skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: 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]; 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
+ 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)
Grant/Contract Number:
AC05-76RL01830
OSTI ID:
1508250
Report Number(s):
PNNL-SA-138579
Journal Information:
ACS Central Science, Vol. 4, Issue 11; ISSN 2374-7943
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 30 works
Citation information provided by
Web of Science

References (36)

Enzyme-Directed Assembly of a Nanoparticle Probe in Tumor Tissue journal May 2013
Enzyme-Responsive Nanoparticles for Targeted Accumulation and Prolonged Retention in Heart Tissue after Myocardial Infarction journal August 2015
Enzyme-targeted nanoparticles for delivery to ischemic skeletal muscle journal January 2017
Therapeutic Enzyme-Responsive Nanoparticles for Targeted Delivery and Accumulation in Tumors journal July 2015
MMP-9 triggered self-assembly of doxorubicin nanofiber depots halts tumor growth journal August 2016
Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG-drug conjugate and cell-penetrating moiety journal September 2013
Methodologies and approaches for the analysis of cell-nanoparticle interactions: Analysis of cell-nanoparticle interactions
  • Ivask, Angela; Mitchell, Andrew J.; Malysheva, Anzhela
  • Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, Vol. 10, Issue 3 https://doi.org/10.1002/wnan.1486
journal July 2017
Advance of Molecular Imaging Technology and Targeted Imaging Agent in Imaging and Therapy journal January 2014
A Molecular Imaging Primer: Modalities, Imaging Agents, and Applications journal April 2012
Overview about the localization of nanoparticles in tissue and cellular context by different imaging techniques journal January 2015
Controlling and Monitoring Intracellular Delivery of Anticancer Polymer Nanomedicines journal April 2017
Functionalized nanomaterials: their use as contrast agents in bioimaging: mono- and multimodal approaches journal April 2013
Correlated optical and isotopic nanoscopy journal April 2014
Cellular Delivery of Nanoparticles Revealed with Combined Optical and Isotopic Nanoscopy journal March 2016
NanoSIMS for biological applications: Current practices and analyses journal June 2018
NanoSIMS combined with fluorescence microscopy as a tool for subcellular imaging of isotopically labeled platinum-based anticancer drugs journal January 2014
Matrix Metalloproteinases: Regulators of the Tumor Microenvironment journal April 2010
Activatable cell penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and MR imaging of proteases journal February 2010
Optical Imaging of Matrix Metalloproteinase–2 Activity in Tumors: Feasibility Study in a Mouse Model journal November 2001
Enzyme-Directed Assembly of Nanoparticles in Tumors Monitored by in Vivo Whole Animal Imaging and ex Vivo Super-Resolution Fluorescence Imaging journal December 2013
Tuning the Amphiphilicity of Building Blocks: Controlled Self-Assembly and Disassembly for Functional Supramolecular Materials journal July 2009
Fluorogenic enzyme-responsive micellar nanoparticles journal January 2012
Dual-responsive nanoparticles release cargo upon exposure to matrix metalloproteinase and reactive oxygen species journal January 2016
Efficient Synthesis of Narrowly Dispersed Brush Copolymers and Study of Their Assemblies: The Importance of Side Chain Arrangement journal December 2009
Dynamics of Soft Nanomaterials Captured by Transmission Electron Microscopy in Liquid Water journal January 2014
Phenylboronic Acid-Installed Polymeric Micelles for Targeting Sialylated Epitopes in Solid Tumors journal October 2013
Cyclic RGD-Linked Polymeric Micelles for Targeted Delivery of Platinum Anticancer Drugs to Glioblastoma through the Blood–Brain Tumor Barrier journal September 2013
Oxaliplatin immuno hybrid nanoparticles for active targeting: an approach for enhanced apoptotic activity and drug delivery to colorectal tumors journal August 2014
Inhibitory Effect of Selenite on Invasion of HT1080 Tumor Cells journal January 2001
Subdiffractive microscopy: techniques, applications, and challenges: Subdiffractive microscopy
  • Long, Brian R.; Robinson, Danielle C.; Zhong, Haining
  • Wiley Interdisciplinary Reviews: Systems Biology and Medicine, Vol. 6, Issue 2 https://doi.org/10.1002/wsbm.1259
journal January 2014
Structure brings clarity: Structured illumination microscopy in cell biology journal June 2009
The mechanism of action of platinum anticancer agents—what do we really know about it? journal January 2009
The status of platinum anticancer drugs in the clinic and in clinical trials journal January 2010
NanoSIMS multi-element imaging reveals internalisation and nucleolar targeting for a highly-charged polynuclear platinum compound journal January 2013
Immunohistochemical Investigation of Predictive Biomarkers for Mandibular Bone Invasion in Oral Squamous Cell Carcinoma journal June 2020
Application of imaging mass spectrometry approaches to facilitate metal-based anticancer drug research journal January 2017

Cited By (3)

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

Figures / Tables (5)

Figure 1(p. 2)figure Figure 1
Figure 2(p. 3)figure Figure 2
Figure 3(p. 4)figure Figure 3
Figure 4(p. 4)figure Figure 4
Figure 5(p. 5)figure Figure 5

Similar Records

Enzyme-Directed Assembly of Nanoparticles in Tumors Monitored by In Vivo Whole Animal and Ex Vivo Super-Resolution Fluorescence Imaging
Journal Article · Wed Dec 18 00:00:00 EST 2013 · Journal of the American Chemical Society, 135(50):18710-18713 · OSTI ID:1508250
+5 more
Poly(N-vinylpyrrolidone)-block-Poly(dimethylsiloxane)-block-Poly(N-vinylpyrrolidone) Triblock Copolymer Polymersomes for Delivery of PARP1 siRNA to Breast Cancers
Journal Article · Wed Mar 16 00:00:00 EDT 2022 · ACS Applied Bio Materials · OSTI ID:1508250
+8 more
Ligand-targeted theranostic nanomedicines against cancer
Journal Article · Sat Oct 01 00:00:00 EDT 2016 · Journal of Controlled Release · OSTI ID:1508250
+10 more

Related Subjects

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