Nanoreporter PET predicts the efficacy of anti-cancer nanotherapy - PubMed (original) (raw)

Nanoreporter PET predicts the efficacy of anti-cancer nanotherapy

Carlos Pérez-Medina et al. Nat Commun. 2016.

Abstract

The application of nanoparticle drug formulations, such as nanoliposomal doxorubicin (Doxil), is increasingly integrated in clinical cancer care. Despite nanomedicine's remarkable potential and growth over the last three decades, its clinical benefits for cancer patients vary. Here we report a non-invasive quantitative positron emission tomography (PET) nanoreporter technology that is predictive of therapeutic outcome in individual subjects. In a breast cancer mouse model, we demonstrate that co-injecting Doxil and a Zirconium-89 nanoreporter ((89)Zr-NRep) allows precise doxorubicin (DOX) quantification. Importantly, (89)Zr-NRep uptake also correlates with other types of nanoparticles' tumour accumulation. (89)Zr-NRep PET imaging reveals remarkable accumulation heterogeneity independent of tumour size. We subsequently demonstrate that mice with >25 mg kg(-1) DOX accumulation in tumours had significantly better growth inhibition and enhanced survival. This non-invasive imaging tool may be developed into a robust inclusion criterion for patients amenable to nanotherapy.

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Figures

Figure 1

Figure 1. Nanoreporter PET imaging concept.

(a) Schematic representation of the FDA-approved Doxil nanoformulation (left) and the 89Zr-NRep doped Doxil nanoformulation used in this study (right). (b) The liposomal nanoreporter 89Zr-NRep modified with 89Zr-chelating DFO. (c) Compared size exclusion retention times for clinical grade Doxil nanoformulation (fluorescence emission, red) and 89Zr-NRep (HPLC γ-counter, black). (d) Co-injecting 89Zr-NRep and Doxil allows non-invasive quantification of DOX delivery. © 2016, Memorial Sloan Kettering Cancer Center. (e) Correlation between 89Zr-NRep (%ID per g) and DOX (%IDeq./g) in blood. Data points (_N_=28) represent individual blood samples, from which activity was counted (γ-counter) before DOX was extracted and quantified. (f) Correlation between 89Zr-NRep (%ID per g) and DOX (%IDeq./g) uptake. Data points (_N_=45) represent tumour tissue from mice euthanized at 6 h (blue), 24 h (orange) or 48 h (green) post administration. Tissues were excised, and associated activity counted (γ-counter), before DOX was extracted from the tissues. Pearson's r coefficients were calculated to determine correlation.

Figure 2

Figure 2. Non-invasive nanoreporter PET quantifies DOX tumour uptake.

(a) Representative images of 4T1 tumour-bearing mice with low 89Zr-NRep uptake (mouse A, left) and high 89Zr-NRep uptake (mouse B, right). (b) Correlation of uptake values generated by non-invasive PET imaging and DOX tumour concentrations and (c) correlation of tumour-associated activity (measured ex vivo, γ-counter) and DOX tumour concentrations (_N_=5). Mice were injected with 89Zr-NRep/Doxil (0.14 mCi 89Zr-NRep, 10 mg kg−1 Doxil), underwent PET imaging at 24 h and were then killed to quantify tumour-associated activity (γ-counter) and DOX. (a) Shows representative mouse PET scans, and panels b and c show the corresponding obtained values. Pearson's r coefficients were calculated to determine correlation.

Figure 3

Figure 3. Nanoreporter PET quantifies nanoemulsion and PLGA nanoparticle uptake.

Structure and composition of (a) NE-DiR and (b) PLGA-Cy7. Correlation between (c) 89Zr-NRep (%ID per g) and DiR (%IDeq./g) uptake (_N_=10), and (d) 89Zr-NRep (%ID per g) and Cy7 (%IDeq./g) uptake (_N_=10), at 24 h post co-administration of NE-DiR and 89Zr-NRep and PLGA-Cy7 and 89Zr-NRep, respectively. (e) Representative PET images of 4T1 tumour-bearing mice at 24 h post co-injection of NE-DiR and 89Zr-NRep showing low (mouse NE3, left) and high (mouse NE2, right) 89Zr uptake. (f) Representative PET images of 4T1 tumour-bearing mice at 24 h post co-injection of PLGA-Cy7 and 89Zr-NRep showing low (mouse PLGA2, left) and high (mouse PLGA10, right) 89Zr uptake. (g) Correlation between 89Zr uptake values generated by non-invasive PET imaging and DiR (purple (_N_=10), _r_=0.83, P<0.01) and Cy7 (pink (_N_=10), _r_=0.33, _P_=0.38) concentrations in tumours from mice co-injected with NE-DiR and 89Zr-NRep, and PLGA-Cy7 and 89Zr-NRep, respectively. Pearson's r coefficients were calculated to determine correlation.

Figure 4

Figure 4. Quantifying DOX in individual mouse tumours by 89Zr-NRep PET imaging.

(a) PET scans of mice HD-10 (large tumour, high uptake), HD-07 (small tumour, high uptake) and HD-18 (medium-sized tumour, low uptake), demonstrating intertumoural uptake heterogeneity. (b) Determination of intratumoural DOX concentrations based on 89Zr-NRep %ID per g uptake values. Only the data for animals injected with 20 mg kg−1 are shown. The data corresponding to the 10 mg kg−1 group are shown in Supplementary Fig. 5a. (c) Individual non-invasively determined intratumoural DOX concentrations for mice receiving either 20 mg kg−1 Doxil (_N_=20) or 10 mg kg−1 Doxil (_N_=10). Labelled red arrows in b and c indicate data points for mice HD-10, HD-07 and HD-18. Their PET scans are shown in a.

Figure 5

Figure 5. Predictive value of 89Zr-NRep PET imaging.

(a) Individual tumour size increase in mouse cohorts treated with 20 mg kg−1 Doxil and >25 mg kg−1 intratumoural DOX concentration (_N_=9, green);<25 mg kg−1 intratumoural Doxil concentration (_N_=11, red) and controls (_N_=15, black). (**b**) Mean values of the groups in **a**. (**c**) Compared tumour growth rates for mice treated with 20 mg kg−1 Doxil that received >25 mg kg−1 intratumoural DOX (green, _N_=9), <25 mg kg−1 DOX (red, _N_=11) or 10 mg kg−1 Doxil (orange, _N_=10) at 2 days (left), 7 days (middle) and 12 days (right) post-treatment. The data from 2 days represent the initial daily growth rate (days 0–2, left); the 7- and 12-day data are the average daily growth rates from day 2 onwards. (**d**) Mean values of the average daily growth rates from day 2 onwards. (**e**,**f**) Kaplan–Meier plot and table showing the survival and median survival of individual mouse cohorts treated with 20 mg kg−1 Doxil (blue, _N_=20), 10 mg kg−1 Doxil (orange, _N_=10), 20 mg kg−1 Doxil and >25 mg intratumoural DOX per kg (green, _N_=9) or <25 mg intratumoural DOX per kg (red, _N_=11), plus the PBS treated control group (black, _N_=15). Error bars are s.e.m. P values were calculated with one-way analysis of variance (ANOVA) followed by Tukey's HSD; NS, not significant, *P<0.05, **P<0.01, ****P<0.0001.

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