Gliomas are the most common malignant human brain tumors. Even when treated with surgery,
radiotherapy, and chemotherapy, patients with the most commonly diagnosed glioma, grade IV glioblastoma
(GB), have a life expectancy of only 14 months. The primary challenge to treating GB is its highly invasive nature,
as infiltrating cancer cells are “protected” from exposure to systemically administered chemotherapies by the
blood brain barrier (BBB). Here, we propose the development of a therapeutic approach for GB that couples
non-invasive BBB opening via the activation of intravascular microbubbles (MBs) with MRI-guided focused
ultrasound (FUS) and biodegradable [polyaspartic acid-polyethyleneglycol (PAA-PEG)], cisplatin (CDDP)-
loaded, “brain-penetrating nanoparticles”. We have previously demonstrated the efficacy of “first-generation”
CDDP-BPN agents, the ability of FUS to precisely target the delivery of BPN across the BBB to MR image-
selected targets in the brain, and the delivery of CDDP-BPN to gliomas.
Here, we propose four specific aims designed to markedly improve the therapeutic efficacy of the
approach and advance it to clinical trials. In Aim 1, we will engineer a “next-generation” CDDP-BPN for
formulation specifically for systemic administration and FUS-targeted delivery. In parallel, Aims 2 and 3 will be
to markedly augment BPN delivery to invasive gliomas via novel, clinically-operable, modifications to FUS
application protocols. These will include extending treatment volumes based on MRI guidance, testing the
concept of “site-selective” acoustic emissions feedback during BBB opening, and evaluating newly identified
FUS “pre-conditioning” pulse sequences for their ability to increase BPN penetration. Of note, an innovative new
MR image-guided transport analysis of tumor interstitial flow and diffusion will be employed in Aims 2 and 3 to
directly ascertain how FUS modulates the tumor microenvironment to facilitate CDDP-BPN spread though the
treatment volume. Aim 4 will then start by establishing the maximum tolerated dose (MTD) of CDDP-BPN and
assessing cisplatin levels in gliomas after CDDP-BPN delivery using optimized FUS protocols. Next, we will test
whether combining next-generation CDDP-BPN with novel FUS protocols for augmented BPN delivery will
control tumor growth, block infiltration, and improve survival. Importantly, we are about to open a clinical trial at
UVA wherein MR image-guided FUS (Insightec Exablate Neuro System) will be used with MBs to open the BBB
and deliver chemotherapy on a weekly basis to GB patients after they have undergone surgical resection and
radiation. Moreover, MPI Hanes has deep experience with advancing controlled-release formulations for drug
delivery to clinical trials. Thus, a clear precedent has been set for translation. Given our infrastructure and
expertise, we are exceptionally well-positioned to translate successful findings to the clinic.
