Microfluidic manufacture of rt-PA -loaded echogenic liposomes

Kandadai, Madhuvanthi A.; Mukherjee, Prithviraj; Shekhar, Himanshu; Shaw, George J.; Papautsky, Ian; Holland, Christy K.

doi:10.1007/s10544-016-0072-0

Cited by 17 publications

(12 citation statements)

References 59 publications

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“…Future studies should focus on the in vivo testing of rt-PA loaded in echogenic liposomes, to shield against PAI-1 degradation, in combination with ultrasound and an echocontrast agent such as Definity. Alternatively, further modification of OFP t-ELIP formulation or fabrication process 67 could improve gas encapsulation and enhance the efficacy of sonothrombolysis.…”

Section: Discussionmentioning

confidence: 99%

In vitro characterization of sonothrombolysis and echocontrast agents to treat ischemic stroke

Shekhar

Kleven

Peng

et al. 2019

Sci Rep

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The development of adjuvant techniques to improve thrombolytic efficacy is important for advancing ischemic stroke therapy. We characterized octafluoropropane and recombinant tissue plasminogen activator (rt-PA)-loaded echogenic liposomes (OFP t-ELIP) using differential interference and fluorescence microscopy, attenuation spectroscopy, and electrozone sensing. The loading of rt-PA in OFP t-ELIP was assessed using spectrophotometry. Further, it was tested whether the agent shields rt-PA against degradation by plasminogen activator inhibitor-1 (PAI-1). An in vitro system was used to assess whether ultrasound (US) combined with either Definity or OFP t-ELIP enhances rt-PA thrombolysis. Human whole blood clots were mounted in a flow system and visualized using an inverted microscope. The perfusate consisted of either (1) plasma alone, (2) rt-PA, (3) OFP t-ELIP, (4) rt-PA and US, (5) OFP t-ELIP and US, (6) Definity and US, or (7) rt-PA, Definity, and US (n = 16 clots per group). An intermittent US insonation scheme was employed (220 kHz frequency, and 0.44 MPa peak-to-peak pressures) for 30 min. Microscopic imaging revealed that OFP t-ELIP included a variety of structures such as liposomes (with and without gas) and lipid-shelled microbubbles. OFP t-ELIP preserved up to 76% of rt-PA activity in the presence of PAI-1, whereas only 24% activity was preserved for unencapsulated rt-PA. The use of US with rt-PA and Definity enhanced lytic efficacy ( p < 0.05) relative to rt-PA alone. US combined with OFP t-ELIP enhanced lysis over OFP t-ELIP alone ( p < 0.01). These results demonstrate that ultrasound combined with Definity or OFP t-ELIP can enhance the lytic activity relative to rt-PA or OFP t-ELIP alone, respectively.

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Section: Discussionmentioning

confidence: 99%

In vitro characterization of sonothrombolysis and echocontrast agents to treat ischemic stroke

Shekhar

Kleven

Peng

et al. 2019

Sci Rep

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“…Conventional manufacturing techniques of ELIP (sonication-lyophilization-rehydration method 78 ) produce a polydisperse ELIP population with only a small percentage of particles containing microbubbles. Lately, a microfluidic flow-focusing device was used to generate monodisperse tPA and PFC co-loaded ELIP (μtELIP) 79 , which improved encapsulation efficiency of both tPA and PFC microbubbles into echogenic liposomes. The resulted μtELIP had a mean diameter of 5 μm, a resonance frequency of 2.2 MHz, and were found to be stable for at least 30 min in 0.5 % bovine serum albumin.…”

Section: Nanocarriers For Tpamentioning

confidence: 99%

Tissue plasminogen activator-based nanothrombolysis for ischemic stroke

Liu

Feng

Jin

et al. 2017

Expert Opinion on Drug Delivery

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Introduction Thrombolysis with intravenous tissue plasminogen activator (tPA) is the only FDA approved treatment for patients with acute ischemic stroke, but its use is limited by narrow therapeutic window, selective efficacy, and hemorrhagic complication. In the past two decades, extensive efforts have been undertaken to extend its therapeutic time window and explore alternative thrombolytic agents, but both show little progress. Nanotechnology has emerged as a promising strategy to improve the efficacy and safety of tPA. Areas covered We reviewed the biology, thrombolytic mechanism, and pleiotropic functions of tPA in the brain and discussed current applications of various nanocarriers intended for the delivery of tPA for treatment of ischemic stroke. Current challenges and potential further directions of t-PA-based nanothrombolysis in stroke therapy are also discussed. Expert opinion Using nanocarriers to deliver tPA offers many advantages to enhance the efficacy and safety of tPA therapy. Further research is needed to characterize the physicochemical characteristics and in vivo behavior of tPA-loaded nanocarriers. Combination of tPA based nanothrombolysis and neuroprotection represents a promising treatment strategy for acute ischemic stroke. Theranostic nanocarriers co-delivered with tPA and imaging agents are also promising for future stroke management.

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“…The observed phenomena could be exploited to optimize the theranostic application of ELIP, either by adjusting the size distribution of ELIP within a population or the excitation frequency. It has recently been demonstrated that monodisperse drug-loaded ELIP in a clinically relevant size range can be manufactured using microfluidic devices (Kandadai et al 2016). Microfluidic sorting techniques (Segers and Versluis 2014, Kok et al 2015) can also be used to obtain a monodisperse bubble population of a particular size.…”

Section: Discussionmentioning

confidence: 99%

Loss of gas from echogenic liposomes exposed to pulsed ultrasound

Raymond

Luan²,

Peng

et al. 2016

Phys. Med. Biol.

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The destruction of echogenic liposomes (ELIP) in response to pulsed ultrasound excitations has been studied acoustically previously. However, the mechanism underlying the loss of echogenicity due to cavitation of ELIP has not been fully clarified. In this study, an ultra-high speed imaging approach was employed to observe the destruction phenomena of single ELIP exposed to ultrasound bursts at a center frequency of 6- MHz. We observed a rapid size reduction during the ultrasound excitation in 139 out of 397 (35 %) ultra-high-speed recordings. The shell dilation rate, which is defined as the microbubble wall velocity divided by the instantaneous radius, Ṙ/R, was extracted from the radius versus time response of each ELIP, and was found to be correlated with the deflation. Fragmentation and surface mode vibrations were also observed and are shown to depend on the applied acoustic pressure and initial radius. Results from this study can be utilized to optimize the theranostic application of ELIP, e.g., by tuning the size distribution or the excitation frequency.

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Microfluidic manufacture of rt-PA -loaded echogenic liposomes

Cited by 17 publications

References 59 publications

In vitro characterization of sonothrombolysis and echocontrast agents to treat ischemic stroke

In vitro characterization of sonothrombolysis and echocontrast agents to treat ischemic stroke

Tissue plasminogen activator-based nanothrombolysis for ischemic stroke

Loss of gas from echogenic liposomes exposed to pulsed ultrasound

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