# Image-guided, ultrasound-enhanced long-term intracranial drug delivery

> **NIH NIH R21** · NORTH CAROLINA STATE UNIVERSITY RALEIGH · 2020 · $167,930

## Abstract

PROJECT SUMMARY
 The blood-brain barrier (BBB) serves as the major hindrance to efficient transport of life-saving therapeutics
to the brain. Image-guided focused ultrasound can disrupt the BBB, but only temporarily and for a short period
of time. Local implantation of drug-eluting depots is another option, but these are single-use systems that cannot
be refilled or reused after implantation at inaccessible sites, limiting their clinical utility. Recently, we introduced
click-modified refillable drug depots: injectable depots that capture prodrug refills from systemic circulation and
release active drugs locally in a sustained manner. Capture of systemically-administered refills serves as an
efficient and non-toxic method to repeatedly refill depots. Refillable depots in combination with prodrug refills
achieve sustained release at tumor sites to improve cancer therapy while eliminating systemic side effects.
Refillable depots have been successful in subcutaneous models of tumor recurrence, preventing tumor growth
while eliminating systemic side effects. Unfortunately, the prodrug refills do not cross the BBB and thus refillable
depots cannot be used alone in brain diseases such as stroke, degenerative disorders and brain cancers.
 We now propose refilling intracranial drug depots through the combination of non-toxic therapeutic
prodrugs and image-guided transient disruption of the blood brain barrier. BBB disruption with focused-
ultrasound provide a transient (~1 hour) window for the refilling of intracranial depots. The use of nontoxic
prodrug refills allows us to administer large doses to maximally exploit the short window for drug delivery,
allowing weeks and potentially months worth of therapeutic to be given in the short time window. After BBB
reformation, the intracranial depots will release active drugs for a long period of time before being non-invasively
refilled again. We further propose testing this innovative drug-delivery strategy in a patient-derived orthotopic
GBM tumor model.
 This innovative combination of these two promising new technologies provides an approach to present
therapeutic agents over a long period of time directly to the brain. Our efforts will further develop this promising
approach, optimize parameters, and validate efficacy in preclinical studies. Clinical applications include the local
release of chemotherapeutics, biologics and immunotherapy agents against GBM and other brain cancers, and
administration of regenerative and immunosuppressive agents after stroke. If successful, the improvements
made to this very innovative drug delivery strategy could open the pathway to clinical translation of refillable drug
delivery technology.

## Key facts

- **NIH application ID:** 9884240
- **Project number:** 1R21CA246414-01
- **Recipient organization:** NORTH CAROLINA STATE UNIVERSITY RALEIGH
- **Principal Investigator:** Yevgeny Brudno
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $167,930
- **Award type:** 1
- **Project period:** 2020-02-15 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9884240

## Citation

> US National Institutes of Health, RePORTER application 9884240, Image-guided, ultrasound-enhanced long-term intracranial drug delivery (1R21CA246414-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9884240. Licensed CC0.

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