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Exploitingthe Metal-Chelating Properties of the Drug Cargo for In Vivo Positron Emission Tomography Imagingof Liposomal Nanomedicines

View Article: PubMed Central - PubMed

ABSTRACT

Theclinical value of current and future nanomedicines can be improvedby introducing patient selection strategies based on noninvasive sensitivewhole-body imaging techniques such as positron emission tomography(PET). Thus, a broad method to radiolabel and track preformed nanomedicinessuch as liposomal drugs with PET radionuclides will have a wide impactin nanomedicine. Here, we introduce a simple and efficient PET radiolabelingmethod that exploits the metal-chelating properties of certain drugs(e.g., bisphosphonates such as alendronate and anthracyclinessuch as doxorubicin) and widely used ionophores to achieve excellentradiolabeling yields, purities, and stabilities with 89Zr, 52Mn, and 64Cu, and without the requirementof modification of the nanomedicine components. In a model of metastaticbreast cancer, we demonstrate that this technique allows quantificationof the biodistribution of a radiolabeled stealth liposomal nanomedicinecontaining alendronate that shows high uptake in primary tumors andmetastatic organs. The versatility, efficiency, simplicity, and GMPcompatibility of this method may enable submicrodosing imaging studiesof liposomal nanomedicines containing chelating drugs in humans andmay have clinical impact by facilitating the introduction of image-guidedtherapeutic strategies in current and future nanomedicine clinicalstudies.

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Related in: MedlinePlus

Multimodal imaging data showing the accumulation of 89Zr-PLA in metastatic lymph nodes (LNmet). (A) Ex vivo biodistribution data at t = 72h showing the uptake of 89Zr-PLA in LNmet (redcircles, 3E.Δ.NT/NSG mice, n = 7), nonmetastaticlymph nodes (LN) (blue circles, 3E.Δ.NT/NSG mice, n = 4), LN (blue triangles, non-tumor-bearing NSG mice, n = 3); or 89Zr-ALD in LNmet (red squares, 3E.Δ.NT/NSGmice, n = 3), LN (blue squares, 3E.Δ.NT/NSGmice, n = 3); **P < 0.01, *P < 0.05, two-tailed t-test (unpaired).(B) Coronal and sagittal SPECT-CT (top) and PET-CT (bottom) imagescentered at the LNmet of same animal from at 72 h afterinjection of 89Zr-PLA. (C) Fluorescence microscopy imagesof sections of LNmet (top) and LN (left brachial, bottom).A high degree of metastasis (green) and microvasculature density (red)is observed in LNmet but not in LN. Scale bar is 250 μm.(D) Quantification of microvasculature density in LNmet (black bar) and LN (gray bar) from fluorescence imaging, *P < 0.05; t-test, one-sided, unpaired,mean ± SEM; n = 2).
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fig4: Multimodal imaging data showing the accumulation of 89Zr-PLA in metastatic lymph nodes (LNmet). (A) Ex vivo biodistribution data at t = 72h showing the uptake of 89Zr-PLA in LNmet (redcircles, 3E.Δ.NT/NSG mice, n = 7), nonmetastaticlymph nodes (LN) (blue circles, 3E.Δ.NT/NSG mice, n = 4), LN (blue triangles, non-tumor-bearing NSG mice, n = 3); or 89Zr-ALD in LNmet (red squares, 3E.Δ.NT/NSGmice, n = 3), LN (blue squares, 3E.Δ.NT/NSGmice, n = 3); **P < 0.01, *P < 0.05, two-tailed t-test (unpaired).(B) Coronal and sagittal SPECT-CT (top) and PET-CT (bottom) imagescentered at the LNmet of same animal from at 72 h afterinjection of 89Zr-PLA. (C) Fluorescence microscopy imagesof sections of LNmet (top) and LN (left brachial, bottom).A high degree of metastasis (green) and microvasculature density (red)is observed in LNmet but not in LN. Scale bar is 250 μm.(D) Quantification of microvasculature density in LNmet (black bar) and LN (gray bar) from fluorescence imaging, *P < 0.05; t-test, one-sided, unpaired,mean ± SEM; n = 2).

Mentions: The presence of the multimodal reporter gene in the 3E.Δ.NTcell line allowed the detection by SPECT and optical imaging of spontaneousmetastases in the left axillary lymph nodes (n =4) and lungs (n = 4) (Figure 2B,C) in all the animals studied. Three morelymph nodes in individual mice were identified as metastatic (oneleft brachial, one right axillary, and one renal). The biodistributionstudies also revealed that all the hNIS-positive, and hence metastaticlymph nodes (LNmet), had a significant higher accumulationof 89Zr-PLA than nonmetastatic lymph nodes (LN) from thesame animals (16.3 ± 7.1 vs 3.8 ± 2.3%ID/g; P = 0.009), or LN from tumor-free mice (16.3 ± 7.1 vs 5.0 ± 3.5%ID/g; P = 0.03) (Figure 4A). Using this information,a closer inspection of the PET images revealed that 89Zrwas visible in the left axillary LNmet of mice with highestuptake (Figure 4B).There was no difference in the uptake of 89Zr-ALD in LNmet and LN (6.9 ± 3.5 vs 5.6 ± 1.5%ID/g; P = 0.6).


