Quantitative Pharmacokinetics Reveal Impact of Lipid Composition on Microbubble and Nanoprogeny Shell Fate
Abstract Microbubble‐enabled focused ultrasound (MB‐FUS) has revolutionized nano and molecular drug delivery capabilities. Yet, the absence of longitudinal, systematic, quantitative studies of microbubble shell pharmacokinetics hinders progress within the MB‐FUS field. Microbubble radiolabeling chal...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202304453 |
| _version_ | 1797262291624787968 |
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| author | Maneesha A. Rajora Alexander Dhaliwal Mark Zheng Victor Choi Marta Overchuk Jenny W. H. Lou Carly Pellow David Goertz Juan Chen Gang Zheng |
| author_facet | Maneesha A. Rajora Alexander Dhaliwal Mark Zheng Victor Choi Marta Overchuk Jenny W. H. Lou Carly Pellow David Goertz Juan Chen Gang Zheng |
| author_sort | Maneesha A. Rajora |
| collection | DOAJ |
| description | Abstract Microbubble‐enabled focused ultrasound (MB‐FUS) has revolutionized nano and molecular drug delivery capabilities. Yet, the absence of longitudinal, systematic, quantitative studies of microbubble shell pharmacokinetics hinders progress within the MB‐FUS field. Microbubble radiolabeling challenges contribute to this void. This barrier is overcome by developing a one‐pot, purification‐free copper chelation protocol able to stably radiolabel diverse porphyrin‐lipid‐containing Definity® analogues (pDefs) with >95% efficiency while maintaining microbubble physicochemical properties. Five tri‐modal (ultrasound‐, positron emission tomography (PET)‐, and fluorescent‐active) [64Cu]Cu‐pDefs are created with varying lipid acyl chain length and charge, representing the most prevalently studied microbubble compositions. In vitro, C16 chain length microbubbles yield 2–3x smaller nanoprogeny than C18 microbubbles post FUS. In vivo, [64Cu]Cu‐pDefs are tracked in healthy and 4T1 tumor‐bearing mice ± FUS over 48 h qualitatively through fluorescence imaging (to characterize particle disruption) and quantitatively through PET and γ‐counting. These studies reveal the impact of microbubble composition and FUS on microbubble dissolution rates, shell circulation, off‐target tissue retention (predominantly the liver and spleen), and FUS enhancement of tumor delivery. These findings yield pharmacokinetic microbubble structure‐activity relationships that disrupt conventional knowledge, the implications of which on MB‐FUS platform design, safety, and nanomedicine delivery are discussed. |
| first_indexed | 2024-03-08T11:21:11Z |
| format | Article |
| id | doaj.art-1ef6eb44bcaf44e38f50b56b8713a512 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-24T23:54:47Z |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-1ef6eb44bcaf44e38f50b56b8713a5122024-03-14T14:01:03ZengWileyAdvanced Science2198-38442024-01-01114n/an/a10.1002/advs.202304453Quantitative Pharmacokinetics Reveal Impact of Lipid Composition on Microbubble and Nanoprogeny Shell FateManeesha A. Rajora0Alexander Dhaliwal1Mark Zheng2Victor Choi3Marta Overchuk4Jenny W. H. Lou5Carly Pellow6David Goertz7Juan Chen8Gang Zheng9Princess Margaret Cancer Centre University Health Network Toronto Ontario M5G 1L7 CanadaPrincess Margaret Cancer Centre University Health Network Toronto Ontario M5G 1L7 CanadaPrincess Margaret Cancer Centre University Health Network Toronto Ontario M5G 1L7 CanadaPrincess Margaret Cancer Centre University Health Network Toronto Ontario M5G 1L7 CanadaPrincess Margaret Cancer Centre University Health Network Toronto Ontario M5G 1L7 CanadaPrincess Margaret Cancer Centre University Health Network Toronto Ontario M5G 1L7 CanadaPrincess Margaret Cancer Centre University Health Network Toronto Ontario M5G 1L7 CanadaDepartment of Medical Biophysics University of Toronto Toronto Ontario M5G 1L7 CanadaPrincess Margaret Cancer Centre University Health Network Toronto Ontario M5G 1L7 CanadaPrincess Margaret Cancer Centre University Health Network Toronto Ontario M5G 1L7 CanadaAbstract Microbubble‐enabled focused ultrasound (MB‐FUS) has revolutionized nano and molecular drug delivery capabilities. Yet, the absence of longitudinal, systematic, quantitative studies of microbubble shell pharmacokinetics hinders progress within the MB‐FUS field. Microbubble radiolabeling challenges contribute to this void. This barrier is overcome by developing a one‐pot, purification‐free copper chelation protocol able to stably radiolabel diverse porphyrin‐lipid‐containing Definity® analogues (pDefs) with >95% efficiency while maintaining microbubble physicochemical properties. Five tri‐modal (ultrasound‐, positron emission tomography (PET)‐, and fluorescent‐active) [64Cu]Cu‐pDefs are created with varying lipid acyl chain length and charge, representing the most prevalently studied microbubble compositions. In vitro, C16 chain length microbubbles yield 2–3x smaller nanoprogeny than C18 microbubbles post FUS. In vivo, [64Cu]Cu‐pDefs are tracked in healthy and 4T1 tumor‐bearing mice ± FUS over 48 h qualitatively through fluorescence imaging (to characterize particle disruption) and quantitatively through PET and γ‐counting. These studies reveal the impact of microbubble composition and FUS on microbubble dissolution rates, shell circulation, off‐target tissue retention (predominantly the liver and spleen), and FUS enhancement of tumor delivery. These findings yield pharmacokinetic microbubble structure‐activity relationships that disrupt conventional knowledge, the implications of which on MB‐FUS platform design, safety, and nanomedicine delivery are discussed.https://doi.org/10.1002/advs.202304453drug‐deliveryfocused ultrasoundMicrobubblesPharmacokineticsradiolabeling |
| spellingShingle | Maneesha A. Rajora Alexander Dhaliwal Mark Zheng Victor Choi Marta Overchuk Jenny W. H. Lou Carly Pellow David Goertz Juan Chen Gang Zheng Quantitative Pharmacokinetics Reveal Impact of Lipid Composition on Microbubble and Nanoprogeny Shell Fate Advanced Science drug‐delivery focused ultrasound Microbubbles Pharmacokinetics radiolabeling |
| title | Quantitative Pharmacokinetics Reveal Impact of Lipid Composition on Microbubble and Nanoprogeny Shell Fate |
| title_full | Quantitative Pharmacokinetics Reveal Impact of Lipid Composition on Microbubble and Nanoprogeny Shell Fate |
| title_fullStr | Quantitative Pharmacokinetics Reveal Impact of Lipid Composition on Microbubble and Nanoprogeny Shell Fate |
| title_full_unstemmed | Quantitative Pharmacokinetics Reveal Impact of Lipid Composition on Microbubble and Nanoprogeny Shell Fate |
| title_short | Quantitative Pharmacokinetics Reveal Impact of Lipid Composition on Microbubble and Nanoprogeny Shell Fate |
| title_sort | quantitative pharmacokinetics reveal impact of lipid composition on microbubble and nanoprogeny shell fate |
| topic | drug‐delivery focused ultrasound Microbubbles Pharmacokinetics radiolabeling |
| url | https://doi.org/10.1002/advs.202304453 |
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