In vitro assessment of nanomedicines' propensity to cause palmar-plantar erythrodysesthesia: A Doxil vs. doxorubicin case study

Palmar-plantar erythrodysesthesia (PPE), also known as hand and foot syndrome, is a condition characterized by inflammation-mediated damage to the skin on the palms and soles of the hands and feet. PPE limits the successful therapeutic applications of anticancer drugs. However, identifying this toxicity during preclinical studies is challenging due to the lack of accurate in vitro and in vivo animal-based models. Therefore, there is a need for reliable models that would allow the detection of this toxicity early during the drug development process. Herein, we describe the use of an in vitro skin explant assay to assess traditional DXR, Doxil reference listed drug (RLD) and two generic PEGylated liposomal DXR formulations for their abilities to cause inflammation and skin damage. We demonstrate that the results obtained with the in vitro skin explant assay model for traditional DXR and Doxil correlate with the clinical data. This manuscript presents a structure-activity relationship (SAR) study demonstrating the utility of an in vitro skin explant assay to detect inflammatory and drug-mediated skin damage consistent with palmar-plantar erythrodysesthesia (PPE), also known as a hand and foot syndrome, that significantly limits the quality of lives of patients undergoing chemotherapy with certain nanomedicines. [Display omitted]