Facile one-pot synthesis of polymer–phospholipid composite microbubbles with enhanced drug loading capacity for ultrasound-triggered therapy

Nakatsuka, Matthew A.; Lee, Joo Hye; Nakayama, Emi E.; Hung, Albert M.; Hsu, Mark J.; Mattrey, Robert F.; Esener, Sadik C.; Jennifer, N.; Goodwin, Andrew P.

doi:10.1039/c0sm01131b

Cited by 20 publications

(21 citation statements)

References 28 publications

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“…[14] Briefly, ten images per sample were taken at 20X in bright field at random locations in the sample. The microbubbles were counted and sized using ImageJ (NIH).…”

Section: Methodsmentioning

confidence: 99%

Aptamer‐Crosslinked Microbubbles: Smart Contrast Agents for Thrombin‐Activated Ultrasound Imaging

et al. 2012

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Thrombosis, or malignant blood clotting, is associated with numerous cardiovascular diseases and cancers. This report describes a microbubble contrast agent that produces ultrasound harmonic signal only when exposed to elevated thrombin levels. Silenced initially, microbubbles activated in the presence of both thrombin-spiked and freshly clotting blood in three minutes with detection limits of 20 nM thrombin and 2 aM microbubbles.

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“…[14] Briefly, ten images per sample were taken at 20X in bright field at random locations in the sample. The microbubbles were counted and sized using ImageJ (NIH).…”

Section: Methodsmentioning

confidence: 99%

Aptamer‐Crosslinked Microbubbles: Smart Contrast Agents for Thrombin‐Activated Ultrasound Imaging

et al. 2012

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“…The ultrasound‐induced targeted delivery is safe and noninvasive, efficient and controllable. Due to the enhanced permeation of cell membrane and vasculature through the sonoporation effect, the cellular uptake and therapeutic efficacy are remarkably improved . Under the guidance of microbubble‐enhanced ultrasonic imaging, cancer treatment has showed significant improvement in the optimization of therapeutic efficiency.…”

Section: Introductionmentioning

confidence: 99%

Enhancing Therapeutic Efficacy of Combined Cancer Phototherapy by Ultrasound‐Mediated In Situ Conversion of Near‐Infrared Cyanine/Porphyrin Microbubbles into Nanoparticles

Liang

Bhattarai

et al. 2017

Adv Funct Materials

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Nanoparticles (NPs)-based diagnosis and phototherapy are emerging as the cutting-edge technologies for detection and treatment of cancer but their applications are still limited since insufficient and heterogeneous NPs accumulation in cancer often causes recurrence. To overcome these limitations, multifunctional microbubbles (MBs) were constructed with 1, 1-dioctadecyl-3, 3, 3, 3-tetramethylindotricarbocyanine iodide (DiR) and porphyrin grafted lipid (PGL). Both DiR and PGL self-assembled as microbubbles, the as-designed PGL-DiR MBs possess remarkably high drug loading contents (5.8% PGL and 10.38% DiR) and stable co-delivery drug combinations. In vivo experiments showed PGL-DiR MBs could serve as an excellent ultrasound contrast agent to enhance ultrasound imaging greatly for identifying the location and size of the tumors. Upon exposure to ultrasound, in situ conversion of PGL-DiR MBs into nanoparticles resulted in a remarkable increase in fluorescence intensity (~5 folds) in tumor compared with PGL-DiR NPs, validating the enhanced tumor accumulation and cellular uptake of therapeutic agents. PGL-DiR MBs showed complete tumor ablation without recurrence in vivo, while PGL-DiR NPs showed only 72.6% tumor growth inhibition at the same dose. We believe that PGL-DiR MBs will soon reach their full potential as an important class of phototherapeutic formulations and will contribute to remarkable advances in cancer treatments.

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“…The various phospholipid formulations are shown in Table 1. The phospholipid mixture was then probe sonicated (Branson) for 10 s under perfluorobutane gas (PFB), as described previously[23]. Bubbles were crosslinked via the addition of the complementary DNA strand GGTTGGTGTGGTTGGTGTTTTTTTTTGTGGTTGGTGTGGTTGG, referred to hereforth as the thrombin aptamer crosslinking sequence (TACS).…”

Section: Methodsmentioning

confidence: 99%

In vivo ultrasound visualization of non-occlusive blood clots with thrombin-sensitive contrast agents

et al. 2013

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The use of microbubbles as ultrasound contrast agents is one of the primary methods to diagnose deep venous thrombosis. However, current microbubble imaging strategies require either a clot sufficiently large to produce a circulation filling defect or a clot with sufficient vascularization to allow for targeted accumulation of contrast agents. Previously, we reported the design of a microbubble formulation that modulated its ability to generate ultrasound contrast from interaction with thrombin through incorporation of aptamer-containing DNA crosslinks in the encapsulating shell, enabling the measurement of a local chemical environment by changes in acoustic activity. However, this contrast agent lacked sufficient stability and lifetime in blood to be used as a diagnostic tool. Here we describe a PEG-stabilized, thrombin-activated microbubble (PSTA-MB) with sufficient stability to be used in vivo in circulation with no change in biomarker sensitivity. In the presence of actively clotting blood, PSTA-MBs showed a 5-fold increase in acoustic activity. Specificity for the presence of thrombin and stability under constant shear flow were demonstrated in a home-built in vitro model. Finally, PSTA-MBs were able to detect the presence of an active clot within the vena cava of a rabbit sufficiently small as to not be visible by current non-specific contrast agents. By activating in non-occlusive environments, these contrast agents will be able to detect clots not diagnosable by current contrast agents.

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Facile one-pot synthesis of polymer–phospholipid composite microbubbles with enhanced drug loading capacity for ultrasound-triggered therapy

Cited by 20 publications

References 28 publications

Aptamer‐Crosslinked Microbubbles: Smart Contrast Agents for Thrombin‐Activated Ultrasound Imaging

Aptamer‐Crosslinked Microbubbles: Smart Contrast Agents for Thrombin‐Activated Ultrasound Imaging

Enhancing Therapeutic Efficacy of Combined Cancer Phototherapy by Ultrasound‐Mediated In Situ Conversion of Near‐Infrared Cyanine/Porphyrin Microbubbles into Nanoparticles

In vivo ultrasound visualization of non-occlusive blood clots with thrombin-sensitive contrast agents

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