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

Journal Article · · ACS Central Science
 [1];  [1];  [2];  [2];  [2];  [3];  [2];  [2];  [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
+ Show Author Affiliations
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

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Cited By (3)

Delivery of Immunotherapeutic Nanoparticles to Tumors via Enzyme‐Directed Assembly journal October 2019
Ring-opening metathesis polymerization-induced self-assembly (ROMPISA) of a cisplatin analogue for high drug-loaded nanoparticles journal January 2019
SIMS imaging in neurobiology and cell biology journal January 2019

Figures / Tables (5)

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Related Subjects

60 APPLIED LIFE SCIENCES
MMP
NanoSIMS
SIM
bioresponsive nanomaterials
drug loaded nanoparticles
multimodal imaging
platinum(II) complexes