Mechanisms of enhanced antiglioma efficacy of polysorbate 80-modified paclitaxel-loaded PLGA nanoparticles by focused ultrasound.
Authors: Li Y, Wu M, Zhang N, Tang C, Jiang P, Liu X, Yan F, Zheng H
The presence of blood-brain barrier (BBB) greatly limits the availability of drugs and their efficacy against glioma. Focused ultrasound (FUS) can induce transient and local BBB opening for enhanced drug delivery. Here, we developed polysorbate 80-modified paclitaxel-loaded PLGA nanoparticles (PS-80-PTX-NPs, PPNP) and examined the enhanced local delivery into the brain for glioma treatment by combining with FUS. Our result showed PPNP had good stability, fast drug release rate and significant toxicity to glioma cells. Combined with FUS, PPNP showed a stronger BBB permeation efficiency both in the in vitro and in vivo BBB models. Mechanism studies revealed the disrupted tight junction, reduced P-glycoprotein expression and ApoE-dependent PS-80 permeation collectively contribute to the enhanced drug delivery, resulting in significantly stronger antitumour efficacy and longer survival time in the tumour-bearing mice. Our study provided a new strategy to efficiently and locally deliver drugs into the brain to treat glioma.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To develop polysorbate 80–modified paclitaxel‑loaded PLGA nanoparticles and evaluate whether combining them with focused ultrasound enhances blood–brain barrier penetration and antitumor efficacy against glioma.
Animal model / Human subject
BALB/c nude Mouse (Mus musculus), strain not specified, age 6-8 weeks, sex not specified
Disease model
glioma
Target coordinates
2 mm right of bregma, 1.3 mm posterior to coronal suture, depth 3 mm
Cargo name and characteristics
Paclitaxel (small-molecule chemotherapeutic) loaded into PLGA nanoparticles modified with polysorbate 80 (PS-80-PTX-NPs, PPNP) — polysorbate 80-coated PLGA nanoparticle formulation with reported good stability and fast drug release designed for enhanced BBB penetration.
Route of administration
Intravenous
Outcomes and Safety
Summary of Outcomes
Combining PS-80-coated paclitaxel-loaded PLGA nanoparticles (PPNP) with focused ultrasound (FUS) plus microbubbles transiently opened the BBB (disrupted tight junctions and reduced P-gp), enhanced ApoE-dependent nanoparticle brain delivery, produced stronger glioma growth inhibition with increased tumour apoptosis and reduced proliferation, and extended median survival in tumour-bearing mice compared with PPNP or FUS alone. The study used FUS in the presence of microbubbles to induce BBB opening but did not report testing multiple distinct FUS parameter sets.
Duration of biological effect
37 days
Safety-related matter
H&E staining of FUS-irradiated brain showed no apparent pathological damage (e.g., no RBC extravasation), and pathological analysis of major organs revealed no appreciable abnormalities; overall the PPNP + FUS treatment was reported as tolerable with no obvious acute toxicity observed in mice.
Brain Region
Ultrasound Parameters
Ultrasound instrument
Single-element FUS transducer
FUS Frequency
1 MHz
FUS Intensity
2.9 W/cm2
FUS Pressure
0.3 Mpa
FUS Mode
Continuous
Duration of a single FUS session
60 s
Focal Characteristics
Focal depth: None; Focal length: None; Aperture size: None
Treatment frequency
multiple sessions
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