Low-intensity pulsed ultrasound combined with microbubbles enhances amphotericin B delivery across the blood-brain barrier for improved therapy of cryptococcal meningitis

  • Drug Deliv. 2026 Dec 31;33(1):2677305. doi: 10.1080/10717544.2026.2677305.
Junyu Liu  1 ,  Zhengtu Li  2 ,  Dongcheng Li  1 ,  Jia Liu  1 ,  Yutian Su  2 ,  Yifei Leng  3 ,  Yongming Li  2 ,  Li Xu  1 ,  Lan Sun  2 ,  Xiaohong Su  1 ,  Xiaotong Li  2 ,  Changyong Tang  1 ,  Ying Jiang  1 ,  Xintao Shuai  4 ,  Fuhua Peng  1
Affiliations
  • 1. Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 2. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 3. Department of Medical Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) imaging, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 4. Nanomedicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
PMID: 42241274 DOI: 10.1080/10717544.2026.2677305
Abstract

Cryptococcal meningitis (CM), a life-threatening fungal Infection of the central nervous system, faces therapeutic challenges due to poor blood‒brain barrier (BBB) penetration of amphotericin B. This study investigates the efficacy of low-intensity pulsed ultrasound (LIPUS) combined with microbubbles in enhancing BBB permeability and improving prognosis in a murine CM model. Our findings suggest that LIPUS combined with microbubbles treatment significantly increased BBB permeability, leading to elevated cerebral concentrations of amphotericin B and improved fungicidal activity against Cryptococcus neoformans in the brain. Mechanistic investigations revealed that LIPUS-microbubble treatment transiently upregulated vascular endothelial growth factor (VEGF) expression levels in cerebral tissues. Notably, these protein expression alterations and the associated BBB permeability enhancement completely normalized within 6 hours post-treatment. Pharmacological inhibition of VEGF abolished the ultrasound-induced BBB permeability increase, indicating that VEGF may serve as a pivotal upstream regulator mediating this transient barrier modulation. Compared with amphotericin B monotherapy, the combined regimen of LIPUS plus microbubbles and amphotericin B achieved a greater reduction in cerebral cryptococcal burden. The India ink staining revealed reduced cryptococcal capsule thickness and smaller yeast cell diameters in treated mice. Furthermore, the intervention ameliorated CM-associated clinical manifestations, including weight loss and neurological deficits, while prolonging survival time. These results suggest the potential of LIPUS-microbubble-mediated BBB modulation as a promising adjunctive strategy to optimize amphotericin B delivery and improve therapeutic efficacy in CM, offering new insights into overcoming the limitations of conventional treatments for neurotropic Fungal infections.

Keywords
Amphotericin B; blood–brain barrier; cryptococcal meningitis; low-intensity pulsed ultrasound; microbubbles.
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