Focused Ultrasound-Augmented Delivery of Biodegradable Multifunctional Nanoplatforms for Imaging-Guided Brain Tumor Treatment.

The blood brain barrier is the main obstacle to delivering diagnostic and therapeutic agents to the diseased sites of brain. It is still of great challenge for the combined use of focused ultrasound (FUS) and theranostic nanotechnology to achieve noninvasive and localized delivery of chemotherapeutic drugs into orthotopic brain tumor. In this work, a unique theranostic nanoplatform for highly efficient photoacoustic imaging-guided chemotherapy of brain tumor both in vitro and in vivo, which is based on the utilization of hollow mesoporous organosilica nanoparticles (HMONs) to integrate ultrasmall Cu2-x Se particles on the surface and doxorubicin inside the hollow interior, is synthesized. The developed multifunctional theranostic nanosystems exhibit tumor-triggered programmed destruction due to the reducing microenvironment-responsive cleavage of disulfide bonds that are incorporated into the framework of HMONs and linked between HMONs and Cu2-x Se, resulting in tumor-specific biodegradation and on-demand drug-releasing behavior. Such tumor microenvironment-responsive biodegradable and biocompatible theranostic nanosystems in combination with FUS provide a promising delivery nanoplatform with high performance for orthotopic brain tumor imaging and therapy.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To develop and evaluate a tumor-microenvironment-responsive, biodegradable theranostic nanosystem (HMONs-ss-Cu2−xSe loaded with doxorubicin) combined with focused ultrasound-induced BBB opening for photoacoustic imaging-guided, localized chemotherapy of orthotopic brain tumors.

Animal model / Human subject Balb/c nude mice (18-20g)

Disease model Orthotopic brain tumor

MRI or image guidance method Photoacoustic imaging–guided delivery combined with focused ultrasound (FUS)

Targeted brain region(s) Striatum

Cargo name and characteristics Hollow mesoporous organosilica nanoparticles (HMONs) theranostic nanoparticle system: HMONs incorporate disulfide bonds for tumor redox-responsive biodegradation, surface-decorated with ultrasmall Cu2−xSe particles (photoacoustic contrast agent) and loaded internally with the small-molecule chemotherapeutic doxorubicin for on-demand, tumor-triggered drug release; used in combination with focused ultrasound for imaging-guided chemotherapy.

Route of administration Intravenous

Outcomes and Safety

Summary of Outcomes The HCu theranostic nanosystem (HMONs with surface Cu2−xSe and encapsulated DOX), especially when combined with focused ultrasound (FUS)–mediated BBB opening, produced tumor‑selective and GSH‑responsive effects: disulfide bond cleavage triggered concentration‑dependent biodegradation and on‑demand DOX release (48 h release: ~10.6% without GSH vs ~49.1% at 5 mM GSH and ~64.2% at 10 mM GSH). In vitro the particles showed enhanced cellular uptake, intracellular biodegradation, greater nuclear delivery of DOX over time and higher cytotoxicity against U87 glioma cells than free DOX. In vivo FUS+HCu enabled significant delivery across the BBB, strong PA imaging contrast in orthotopic brain tumors, ~4× higher tumor fluorescence accumulation with FUS, and increased renal excretion of degradation products (Si, Cu). Therapeutically, DOX‑HCu+FUS produced markedly improved antitumor efficacy (≈91.1% tumor growth inhibition vs control at day 22) and extended median survival (52 days) compared with FUS alone (24 d), free DOX (32 d), free DOX+FUS (42 d) and DOX‑HCu without FUS (35 d). The nanosystem also showed reduced hemolysis, negligible systemic toxicity, and no observable brain damage at the applied FUS conditions.

Duration of biological effect 52 days (median survival time for DOX-HCu/FUS-treated mice)

Safety-related matter The paper reports multiple safety assessments: FUS‑induced BBB opening at 0.3 MPa produced Evans blue staining without visible brain damage or pathological changes on H&E, indicating safe delivery; HCu decoration reduced silanol groups leading to decreased hemolytic activity and enhanced hemocompatibility (hemolysis assay performed); HCu showed no significant cytotoxicity to U87 glioma cells up to 400 μg·mL−1 over 48 h, indicating high biocompatibility; bio‑TEM and excretion studies indicate tumor‑triggered biodegradation and enhanced Si and Cu excretion in urine (facilitating clearance); in vivo summary states negligible systemic toxicities and high histocompatibility; overall described as safe delivery and lowered adverse effects in the reported assays.

Brain Region

Ultrasound Parameters

Ultrasound instrument Not specified

FUS Frequency 1.0 MHz

FUS Intensity Not specified in provided text

FUS Pressure 0.3MPa

FUS Mode pulsed

Pulse duration 10 ms

Duration of a single FUS session 60 s

Focal Characteristics No focal size, depth, or beam diameter information reported in the provided text.

Treatment frequency single session

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