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The introduction of degradable oligopeptide sequences into the backbone of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates resulted in prolonged circulation time and increased tumor to tissue ratio [1].In order to independently evaluate the fate of the polymer backbone and the drug (epirubicin) we prepared conjugates double-labeled with a FRET pair—the polymer backbone was labeled with Cy5 (via an enzymatically non-cleavable bond),whereas the oliogopeptide side-chains were terminated either in Cy3 (drug model) or epirubicin (EPR).Upon enzymatic cleavage of EPR or Cy3 the FRET signal receded.The emission spectra of the conjugates before and after incubation with enzyme solution were measured with an LS 55 Luminescence Spectrometer (Perkin Elmer) (Fig.1 insert).The internalization of the conjugate and drug release at the single A2780 cell level were visualized using a 3D super-resolution Vutara SR-200 fluorescence microscope.