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Objective <p>Breast tumors present substantial barriers to chemotherapeutic penetration, limiting the efficacy of conventional paclitaxel (PTX) formulations. We developed PTX-loaded lipid– poly(lactide-co-glycolide) (PLGA) hybrid nanobubbles (PTX-NBs) as an ultrasound (US)-responsive delivery platform capable of deep intratumoral transport and spatiotemporally controlled PTX release to address the above challenge.</p> Methods <p>We constructed PTX-NBs by coupling a stabilizing PLGA shell with a lipid monolayer to form a gas-core nanosystem optimized for US activation. We systematically characterized the morphology, size distribution, zeta potential, and drug-loading capacity of PTX-NBs. We examined pH-responsive and US-triggered release behaviors alongside hemocompatibility. We evaluated therapeutic efficacy and US-mediated enhancement in a VX2 rabbit breast tumor model by using four groups, namely, the control, US alone, PTX-NB alone, and PTX-NBs + US groups (n = 3 per group).</p> Results <p>The hybrid nanobubbles exhibited uniform nanoscale architecture (~ 390&#xa0;nm), stable surface charge, and reliable PTX encapsulation. Our engineered structure enabled dual-responsive release, with accelerated PTX discharge in acidic environments and rapid on-demand release upon US irradiation. PTX-NBs showed excellent blood compatibility. In vivo fluorescence imaging demonstrated the pronounced accumulation of PTX-NBs at tumor sites after US irradiation, confirming effective US-mediated targeting. PTX-NB treatment significantly suppressed tumor growth compared with control and US-only treatments (achieving ~ 68.5% inhibition). This effect was further enhanced by US exposure, resulting in 85.8% tumor growth inhibition (P &lt; 0.001 vs. control). Consistently, the combined PTX-NB and US treatment induced extensive tumor necrosis and an increase in apoptotic cells (P &lt; 0.01 vs. control), accompanied with the upregulation of the proapoptotic markers Bax and Caspase-3 and downregulation of Bcl-2 and Ki67 at the transcriptional and protein levels.</p> Conclusion <p>Our study establishes PTX-NBs as a promising US-responsive delivery platform that alleviates physiological barriers to chemotherapeutic transport in a rabbit VX2 breast tumor model. By facilitating precise, externally controllable PTX release, this technology may serve as a basis for the further development of US‑guided breast cancer therapy in preclinical settings.</p>

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Ultrasound-responsive lipid–PLGA hybrid nanobubbles enable spatiotemporally controlled paclitaxel delivery for enhanced breast tumor therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月15日

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  • Xing Li,
  • Weiyang Lv,
  • Chunxin Huang,
  • Wei Dou,
  • Jiayi Qian,
  • Zihe Chen,
  • Huilin Liu

摘要

Objective

Breast tumors present substantial barriers to chemotherapeutic penetration, limiting the efficacy of conventional paclitaxel (PTX) formulations. We developed PTX-loaded lipid– poly(lactide-co-glycolide) (PLGA) hybrid nanobubbles (PTX-NBs) as an ultrasound (US)-responsive delivery platform capable of deep intratumoral transport and spatiotemporally controlled PTX release to address the above challenge.

Methods

We constructed PTX-NBs by coupling a stabilizing PLGA shell with a lipid monolayer to form a gas-core nanosystem optimized for US activation. We systematically characterized the morphology, size distribution, zeta potential, and drug-loading capacity of PTX-NBs. We examined pH-responsive and US-triggered release behaviors alongside hemocompatibility. We evaluated therapeutic efficacy and US-mediated enhancement in a VX2 rabbit breast tumor model by using four groups, namely, the control, US alone, PTX-NB alone, and PTX-NBs + US groups (n = 3 per group).

Results

The hybrid nanobubbles exhibited uniform nanoscale architecture (~ 390 nm), stable surface charge, and reliable PTX encapsulation. Our engineered structure enabled dual-responsive release, with accelerated PTX discharge in acidic environments and rapid on-demand release upon US irradiation. PTX-NBs showed excellent blood compatibility. In vivo fluorescence imaging demonstrated the pronounced accumulation of PTX-NBs at tumor sites after US irradiation, confirming effective US-mediated targeting. PTX-NB treatment significantly suppressed tumor growth compared with control and US-only treatments (achieving ~ 68.5% inhibition). This effect was further enhanced by US exposure, resulting in 85.8% tumor growth inhibition (P < 0.001 vs. control). Consistently, the combined PTX-NB and US treatment induced extensive tumor necrosis and an increase in apoptotic cells (P < 0.01 vs. control), accompanied with the upregulation of the proapoptotic markers Bax and Caspase-3 and downregulation of Bcl-2 and Ki67 at the transcriptional and protein levels.

Conclusion

Our study establishes PTX-NBs as a promising US-responsive delivery platform that alleviates physiological barriers to chemotherapeutic transport in a rabbit VX2 breast tumor model. By facilitating precise, externally controllable PTX release, this technology may serve as a basis for the further development of US‑guided breast cancer therapy in preclinical settings.