Anthracyclines are a widely used class of chemotherapy in pediatric and adult cancers, however, their use is hampered by the development of cardiotoxic side-effects and ensuing complications, primarily heart failure. Clinically used imaging modalities to screen for cardiotoxicity are mostly echocardiography and occasionally cardiac magnetic resonance imaging. However, the assessment of diastolic and global or segmental systolic function may not be sensitive to detect subclinical or early stages of cardiotoxicity. Multiple studies have scrutinized molecular nuclear imaging strategies to improve the detection of anthracycline-induced cardiotoxicity. Anthracyclines can activate all forms of cell death in cardiomyocytes. Injury mechanisms associated with anthracycline usage include apoptosis, necrosis, autophagy, ferroptosis, pyroptosis, reactive oxygen species, mitochondrial dysfunction, as well as cardiac fibrosis and perturbation in sympathetic drive and myocardial blood flow; some of which have been targeted using nuclear probes. This review retraces the pathobiology of anthracycline-induced cardiac injury, details the evidence to date supporting a molecular nuclear imaging strategy, explores disease mechanisms which have not yet been targeted, and proposes a clinical strategy incorporating molecular imaging to improve patient management.
Objective Cisplatin is a platinum-based chemotherapeutic drug that secondarily induces toxicity in inner ear sensory epithelia, contributing to auditory and vestibular dysfunction. We describe the creation of a drug reservoir device (DRD) to combat this ototoxicity for the duration of chemotherapy. As ototoxic side effects of chemotherapy may limit an oncologist’s ability to prescribe first-line agents such as cisplatin, mitigating such devastating effects through prolonged topical therapy would be tremendously valuable. Study Design We investigated (1) the ability of an electrospun polylactic acid DRD to provide prolonged delivery of the posited otoprotectant metformin and (2) the development of an in vitro model utilizing Sh-Sy5y human neuroblastoma cells to assess the efficacy of metformin in reducing cisplatin-induced toxicity. Setting Neurophysiology laboratory. Methods Basic science experiments were performed to assess DRD properties and metformin’s effects on cisplatin toxicity in culture. Results We found that DRDs with increasing polylactic acid concentrations exhibited metformin release for up to 8 weeks. In modeling elution across the round window in vitro, continued elution of metformin was observed for at least 6 weeks, as quantified by spectrophotometry. Unfortunately, metformin did not exhibit protective efficacy in this model using Sh-Sy5y cells. Conclusion While metformin was not found to be protective in Sh-Sy5y cells, these results suggest that an electrospun DRD can provide a tailorable drug delivery system providing medication for the duration of chemotherapy treatment. This represents a novel drug delivery system and efficacy screening assay with broad clinical applications in personalized delivery of inner ear therapies.
Anthracyclines such as doxorubicin (Dox) are effective chemotherapeutic agents; however, their use is hampered by subsequent cardiotoxicity risk. Our understanding of cardiomyocyte protective pathways activated following anthracyclineinduced cardiotoxicity (AIC) remains incomplete. Insulin-like growth factor binding protein (IGFBP) 3 (Igfbp-3), the most abundant IGFBP family member in the circulation, is associated with effects on the metabolism, proliferation, and survival of various cells. Whereas Igfbp-3 is induced by Dox in the heart, its role in AIC is ill-defined. We investigated molecular mechanisms as well as systemslevel transcriptomic consequences of manipulating Igfbp-3 in AIC using neonatal rat ventricular myocytes and human-induced pluripotent stem cell-derived cardiomyocytes. Our findings reveal that Dox induces the nuclear enrichment of
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