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

Abstract

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 substratemore » 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.« less

Authors:
 [1];  [1];  [2];  [2]; ORCiD logo [2];  [3];  [2]; ORCiD logo [2]; ORCiD logo [1]
  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
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1508250
Report Number(s):
PNNL-SA-138579
Journal ID: ISSN 2374-7943
Grant/Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
ACS Central Science
Additional Journal Information:
Journal Volume: 4; Journal Issue: 11; Journal ID: ISSN 2374-7943
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; NanoSIMS; SIM; drug loaded nanoparticles; multimodal imaging; platinum(II) complexes; MMP; bioresponsive nanomaterials

Citation Formats

Proetto, Maria T., Callmann, Cassandra E., Cliff, John, Szymanski, Craig J., Hu, Dehong, Howell, Stephen B., Evans, James E., Orr, Galya, and Gianneschi, Nathan C. Tumor Retention of Enzyme-Responsive Pt(II) Drug-Loaded Nanoparticles Imaged by Nanoscale Secondary Ion Mass Spectrometry and Fluorescence Microscopy. United States: N. p., 2018. Web. doi:10.1021/acscentsci.8b00444.
Proetto, Maria T., Callmann, Cassandra E., Cliff, John, Szymanski, Craig J., Hu, Dehong, Howell, Stephen B., Evans, James E., Orr, Galya, & Gianneschi, Nathan C. Tumor Retention of Enzyme-Responsive Pt(II) Drug-Loaded Nanoparticles Imaged by Nanoscale Secondary Ion Mass Spectrometry and Fluorescence Microscopy. United States. doi:10.1021/acscentsci.8b00444.
Proetto, Maria T., Callmann, Cassandra E., Cliff, John, Szymanski, Craig J., Hu, Dehong, Howell, Stephen B., Evans, James E., Orr, Galya, and Gianneschi, Nathan C. Tue . "Tumor Retention of Enzyme-Responsive Pt(II) Drug-Loaded Nanoparticles Imaged by Nanoscale Secondary Ion Mass Spectrometry and Fluorescence Microscopy". United States. doi:10.1021/acscentsci.8b00444. https://www.osti.gov/servlets/purl/1508250.
@article{osti_1508250,
title = {Tumor Retention of Enzyme-Responsive Pt(II) Drug-Loaded Nanoparticles Imaged by Nanoscale Secondary Ion Mass Spectrometry and Fluorescence Microscopy},
author = {Proetto, Maria T. and Callmann, Cassandra E. and Cliff, John and Szymanski, Craig J. and Hu, Dehong and Howell, Stephen B. and Evans, James E. and Orr, Galya and Gianneschi, Nathan C.},
abstractNote = {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.},
doi = {10.1021/acscentsci.8b00444},
journal = {ACS Central Science},
issn = {2374-7943},
number = 11,
volume = 4,
place = {United States},
year = {2018},
month = {10}
}

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Figures / Tables:

Figure 1 Figure 1: Polymer structure, assembly, and characterization of labeled micellar nanoparticles. Left: Pep-Pt-P chemical structure. Dialysis of the 15N, Pt, and Cy5.5 multilabeled polymer (Pep-Pt-P) from DMSO to water yields well-defined micellar nanoparticles of approximately 20 nm in diameter. L-Amino acid peptide sequence “GPLGLAGGERDG” for L-Pep-Pt-NP and D-amino acid sequencemore » “gplglaggerdg” for D-Pep-Pt-NP. As previously shown, cleavage of the L-amino acid peptide sequence “GPLGLAGGERDG” occurs between the italicized G and L, promoting the release of the hydrophilic peptide sequence “LAGGERDG” which triggers the nano- to micrometer morphology change.1 Right: TEM image (dry state, negative uranyl acetate stain) of L-Pep-Pt-NP before (left) and after (right) exposure to MMP, demonstrating enzyme-induced morphology change. For TEM images of D-Pep-Pt-NP before and after MMP exposure, see Figure S3.« less

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