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.

A Supramolecular Nanocarrier for Delivery of Amiodarone Anti-Arrhythmic Therapy to the Heart

“…Nanoparticle distribution was quantified from fluorescence reflectance imaging (Figure 5B) and indicated an accumulation of nanoparticles in macrophage-rich tissue (i.e., liver, spleen, and heart) relative to other tissue (muscle and lung). The accumulation within macrophage-rich tissues is an observation in alignment with prior results for similarly composed nanomaterials, 17,20,37 and are supported by the general consensus that macrophage uptake heavily influences nanoparticle biodistribution.…”

A Supramolecular Nanocarrier for Delivery of Amiodarone Anti-Arrhythmic Therapy to the Heart

“…Nanoparticle distribution was quantified from fluorescence reflectance imaging (Figure 5B) and indicated an accumulation of nanoparticles in macrophage-rich tissue (i.e., liver, spleen, and heart) relative to other tissue (muscle and lung). The accumulation within macrophage-rich tissues is an observation in alignment with prior results for similarly composed nanomaterials, 17,20,37 and are supported by the general consensus that macrophage uptake heavily influences nanoparticle biodistribution.…”

Supermagnetic Human Serum Albumin (HSA) Nanoparticles and PLGA-Based Doxorubicin Nanoformulation: A Duet for Selective Nanotherapy

“…Although direct comparison of the results is not possible due to the different experimental designs of these studies, it appears that at least in this tumor model the dynamic EPR effect is not so selective in relation to the above NP parameters. Together with the previous findings of Miller et al [17] who observed colocalization of the NP on the macroscopic but not single-cell level, the obtained results strongly suggest that the most important parameter for a successful theranostic pair is the ability of both nanoparticle agents to accumulate in the same ROIs of the peritumoral area or highly vascularized tumor regions rather than the direct overlap of the nanoparticle fluorescent signals within the single cell.…”

“…At the same time, as shown by IVM, both NP have a considerable and simultaneous access to the 4T1 tumor and their accumulation areas appeared to almost overlap. Interestingly, considerable co-accumulation in the same tumor model was observed by Miller et al [17] for the less similar diagnostic IONP coated with carbohydrate (ferumoxytol) and therapeutic PEG-PLGA NP (ferumoxytol NP: size 19 nm, zeta potential −17 mV, T 1/2 70 min; PEG-PLGA NP: size 90 nm, zeta potential −33 mV, T 1/2 55 min). Although direct comparison of the results is not possible due to the different experimental designs of these studies, it appears that at least in this tumor model the dynamic EPR effect is not so selective in relation to the above NP parameters.…”

Quantitative Imaging of Tumor-Associated Macrophages and Their Response to Therapy Using 64Cu-Labeled Macrin

“…Briefly, nanoprecipitation was used, first combining 5 mg PLGA­(75:25 lactide:glycolide) 8.3 kDa -PEG 5.5 kDa (Advanced Polymer Materials, Inc.; 70% functionality by 1 H NMR, PI 1.38 according to GPC according to manufacturer) and 1 mg BODIPY-TMR labeled PLGA­(50:50 lactide:glycolide) 30–60 kDa (Sigma) in a 200 μL mixture of 1:1 dimethylformamide (DMF):acetonitrile (MeCN), then added dropwise to 10 mL H 2 O under room temperature stirring for at least 6 h, then filtered through a cellulose acetate 0.45 μm filter (Cole-Parmer), and concentrated using Amicon 100 kDa molecular-weight-cutoff centrifugal filters (Millipore). PLGA-BODIPY-TMR was synthesized and characterized as previously described . Size and ζ potential measurements were performed using DLS (Malvern Zetasizer) and determined to be ∼75 nm (PDI = 0.137) and −16.5 mV, consistent with previous results using similar nanoformulation routes.…”

A Supramolecular Nanocarrier for Delivery of Amiodarone Anti-Arrhythmic Therapy to the Heart

“…Nanoparticle distribution was quantified from fluorescence reflectance imaging (Figure 5B) and indicated an accumulation of nanoparticles in macrophage-rich tissue (i.e., liver, spleen, and heart) relative to other tissue (muscle and lung). The accumulation within macrophage-rich tissues is an observation in alignment with prior results for similarly composed nanomaterials, 17,20,37 and are supported by the general consensus that macrophage uptake heavily influences nanoparticle biodistribution.…”

Supermagnetic Human Serum Albumin (HSA) Nanoparticles and PLGA-Based Doxorubicin Nanoformulation: A Duet for Selective Nanotherapy

“…Although direct comparison of the results is not possible due to the different experimental designs of these studies, it appears that at least in this tumor model the dynamic EPR effect is not so selective in relation to the above NP parameters. Together with the previous findings of Miller et al [17] who observed colocalization of the NP on the macroscopic but not single-cell level, the obtained results strongly suggest that the most important parameter for a successful theranostic pair is the ability of both nanoparticle agents to accumulate in the same ROIs of the peritumoral area or highly vascularized tumor regions rather than the direct overlap of the nanoparticle fluorescent signals within the single cell.…”

