Sustained-Release 9-cis Retinoic Acid Pellets for the Prevention of Postsurgical Lymphedema
Giulia Daneshgaran, BS, Connie B. Paik, BS, Michael N. Cooper, BA, Wan Jiao, MD, PhD, Young-Kwon Hong, PhD, Alex K. Wong, MD.
University of Southern California, Los Angeles, CA, USA.
PURPOSE: Lymphedema is a disfiguring disease affecting over 200 million people worldwide, and over 5 million cancer survivors in the US. Nine-cis retinoic acid (9-cis RA) has recently been shown to stimulate lymphangiogenesis in vivo and limit postsurgical lymphedema. Nine-cis RA demonstrates a favorable risk profile in cancer patients, unlike other pro-lymphangiogenic drugs being studied, and has already been approved for clinical use outside the US. Previous animal studies have tested the drug in intraperitoneal injection form, which has poor translatability to future clinical trials. As such, the purpose of this research study is to investigate the pro-lymphangiogenic effects of 9-cis RA contained within a single-use depot pellet drug delivery system in a clinically relevant mouse lymphedema model.
METHODS: Hindlimb lymphedema was induced in 18 mice via combined lymphatic injury, consisting of inguinal and popliteal lymphadenectomy followed by radiation therapy. The animals were split into 2 groups: 1) 9 animals in the treatment group received pellets containing 9-cis RA, 2) 9 animals in the control group received placebo pellets. Pellets were placed within the surgical wound intraoperatively, with experimental pellets resulting in sustained release of 9-cis RA. Bilateral paw thickness was measured weekly for 5 weeks. Values were normalized by calculating percent change in paw thickness relative to the unaffected extremity.
RESULTS: Compared to the control group, significantly less paw swelling was observed in the treatment group at day 21 (7% change, P=0.009), day 28 (9% change, P=0.03), and day 35 (8% change, P=0.001). Within the treatment group, there was no statistically significant difference in paw thickness over time, indicating reduced lymphedema progression in the distal hindlimb.
CONCLUSION: Animals treated with 9-cis RA pellets at the time of surgery demonstrate significantly less paw swelling the first 5 weeks after lymphatic injury compared to control animals. In conclusion, we demonstrate that single-use 9-cis RA pellets have favorable properties in limiting postsurgical lymphedema.
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