Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma.

The morbidity associated with pediatric medulloblastoma, in particular 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 and focus delivery of drugs to the site of tumor. However, high rates of CSF turnover prevent adequate drug accumulation and lead to rapid systemic clearance and toxicity. Here, we show that PLA-HPG nanoparticles, made with a single-emulsion, solvent evaporation process, can encapsulate talazoparib, a PARP inhibitor (BMN-673). These degradable polymer nanoparticles improve the therapeutic index when delivered intrathecally and lead to sustained drug retention in the tumor as measured with PET imaging and fluorescence microscopy. We demonstrate that administration of these particles into the CSF, alone or in combination with systemically administered temozolomide, is a highly effective therapy for tumor regression and prevention of leptomeningeal spread in xenograft 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.

Manufacturing innovation to drive down cell therapy costs.

Chimeric antigen receptor T cells (CAR-T) have demonstrated their potential to revolutionize cancer treatment. However, manufacturing remains a challenge. Multiple manufacturing innovations [e.g., vector and gene engineering, process improvements, hardware innovation, digital innovation, and point-of-care (POC) manufacturing] have the potential to help realize the full potential of CAR-T therapies.

Intrathecal delivery and its applications in leptomeningeal disease.

Intrathecal delivery (IT) of opiates into the cerebrospinal fluid (CSF) for anesthesia and pain relief has been used clinically for decades, but this relatively straightforward approach of bypassing the blood-brain barrier has been underutilized for other indications because of its lack of utility in delivering small lipid-soluble drugs. However, emerging evidence suggests that IT drug delivery be an efficacious strategy for the treatment of cancers in which there is leptomeningeal spread of disease. In this review, we discuss CSF flow dynamics and CSF clearance pathways in the context of intrathecal delivery. We discuss human and animal studies of several new classes of therapeutic agents-cellular, protein, nucleic acid, and nanoparticle-based small molecules-that may benefit from IT delivery. The complexity of the CSF compartment presents several key challenges in predicting biodistribution of IT-delivered drugs. New approaches and strategies are needed that can overcome the high rates of turnover in the CSF to reach specific tissues or cellular targets.

Tuning protein half-life in mouse using sequence-defined biopolymers functionalized with lipids.

The use of biologics in the treatment of numerous diseases has increased steadily over the past decade due to their high specificities, low toxicity, and limited side effects. Despite this success, peptide- and protein-based drugs are limited by short half-lives and immunogenicity. To address these challenges, we use a genomically recoded organism to produce genetically encoded elastin-like polypeptide-protein fusions containing multiple instances of para-azidophenylalanine (pAzF). Precise lipidation of these pAzF residues generated a set of sequence-defined synthetic biopolymers with programmable binding affinity to albumin without ablating the activity of model fusion proteins, and with tunable blood serum half-lives spanning 5 to 94% of albumin's half-life in a mouse model. Our findings present a proof of concept for the use of genetically encoded bioorthogonal conjugation sites for multisite lipidation to tune protein stability in mouse serum. This work establishes a programmable approach to extend and tune the half-life of protein or peptide therapeutics and a technical foundation to produce functionalized biopolymers endowed with programmable chemical and biophysical properties with broad applications in medicine, materials science, and biotechnology.