 2022: The University of Tennessee, Knoxville