Intrathecal Delivery of Nanoparticles for Treatment of Metastatic Medulloblastoma / Minsoo Khang.

9798837552007

[New Haven, Connecticut] : Yale University, 2022.

1 online resource (175 pages)

The morbidity associated with pediatric medulloblastoma, particularly in patients who develop leptomeningeal metastases, remains high in the absence of effective therapies. Administration of substances directly into the cerebrospinal fluid (CSF) is one approach to circumvent the blood brain barrier (BBB) and focus delivery of drugs to the site of tumor, but high rates of CSF turnover prevent adequate drug accumulation and lead to rapid systemic clearance and toxicity. Here, we show that the nanoparticle encapsulation of talazoparib (BMN-673) significantly improves the therapeutic index when delivered intrathecally and leads to sustained drug retention at tumor site. We demonstrate that administration of these particles into the CSF, alone or in combination with temozolomide, is a highly effective therapy leading to tumor regression and prevention of leptomeningeal spread in mouse models of medulloblastoma. These results provide a rationale for harnessing nanoparticles for the delivery of drugs limited by brain penetration and therapeutic index, and demonstrate important advantages in tolerability and efficacy for encapsulated drugs delivered locoregionally.

Proquest dissertation Dissertations & Theses @ Yale University.

Books / Online

English

April 21, 2023

Ph.D. Yale University 2022.

Academic theses.