Increasing Distribution of Drugs Released from In Situ Forming PLGA Implants Using Therapeutic Ultrasound

Abstract

One of the challenges in developing sustained-release local drug delivery systems is the limited treatment volume that can be achieved. In this work, we examine the effectiveness of using low frequency, high intensity ultrasound to promote the spatial penetration of drug molecules away from the implant/injection site boundary upon release from injectable, phase inverting poly(lactic acid-co-glycolic acid) (PLGA) implants. Fluorescein-loaded PLGA solutions were injected into poly(acrylamide) phantoms, and the constructs were treated daily for 14 days with ultrasound at 2.2 W/cm2 for 10 minutes. The 2D distribution of fluorescein within the phantoms was quantified using fluorescence imaging. Implants receiving ultrasound irradiation showed a 1.7-5.6 fold increase (p < 0.05) in fluorescence intensity and penetration distance, with the maximum increase observed 5 days post-implantation. However, this evidence was not seen when the same experiment was also carried out in phosphate buffer saline (pH 7.4). Results suggest an active role of ultrasound in local molecular transport in the phantom. An increase of fluorescein release and penetration depth in phantoms can be accomplished through brief application of ultrasound. This simple technique offers an opportunity to eventually enhance the therapeutic efficacy and broaden the application of local drug delivery systems.

Low-frequency ultrasound can drive the transport of nanoparticles and molecules in polymer gels for biotechnology applications

“…The use of low-frequency ultrasound to stimulate the release of molecules from polymers has been reported previously. However, in those previous reports the ultrasound transducer enhanced the release of molecules from polymers immersed in liquids and at a distance more than 1 cm remote from the ultrasound transducer (6,7). Moreover, the power required for the enhanced release was usually more than 10 W/cm 2 , since that level of power is required to be greater than the cavitation threshold, since interial cavitation is the usual explanation for the enhanced delivery.…”

“…Ultrasonic horns immersed in aqueous fluids have been reported to stimulate, remotely, drug-release from polymers. For a recently published example, the application of ultrasound using an immersed transducer held remotely at a distance of 1.5 cm enhanced release of fluorescein from poly(lactic acid-co-glycolic acid), PLGA, implants that were injected into tissue-mimicking hydrogel phantoms (acrylamide, 2kPa elastic modulus) (6). However, in that example, ultrasound at 3MHz and only at an intensity of 2.2 W/cm 2 , but not at 0.7 W/cm 2 , was capable to enhance release of fluorescein with a concomitant induced degradation of the PLGA.…”

Conventional polymers may unintentionally refill in vivo with unassociated drugs

“…Regarding the type of drug delivery implant selected, drug release from diffusion-governed drug delivery devices have limited drug penetration depth through tissue, limiting therapeutic effects to within a few millimeters of the device. 34 However, it is known that PLGA implants with increased swelling (generally more swelling with lower molecular weight polymers) experience greater pressure from the surrounding tissue environment, creating compressive forces that induces convective transport of solvent and drug from implants. This may even increase tissue penetration depth.…”

Low-Intensity Focused Ultrasound-Augmented Multifunctional Nanoparticles for Integrating Ultrasound Imaging and Synergistic Therapy of Metastatic Breast Cancer

“…It has been greatly acknowledged that the metastasis of breast cancer will extensively influence its poor prognosis [ 3 , 49 ]. As a desirable therapeutic approach, SDT may serve for its high efficiency and deep penetrating capability has been extensively convinced [ 11 , 50 ]. Admittedly, since certain limitations exist in the single application of sonosensitizers, using SDT alone may still be less sufficient in further cancer exploration.…”