Label-free protein-structure-sensitive live-cell microscopy for patient-specific assessment of myeloma therapy

The efficacy of drug therapy in multiple myeloma is conventionally assessed by whole-cell-population methods, serum analysis of light chains and monoclonal antibodies, immunofixation electrophoresis, or by flow cytometry of bone marrow aspirates and biopsies. These methods provide relevant information on the presence of specific immunoglobulins at high sensitivity and specificity but require a large number of cells, involve long and laborious sample preparation steps, and provide only tumour bulk information. Here we develop a single-cell imaging technique requiring a reduced number of primary cells for longitudinal evaluation of patient-specific treatment and assessment of treatment heterogeneity. By exploiting the mechanistic action of proteasome inhibition and in synergy with the label-free protein-structure specificity of mid-infrared optoacoustic microscopy, we present a technology that facilitates longitudinal evaluation of myeloma treatment and a patient’s heterogeneous response. Detecting optical-generated ultrasound waves that intensify with optical absorption, this technology allows observation of proteins in living cells with high sensitivity. Specifically, we use intermolecular β-sheet formation as a biomarker for cell viability during therapy and apply it to assess drug-treatment performance in multiple myeloma patients.