In nanomedicine, determining the spatial distribution of particles and drugs, together and apart, at high resolution within tissues, remains a major challenge because each must have a different label or detectable feature that can be observed with high sensitivity and resolution. We prepared nanoparticles capable of
enzyme-directed assembly of particle
therapeutics (EDAPT), containing an analogue of the Pt(II)-containing drug
oxaliplatin, an 15N-labeled monomer in the hydrophobic block of the backbone of the
polymer, the near-infrared
dye Cy5.5, and a
peptide that is a substrate for
tumor metalloproteinases in the hydrophilic block. When these particles reach an environment rich in
tumor associated
proteases, the hydrophilic
peptide substrate is cleaved, causing the particles to accumulate through a morphology transition, locking them in the
tumor extracellular matrix. To evaluate the distribution of drug and EDAPT carrier in vivo, the localization of the isotopically labeled
polymer backbone was compared to that of Pt by nanoscale secondary ion mass spectrometry (NanoSIMS). The correlation of NanoSIMS with super-resolution fluorescence microscopy revealed the release of the drug from the nanocarrier and colocalization with cellular
DNA within
tumor tissue. The results confirmed the dependence of particle accumulation and Pt(II) drug delivery on the presence of a
Matrix Metalloproteinase (
MMP) substrate and demonstrated antitumor activity. We conclude that these techniques are powerful for the elucidation of the localization of cargo and carrier, and enable a high-resolution assessment of their performance following in vivo delivery.