“…At the same time, as shown by IVM, both NP have a considerable and simultaneous access to the 4T1 tumor and their accumulation areas appeared to almost overlap. Interestingly, considerable co-accumulation in the same tumor model was observed by Miller et al [17] for the less similar diagnostic IONP coated with carbohydrate (ferumoxytol) and therapeutic PEG-PLGA NP (ferumoxytol NP: size 19 nm, zeta potential −17 mV, T 1/2 70 min; PEG-PLGA NP: size 90 nm, zeta potential −33 mV, T 1/2 55 min). Although direct comparison of the results is not possible due to the different experimental designs of these studies, it appears that at least in this tumor model the dynamic EPR effect is not so selective in relation to the above NP parameters.…”

Quantitative Imaging of Tumor-Associated Macrophages and Their Response to Therapy Using 64Cu-Labeled Macrin

“…Briefly, nanoprecipitation was used, first combining 5 mg PLGA­(75:25 lactide:glycolide) 8.3 kDa -PEG 5.5 kDa (Advanced Polymer Materials, Inc.; 70% functionality by 1 H NMR, PI 1.38 according to GPC according to manufacturer) and 1 mg BODIPY-TMR labeled PLGA­(50:50 lactide:glycolide) 30–60 kDa (Sigma) in a 200 μL mixture of 1:1 dimethylformamide (DMF):acetonitrile (MeCN), then added dropwise to 10 mL H 2 O under room temperature stirring for at least 6 h, then filtered through a cellulose acetate 0.45 μm filter (Cole-Parmer), and concentrated using Amicon 100 kDa molecular-weight-cutoff centrifugal filters (Millipore). PLGA-BODIPY-TMR was synthesized and characterized as previously described . Size and ζ potential measurements were performed using DLS (Malvern Zetasizer) and determined to be ∼75 nm (PDI = 0.137) and −16.5 mV, consistent with previous results using similar nanoformulation routes.…”

A Supramolecular Nanocarrier for Delivery of Amiodarone Anti-Arrhythmic Therapy to the Heart

“…Nanoparticle distribution was quantified from fluorescence reflectance imaging (Figure 5B) and indicated an accumulation of nanoparticles in macrophage-rich tissue (i.e., liver, spleen, and heart) relative to other tissue (muscle and lung). The accumulation within macrophage-rich tissues is an observation in alignment with prior results for similarly composed nanomaterials, 17,20,37 and are supported by the general consensus that macrophage uptake heavily influences nanoparticle biodistribution.…”

Supermagnetic Human Serum Albumin (HSA) Nanoparticles and PLGA-Based Doxorubicin Nanoformulation: A Duet for Selective Nanotherapy

“…Although direct comparison of the results is not possible due to the different experimental designs of these studies, it appears that at least in this tumor model the dynamic EPR effect is not so selective in relation to the above NP parameters. Together with the previous findings of Miller et al [17] who observed colocalization of the NP on the macroscopic but not single-cell level, the obtained results strongly suggest that the most important parameter for a successful theranostic pair is the ability of both nanoparticle agents to accumulate in the same ROIs of the peritumoral area or highly vascularized tumor regions rather than the direct overlap of the nanoparticle fluorescent signals within the single cell.…”

“…At the same time, as shown by IVM, both NP have a considerable and simultaneous access to the 4T1 tumor and their accumulation areas appeared to almost overlap. Interestingly, considerable co-accumulation in the same tumor model was observed by Miller et al [17] for the less similar diagnostic IONP coated with carbohydrate (ferumoxytol) and therapeutic PEG-PLGA NP (ferumoxytol NP: size 19 nm, zeta potential −17 mV, T 1/2 70 min; PEG-PLGA NP: size 90 nm, zeta potential −33 mV, T 1/2 55 min). Although direct comparison of the results is not possible due to the different experimental designs of these studies, it appears that at least in this tumor model the dynamic EPR effect is not so selective in relation to the above NP parameters.…”

Quantitative Imaging of Tumor-Associated Macrophages and Their Response to Therapy Using 64Cu-Labeled Macrin

“…Briefly, nanoprecipitation was used, first combining 5 mg PLGA­(75:25 lactide:glycolide) 8.3 kDa -PEG 5.5 kDa (Advanced Polymer Materials, Inc.; 70% functionality by 1 H NMR, PI 1.38 according to GPC according to manufacturer) and 1 mg BODIPY-TMR labeled PLGA­(50:50 lactide:glycolide) 30–60 kDa (Sigma) in a 200 μL mixture of 1:1 dimethylformamide (DMF):acetonitrile (MeCN), then added dropwise to 10 mL H 2 O under room temperature stirring for at least 6 h, then filtered through a cellulose acetate 0.45 μm filter (Cole-Parmer), and concentrated using Amicon 100 kDa molecular-weight-cutoff centrifugal filters (Millipore). PLGA-BODIPY-TMR was synthesized and characterized as previously described . Size and ζ potential measurements were performed using DLS (Malvern Zetasizer) and determined to be ∼75 nm (PDI = 0.137) and −16.5 mV, consistent with previous results using similar nanoformulation routes.…”