en
Scientific article
English

Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle

Published inScience Translational Medicine, vol. 7, no. 314, 314ra183
Publication date2015
Abstract

Therapeutic nanoparticles (TNPs) have shown heterogeneous responses in human clinical trials, raising questions of whether imaging should be used to identify patients with a higher likelihood of NP accumulation and thus therapeutic response. Despite extensive debate about the enhanced permeability and retention (EPR) effect in tumors, it is increasingly clear that EPR is extremely variable; yet, little experimental data exist to predict the clinical utility of EPR and its influence on TNP efficacy. We hypothesized that a 30-nm magnetic NP (MNP) in clinical use could predict colocalization of TNPs by magnetic resonance imaging (MRI). To this end, we performed single-cell resolution imaging of fluorescently labeled MNPs and TNPs and studied their intratumoral distribution in mice. MNPs circulated in the tumor microvasculature and demonstrated sustained uptake into cells of the tumor microenvironment within minutes. MNPs could predictably demonstrate areas of colocalization for a model TNP, poly(d,l-lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG), within the tumor microenvironment with >85% accuracy and circulating within the microvasculature with >95% accuracy, despite their markedly different sizes and compositions. Computational analysis of NP transport enabled predictive modeling of TNP distribution based on imaging data and identified key parameters governing intratumoral NP accumulation and macrophage uptake. Finally, MRI accurately predicted initial treatment response and drug accumulation in a preclinical efficacy study using a paclitaxel-encapsulated NP in tumor-bearing mice. These approaches yield valuable insight into the in vivo kinetics of NP distribution and suggest that clinically relevant imaging modalities and agents can be used to select patients with high EPR for treatment with TNPs.

Keywords
  • Animals
  • Antineoplastic Agents
  • Phytogenic/administration & dosage/chemistry/metabolism
  • Cell Line
  • Tumor
  • Chemistry
  • Pharmaceutical
  • DNA Damage
  • Disease Progression
  • Female
  • Ferrosoferric Oxide/chemistry/metabolism
  • Fibrosarcoma/drug therapy/genetics/metabolism/pathology
  • Humans
  • Macrophages/metabolism
  • Magnetic Resonance Imaging/methods
  • Magnetics/methods
  • Mice
  • Inbred BALB C
  • Mice
  • Inbred C57BL
  • Mice
  • Nude
  • Mice
  • Transgenic
  • Nanomedicine/methods
  • Nanoparticles
  • Ovarian Neoplasms/drug therapy/genetics/metabolism/pathology
  • Paclitaxel/administration & dosage/chemistry/metabolism
  • Particle Size
  • Polyethylene Glycols/chemistry/metabolism
  • Polyglactin 910/chemistry/metabolism
  • Predictive Value of Tests
  • Time Factors
  • Tissue Distribution
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays
Affiliation Not a UNIGE publication
Citation (ISO format)
MILLER, Miles A et al. Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle. In: Science Translational Medicine, 2015, vol. 7, n° 314, p. 314ra183. doi: 10.1126/scitranslmed.aac6522
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Article (Published version)
accessLevelRestricted
Identifiers
ISSN of the journal1946-6234
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