Targeted and pH-facilitated theranostic of orthotopic gastric cancer via phase-transformation doxorubicin-encapsulated nanoparticles enhanced by low-intensity focused ultrasound (LIFU) with reduced side effect

PURPOSE: Focused ultrasound-mediated chemotherapy, as a non-invasive therapeutic modality, has been extensively explored in combating deep tumors for predominant penetration performance. However, the generally used high-intensity focused ultrasound (HIFU) inevitably jeopardizes normal tissue around the lesion for hyperthermal energy. To overcome this crucial issue, low-intensity focused ultrasound (LIFU) was introduced to fulfill precisely controlled imaging and therapy in lieu of HIFU. The objective of this study was to develop a facile and versatile nanoplatform (DPP-R) in response to LIFU and provide targeted drug delivery concurrently. METHODS: Multifunctional DPP-R was fabricated by double emulsion method and carbodiimide method. Physicochemical properties of DPP-R were detected respectively and the bio-compatibility and bio-safety were evaluated by CCK-8 assay, blood analysis, and histologic section. The targeted ability, imaging function, and anti-tumor effect were demonstrated in vitro and vivo. RESULTS: The synthetic DPP-R showed an average particle size at 367 nm, stable physical-chemical properties in different media, and high bio-compatibility and bio-safety. DPP-R was demonstrated to accumulate at the tumor site by active receptor/ligand reaction and passive EPR effect with intravenous administration. Stimulated by LIFU at the tumor site, phase-transformable PFH was vaporized in the core of the integration offering contrast-enhanced ultrasound imaging. The stimuli led to encapsulated DOX's initial burst release and subsequent sustained release for anti-tumor therapy which was verified to be more effective and have less adverse effects than free DOX. CONCLUSION: DPP-R combined with LIFU provides a novel theranostic modality for GC treatment with potent therapeutic effect, including prominent performance of targeting, ultrasound imaging, and accurate drug release.