Clinical cancer research : an official journal of the American Association for Cancer Research · 2020
VLA4-Targeted Nanoparticles Hijack Cell Adhesion-Mediated Drug Resistance to Target Refractory Myeloma Cells and Prolong Survival.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Fontana Francesca, Scott Michael J, Allen John S, Yang Xiaoxia, Cui Grace, Pan Dipanjan, Yanaba Noriko, Fiala Mark A, O'Neal Julie, Schmieder-Atteberry Anne H, Ritchey Julie, Rettig Michael, Simons Kathleen, Fletcher Steven, Vij Ravi, DiPersio John F, Lanza Gregory M
Аннотация
PURPOSE: In multiple myeloma, drug-resistant cells underlie relapse or progression following chemotherapy. Cell adhesion-mediated drug resistance (CAM-DR) is an established mechanism used by myeloma cells (MMC) to survive chemotherapy and its markers are upregulated in residual disease. The integrin very late antigen 4 (VLA4; α4β1) is a key mediator of CAM-DR and its expression affects drug sensitivity of MMCs. Rather than trying to inhibit its function, here, we hypothesized that upregulation of VLA4 by resistant MMCs could be exploited for targeted delivery of drugs, which would improve safety and efficacy of treatments.
EXPERIMENTAL DESIGN: We synthetized 20 nm VLA4-targeted micellar nanoparticles (V-NP) carrying DiI for tracing or a novel camptothecin prodrug (V-CP). Human or murine MMCs, alone or with stroma, and immunocompetent mice with orthotopic multiple myeloma were used to track delivery of NPs and response to treatments.
RESULTS: V-NPs selectively delivered their payload to MMCs in vitro and in vivo, and chemotherapy increased their uptake by surviving MMCs. V-CP, alone or in combination with melphalan, was well tolerated and prolonged survival in myeloma-bearing mice. V-CP also reduced the dose requirement for melphalan, reducing tumor burden in association with suboptimal dosing without increasing overall toxicity.
CONCLUSIONS: V-CP may be a safe and effective strategy to prevent or treat relapsing or refractory myeloma. V-NP targeting of resistant cells may suggest a new approach to environment-induced resistance in cancer.
EXPERIMENTAL DESIGN: We synthetized 20 nm VLA4-targeted micellar nanoparticles (V-NP) carrying DiI for tracing or a novel camptothecin prodrug (V-CP). Human or murine MMCs, alone or with stroma, and immunocompetent mice with orthotopic multiple myeloma were used to track delivery of NPs and response to treatments.
RESULTS: V-NPs selectively delivered their payload to MMCs in vitro and in vivo, and chemotherapy increased their uptake by surviving MMCs. V-CP, alone or in combination with melphalan, was well tolerated and prolonged survival in myeloma-bearing mice. V-CP also reduced the dose requirement for melphalan, reducing tumor burden in association with suboptimal dosing without increasing overall toxicity.
CONCLUSIONS: V-CP may be a safe and effective strategy to prevent or treat relapsing or refractory myeloma. V-NP targeting of resistant cells may suggest a new approach to environment-induced resistance in cancer.