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

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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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Liposomal nanomedicine PET radiolabeling method. (A) Chemicalstructureof drugs explored in this study, with metal-binding motifs highlightedin color. (B) Radiometal–ionophore complexes used to radiolabelliposomal nanomedicines: 8HQ = 8-hydroquinoline; 2HQ = 2-hydroxyquinoline.(C) Schematic representation of the liposome radiolabeling method.Top: Incubation of empty liposomes, lacking encapsulated drug, donot radiolabel after incubating with the radiometal–ionophorecomplex in PBS or saline at 50 °C for 30 min. Bottom: Drug-loadedliposomes efficiently radiolabel under the same conditions. (D) Radiolabelingyields of different liposomes with different PET radiometals and atdifferent liposome concentrations (n = 3). Note the x-axis is in log scale. (E) Serum stabilities after incubatingliposomes in human serum at 37 °C for up to 72 h (89Zr, 52Mn) or 48 h (64Cu) (n = 3).
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fig1: Liposomal nanomedicine PET radiolabeling method. (A) Chemicalstructureof drugs explored in this study, with metal-binding motifs highlightedin color. (B) Radiometal–ionophore complexes used to radiolabelliposomal nanomedicines: 8HQ = 8-hydroquinoline; 2HQ = 2-hydroxyquinoline.(C) Schematic representation of the liposome radiolabeling method.Top: Incubation of empty liposomes, lacking encapsulated drug, donot radiolabel after incubating with the radiometal–ionophorecomplex in PBS or saline at 50 °C for 30 min. Bottom: Drug-loadedliposomes efficiently radiolabel under the same conditions. (D) Radiolabelingyields of different liposomes with different PET radiometals and atdifferent liposome concentrations (n = 3). Note the x-axis is in log scale. (E) Serum stabilities after incubatingliposomes in human serum at 37 °C for up to 72 h (89Zr, 52Mn) or 48 h (64Cu) (n = 3).

Mentions: We noticed that many drugs of clinical interestin nanomedicinehave metal-binding motifs (Figure 1A and Figure S1). Hence,we hypothesized that preformed liposomal nanomedicines containingsuch drugs could be efficiently radiolabeled with metallic PET isotopessuch as 89Zr (t1/2 = 78.4 h), 52Mn (t1/2 = 134.2 h), and 64Cu (t1/2 = 12.7 h), by usingwell-established metal ionophores (Figure 1B,C). Furthermore, the high concentrationof metal-binding drug molecules inside the liposome and the protectiveeffect of the phospholipid bilayer from plasma protein transchelationshould result in high radiolabeling yields, specific activities, andstabilities compared to previously reported methods. This strategywould allow the simple radiolabeling and PET imaging of many currentand future liposomal nanomedicines and facilitate the introductionof treatment response prediction tools based on PET in the clinicalsetting. Here, we demonstrate and discuss the feasibility and effectivenessof this method, as well as its advantages and limitations, and showits utility for detecting and quantifying the biodistribution of aliposomal nanomedicine containing an aminobisphosphonate invivo.


Exploitingthe Metal-Chelating Properties of the Drug Cargo for In Vivo Positron Emission Tomography Imagingof Liposomal Nanomedicines
Liposomal nanomedicine PET radiolabeling method. (A) Chemicalstructureof drugs explored in this study, with metal-binding motifs highlightedin color. (B) Radiometal–ionophore complexes used to radiolabelliposomal nanomedicines: 8HQ = 8-hydroquinoline; 2HQ = 2-hydroxyquinoline.(C) Schematic representation of the liposome radiolabeling method.Top: Incubation of empty liposomes, lacking encapsulated drug, donot radiolabel after incubating with the radiometal–ionophorecomplex in PBS or saline at 50 °C for 30 min. Bottom: Drug-loadedliposomes efficiently radiolabel under the same conditions. (D) Radiolabelingyields of different liposomes with different PET radiometals and atdifferent liposome concentrations (n = 3). Note the x-axis is in log scale. (E) Serum stabilities after incubatingliposomes in human serum at 37 °C for up to 72 h (89Zr, 52Mn) or 48 h (64Cu) (n = 3).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5121927&req=5

fig1: Liposomal nanomedicine PET radiolabeling method. (A) Chemicalstructureof drugs explored in this study, with metal-binding motifs highlightedin color. (B) Radiometal–ionophore complexes used to radiolabelliposomal nanomedicines: 8HQ = 8-hydroquinoline; 2HQ = 2-hydroxyquinoline.(C) Schematic representation of the liposome radiolabeling method.Top: Incubation of empty liposomes, lacking encapsulated drug, donot radiolabel after incubating with the radiometal–ionophorecomplex in PBS or saline at 50 °C for 30 min. Bottom: Drug-loadedliposomes efficiently radiolabel under the same conditions. (D) Radiolabelingyields of different liposomes with different PET radiometals and atdifferent liposome concentrations (n = 3). Note the x-axis is in log scale. (E) Serum stabilities after incubatingliposomes in human serum at 37 °C for up to 72 h (89Zr, 52Mn) or 48 h (64Cu) (n = 3).
Mentions: We noticed that many drugs of clinical interestin nanomedicinehave metal-binding motifs (Figure 1A and Figure S1). Hence,we hypothesized that preformed liposomal nanomedicines containingsuch drugs could be efficiently radiolabeled with metallic PET isotopessuch as 89Zr (t1/2 = 78.4 h), 52Mn (t1/2 = 134.2 h), and 64Cu (t1/2 = 12.7 h), by usingwell-established metal ionophores (Figure 1B,C). Furthermore, the high concentrationof metal-binding drug molecules inside the liposome and the protectiveeffect of the phospholipid bilayer from plasma protein transchelationshould result in high radiolabeling yields, specific activities, andstabilities compared to previously reported methods. This strategywould allow the simple radiolabeling and PET imaging of many currentand future liposomal nanomedicines and facilitate the introductionof treatment response prediction tools based on PET in the clinicalsetting. Here, we demonstrate and discuss the feasibility and effectivenessof this method, as well as its advantages and limitations, and showits utility for detecting and quantifying the biodistribution of aliposomal nanomedicine containing an aminobisphosphonate invivo.

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