Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle

Abstract

Therapeutic nanoparticles (TNPs) have shown heterogeneous responses in human clinical trials, raising the question of whether imaging should be used to identify patients with a higher likelihood of nanoparticle 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 exists to predict its clinical utility. Based on the hypothesis that an FDA-approved 30-nm magnetic nanoparticle (MNP) could predict co-localization of therapeutic nanoparticles by MRI, we performed single-cell resolution imaging of fluorescently labeled MNPs and TNPs and studied their intratumoral distribution. We visualized MNPs circulating in tumor microvasculature and found sustained uptake into cells of the tumor microenvironment within minutes. MNPs could predictably demonstrate areas of co-localization for a model TNP [poly(D,L-lactic-co-glycolic acid)-b-polyethylene glycol; PLGA-b-PEG] within the tumor microenvironment (> 85% accuracy) and circulating within the microvasculature (>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 imaging accurately predicted initial treatment response and drug accumulation in a therapeutic study testing for the efficacy of paclitaxel-encapsulated nanoparticle. These approaches yield valuable insight into the in vivo kinetics of NP distribution and suggest that clinically-relevant imaging can be used to select patients with high EPR for treatment with TNPs.

Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study

“…Broad colocalization of liposomes and FMX was observed in perivascular stromal areas, and correlation between the FMX-MRI signal and tumor drug uptake was seen particularly in tumors with high liposomal drug delivery (25). Comparable results were reported with PLGA-PEG-based polymeric therapeutic nanoparticles (27). We hypothesized that FMX-MRI could be used as a clinical imaging approach for predicting delivery to tumor lesions and subsequent antitumor activity of nanotherapeutics.…”

“…For example, experiments in murine syngeneic or xenogeneic models have demonstrated that myeloid cells, particularly TAMs, accumulate the largest share (78%-94% depending on tumor model at 24 hours) of nal-IRI (40). Miller and colleagues (27) noted similar patterns of colocalization and predominant accumulation of FMX and nanoparticles in host cells, driven by the comparable extended circulating half-life of both nanoparticles and the EPR effect. Both nanoparticles take advantage of overlapping microvascular accessibility, even if deposition kinetics for FMX are faster and the distribution of the two nanoparticles within the perivascular space of the tumor can be more divergent on the cellular level.…”

“…Variable coatings applied to these particles can modulate their pharmacokinetic behavior. Longer-circulating iron oxide nanoparticles exhibit delayed enhancement and uptake into reactive cells within lesions (23,24) and mirror pharmacokinetic and distribution characteristics seen for liposomes (25,26) and similarly sized nanotherapeutics (27).…”

Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

“…In addition, it has been increasingly recognized that the EPR effect varies substantially among both patients and tumor types and even within the same patient/tumor type over time (9), representing another important challenge for RNAi nanotherapeutics to identify patients most likely to benefit from them. The heterogeneous response of cancer nanomedicines in clinical trials has recently prompted the need to incorporate imaging modalities to identify cancer patients with stronger EPR effects and NP accumulation (10,11). By integrating diagnostic and therapeutic functions into a single NP formulation, theranostic nanomedicine offers a promising strategy to monitor the therapeutic pharmacokinetics and accumulation and the pathological process longitudinally, yielding important insights into tumor heterogeneities and EPR for patient selection and predictive nanomedicine (12).…”

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

“…Recently, it was shown that carboxymethyl dextran-coated magnetic particle (MNP) (size of 30 nm) can be used as companion diagnostics to stratify the tumors accumulation rate and predict the therapeutic response of the subsequent paclitaxel/ docetaxel loaded PEG-PLG nanoparticle (size of 100 nm) as a model nanomedicine treatment in xenograft tumor models. [221] Tumor accumulation and distribution of MNP was imaged by clinical MRI and high resolution intravital microscopy to categorize the different levels of tumor accumulation (high-moderatelow). While tumors with low accumulation of diagnostic MNPs after the treatment with nanomedicines shown less therapeutic response, faster tumor growth, whereas high-MNP accumulation had higher therapeutic response and did not show any increase in the tumor size.…”