Exploitingthe Metal-Chelating Properties of the Drug Cargo for In Vivo Positron Emission Tomography Imagingof Liposomal Nanomedicines
Multimodal imaging data showing the accumulation of 89Zr-PLA in metastatic lymph nodes (LNmet). (A) Ex vivo biodistribution data at t = 72h showing the uptake of 89Zr-PLA in LNmet (redcircles, 3E.Δ.NT/NSG mice, n = 7), nonmetastaticlymph nodes (LN) (blue circles, 3E.Δ.NT/NSG mice, n = 4), LN (blue triangles, non-tumor-bearing NSG mice, n = 3); or 89Zr-ALD in LNmet (red squares, 3E.Δ.NT/NSGmice, n = 3), LN (blue squares, 3E.Δ.NT/NSGmice, n = 3); **P < 0.01, *P < 0.05, two-tailed t-test (unpaired).(B) Coronal and sagittal SPECT-CT (top) and PET-CT (bottom) imagescentered at the LNmet of same animal from at 72 h afterinjection of 89Zr-PLA. (C) Fluorescence microscopy imagesof sections of LNmet (top) and LN (left brachial, bottom).A high degree of metastasis (green) and microvasculature density (red)is observed in LNmet but not in LN. Scale bar is 250 μm.(D) Quantification of microvasculature density in LNmet (black bar) and LN (gray bar) from fluorescence imaging, *P < 0.05; t-test, one-sided, unpaired,mean ± SEM; n = 2).
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fig4: Multimodal imaging data showing the accumulation of 89Zr-PLA in metastatic lymph nodes (LNmet). (A) Ex vivo biodistribution data at t = 72h showing the uptake of 89Zr-PLA in LNmet (redcircles, 3E.Δ.NT/NSG mice, n = 7), nonmetastaticlymph nodes (LN) (blue circles, 3E.Δ.NT/NSG mice, n = 4), LN (blue triangles, non-tumor-bearing NSG mice, n = 3); or 89Zr-ALD in LNmet (red squares, 3E.Δ.NT/NSGmice, n = 3), LN (blue squares, 3E.Δ.NT/NSGmice, n = 3); **P < 0.01, *P < 0.05, two-tailed t-test (unpaired).(B) Coronal and sagittal SPECT-CT (top) and PET-CT (bottom) imagescentered at the LNmet of same animal from at 72 h afterinjection of 89Zr-PLA. (C) Fluorescence microscopy imagesof sections of LNmet (top) and LN (left brachial, bottom).A high degree of metastasis (green) and microvasculature density (red)is observed in LNmet but not in LN. Scale bar is 250 μm.(D) Quantification of microvasculature density in LNmet (black bar) and LN (gray bar) from fluorescence imaging, *P < 0.05; t-test, one-sided, unpaired,mean ± SEM; n = 2).
Mentions: The presence of the multimodal reporter gene in the 3E.Δ.NTcell line allowed the detection by SPECT and optical imaging of spontaneousmetastases in the left axillary lymph nodes (n =4) and lungs (n = 4) (Figure 2B,C) in all the animals studied. Three morelymph nodes in individual mice were identified as metastatic (oneleft brachial, one right axillary, and one renal). The biodistributionstudies also revealed that all the hNIS-positive, and hence metastaticlymph nodes (LNmet), had a significant higher accumulationof 89Zr-PLA than nonmetastatic lymph nodes (LN) from thesame animals (16.3 ± 7.1 vs 3.8 ± 2.3%ID/g; P = 0.009), or LN from tumor-free mice (16.3 ± 7.1 vs 5.0 ± 3.5%ID/g; P = 0.03) (Figure 4A). Using this information,a closer inspection of the PET images revealed that 89Zrwas visible in the left axillary LNmet of mice with highestuptake (Figure 4B).There was no difference in the uptake of 89Zr-ALD in LNmet and LN (6.9 ± 3.5 vs 5.6 ± 1.5%ID/g; P = 0.6).

View Article: PubMed Central - PubMed

ABSTRACT

Theclinical value of current and future nanomedicines can be improvedby introducing patient selection strategies based on noninvasive sensitivewhole-body imaging techniques such as positron emission tomography(PET). Thus, a broad method to radiolabel and track preformed nanomedicinessuch as liposomal drugs with PET radionuclides will have a wide impactin nanomedicine. Here, we introduce a simple and efficient PET radiolabelingmethod that exploits the metal-chelating properties of certain drugs(e.g., bisphosphonates such as alendronate and anthracyclinessuch as doxorubicin) and widely used ionophores to achieve excellentradiolabeling yields, purities, and stabilities with 89Zr, 52Mn, and 64Cu, and without the requirementof modification of the nanomedicine components. In a model of metastaticbreast cancer, we demonstrate that this technique allows quantificationof the biodistribution of a radiolabeled stealth liposomal nanomedicinecontaining alendronate that shows high uptake in primary tumors andmetastatic organs. The versatility, efficiency, simplicity, and GMPcompatibility of this method may enable submicrodosing imaging studiesof liposomal nanomedicines containing chelating drugs in humans andmay have clinical impact by facilitating the introduction of image-guidedtherapeutic strategies in current and future nanomedicine clinicalstudies.

No MeSH data available.


Related in: MedlinePlus