Tumor Retention of Enzyme-Responsive Pt(II) Drug-Loaded Nanoparticles Imaged by Nanoscale Secondary Ion Mass Spectrometry and Fluorescence Microscopy

Journal Article · 22 October 2018 · ACS Central Science

DOI: https://doi.org/10.1021/acscentsci.8b00444 · OSTI ID:1508250

Proetto, Maria T. ^[1]; Callmann, Cassandra E. ^[1]; Cliff, John ^[2]; Szymanski, Craig J. ^[2]; Hu, Dehong  ^[2]; Howell, Stephen B. ^[3]; Evans, James E. ^[2]; Orr, Galya  ^[2]; Gianneschi, Nathan C.  ^[1]

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1. Univ. of California, San Diego, CA (United States). Dept. of Chemistry & Biochemistry; Northwestern Univ., Evanston, IL (United States)
2. Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
3. Univ. of California, La Jolla, CA (United States). Moores Cancer Center

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 analog 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 co-localization with cellular DNA within tumor tissue. The results confirmed the dependence of particle accumulation and Pt(II) drug delivery on the presence of an 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.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
• Sponsoring Organization: USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
• Grant/Contract Number: AC05-76RL01830
• OSTI ID: 1508250
• Report Number(s): PNNL-SA-138579
• Journal Information: ACS Central Science, Journal Name: ACS Central Science Journal Issue: 11 Vol. 4; ISSN 2374-7943
• Publisher: American Chemical Society (ACS)Copyright Statement
• Country of Publication: United States
• Language: English