Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts

Abstract

Paclitaxel liposomes (PTX-LIPO) are a clinically promising antineoplastic drug formulation for the treatment of various extracranial cancers, excluding glioblastoma. A main reason for this is the presence of the blood–brain barrier (BBB) or blood–tumor barrier (BTB), preventing liposomal drugs from crossing at a therapeutically meaningful level. Focused ultrasound (FUS) in conjunction with microbubbles (MBs) has been suggested in many studies to be an effective approach to increase the BBB or BTB permeability. In this study, we investigated the feasibility of enhancing the delivery of PTX-LIPO in intracranial glioblastoma-bearing nude mice using pulsed low-intensity FUS exposure in the presence of MBs. Our results showed that the delivery efficiency of PTX-LIPO could be effectively improved in terms of the penetration of both the BBB in vitro and BTB in vivo by pulsed FUS sonication with a 10 ms pulse length and 1 Hz pulse repetition frequency at 0.64 MPa peak-rarefactional pressure in the presence of MBs. Quantitative analysis showed that a 2-fold higher drug concentration had accumulated in the glioblastoma 3 h after FUS treatment, with 7.20±1.18 µg PTX per g glioma tissue. Longitudinal magnetic resonance imaging analysis illustrated that the intracranial glioblastoma progression in nude mice treated with PTX-LIPO delivered via FUS with MBs was suppressed consistently for 4 weeks compared to the untreated group. The medium survival time of these tumor-bearing nude mice was significantly prolonged by 20.8%, compared to the untreated nude mice. Immunohistochemical analysis further confirmed the antiproliferation effect and cell apoptosis induction. Our study demonstrated that noninvasive low-intensity FUS with MBs can be used as an effective approach to deliver PTX-LIPO in order to improve their chemotherapy efficacy toward glioblastoma.

Effects of Focused-Ultrasound-and-Microbubble-Induced Blood-Brain Barrier Disruption on Drug Transport under Liposome-Mediated Delivery in Brain Tumour: A Pilot Numerical Simulation Study

“…Although the loss of free doxorubicin by capillary drainage was slightly raised, as shown in Figure 13, the modelling results showed that keeping the BBB open for a longer time effectively improved the accumulation of both the liposome-encapsulated and free doxorubicin, which could lead to better therapy. However, it is important to note that the enhancement of drug transvascular permeability is very limited when FUS is applied in isolation [31]. Therefore, the pharmacokinetics of MB must be considered in treatment design in order to achieve continuous BBBD.…”

“…in which P Gd−DPTA is the transvascular permeability of Gd-DPTA, which was measured to be 2.0 × 10 −6 m/s [30] when 0.6 MPa FUS was applied. Under similar sonication conditions, the transvascular permeability of 120 nm liposomes was about 4.25 times higher than the baseline value [31]. k r stands for the BBBD recovery rate, which can be calibrated using the semi-empirical formula [32]…”

Mechanisms of enhanced antiglioma efficacy of polysorbate 80‐modified paclitaxel‐loaded PLGA nanoparticles by focused ultrasound

“…The transwell was exposed under 1.26 W/cm 2 for 60 seconds. The microbubbles that have good stability were obtained according to our previous study . Fluorescence intensity of abluminal medium was measured at 1, 2, 4, 8 and 12 hours after FUS exposure.…”

A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy

“…Recent evaluation of a stabilized long-circulating liposomal paclitaxel (LePTX) in a mouse model of glioblastoma showed results similar to the Le-DOX studies, with a significantly improved median survival time (47 days vs 39 days, p < 0.001) compared with no treatment. 51 Again, results were not directly compared with LePTX alone, but LePTX alone failed to demonstrate significance compared with no treatment (41 days vs 39 days, p = 0.07).…”