Page 76 - Read Online

Page 2 of 20 Choi et al. Cancer Drug Resist. 2026;9:12

field, we comprehensively review US-based glymphatic modulation research to date and identify their implications
and future opportunities for brain cancer applications.

INTRODUCTION
The “glymphatic” (“glia” plus “lymphatic”) system refers to the brain’s waste-clearance pathway, which
encompasses periarterial cerebrospinal fluid (CSF) influx, CSF–interstitial fluid (ISF) exchange, perivenous
CSF efflux, and final drainage through meningeal lymphatic vessels (mLV) [1-4] . CSF enters the brain
parenchyma via periarterial spaces, driven primarily by arterial pulsation and respiratory dynamics . It
[5-8]
then exchanges with ISF through aquaporin-4 (AQP4) water channels located on astrocytic endfeet
surrounding the cerebral vasculature [9-13] . This convective flux enables the removal of neurotoxic metabolites
- including amyloid-β, tau, and lactate - from the interstitial compartment [14-18] . Cleared solutes subsequently
migrate toward perivenous spaces and ultimately drain into the mLVs and systemic circulation [19-21] .
Understanding the dynamics of glymphatic transport has therefore become central to studies of brain waste
clearance and neurodegenerative disease mechanisms [22-24] .

Alongside this mechanistic understanding, there has been growing interest in exploiting the glymphatic
system as a therapeutic delivery route for brain diseases [25-27] . Intrathecal administration enables therapeutics
to enter the CSF, providing a complementary pathway to the classical blood-brain barrier (BBB) and
potentially improving delivery efficiency by bypassing BBB filtration [28-30] . However, glymphatic flow is
inherently passive, relying on convection generated by arterial pulsation, and its efficiency is substantially
diminished in pathological conditions such as Alzheimer’s disease, Parkinson’s disease, traumatic brain
injury, and cerebral small vessel disease. In brain tumors such as gliomas, reduced glymphatic transport has
been reported, correlating with clinical manifestations including brain edema and intracranial
hypertension [31,32] . Consequently, using the glymphatic pathway for chemotherapeutic delivery is
paradoxically limited in many brain disorders.

To achieve controlled upregulation of glymphatic flow, we review ultrasound (US)-based modulation studies
that have demonstrated significant augmentation of glymphatic transport, highlighting its potential as an
alternative drug-delivery pathway for brain diseases [Figure 1]. US modulation has been extensively studied
for its efficacy in reversible BBB opening, owing to its non-invasiveness, non-ionizing nature, and capability
for localized targeting [34-37] . Similar principles also apply to US-mediated glymphatic augmentation, which has
been observed under clinically relevant exposure levels and across various imaging modalities, from live
functional imaging to histological analysis [38,39] . While most glymphatic-focused studies have centered on
neuro-degenerative diseases such as Alzheimer’s disease, research on brain tumors remains at an early
stage [31,32] . Given the limited number of tumor-related reports, we broadly introduce US-based approaches for
augmenting glymphatic flow and discuss their implications for improving drug delivery to brain tumors.

THE GLYMPHATIC SYSTEM AS AN ALTERNATIVE DRUG DELIVERY ROUTE
Despite the severity of central nervous system diseases, including neurodegenerative disorders, stroke, and
cancer, therapeutic drug delivery into the brain remains physiologically challenging. Systemic drug delivery
is restricted by the BBB, which consists of tight junctions between vascular endothelial cells that block most
exogenous molecules and permit only a small fraction of lipophilic, low-molecular-weight compounds
(~0.4 kDa) . As a result, only minimal amounts of systemically administered drugs reach the brain
[40]
parenchyma, while most circulating drugs unintentionally accumulate in peripheral tissues. BBB-opening
techniques such as focused US can reversibly widen endothelial junctions to increase drug penetration, but
transport still relies on passive diffusion and remains limited by molecular size (approximately up to 70
kDa) .
[41]

69