Overview

Projects in the Sirianni Research Group are focused on the development and translation of novel therapeutics for the treatment of pediatric brain tumors. Our approach focuses on encapsulation of drugs within biocompatible and biodegradable nanoparticles, which serve as drug carriers to prolong drug action and target drug delivery to specific tissue sites. In the past, we have developed a number of novel approaches for engineering nanoparticle composition and surface properties to enable central nervous system drug delivery in adult brain cancer and neurodegeneration. More recently, we are focused on developing these systems for intrathecal and intraventricular drug delivery for treatment of brain tumors in children. These approaches are designed to target leptomeningeal metastasis, infiltrative disease, and residual tumor following surgical resection. We have also developed a number of tissue engineering models to study microenvironmental regulation of tumor growth, treatment resistance, and metastasis in the central nervous system. Our current efforts are focused on clinical translation of novel therapeutics.

 

Nanoparticle Engineering

We specialize in engineering polymeric nanoparticles for encapsulation and slow release of small molecules. Drug encapsulation provides a variety of delivery benefits for treatment of disease. Slow release ensures a reduced peak concentration and sustained exposure of cells or tissues to the therapeutic molecule, which often has the effect of reducing toxicity and enhancing drug efficacy. Nanoparticle properties can also be engineered to alter distribution of drug in the body. Targeted or compartmental drug delivery is an important approach for chemotherapeutics, especially, where off-target toxicity is a major limitation for effective therapy.

 

The majority of our published work has focused on poly(lactic-co-glycolic acid) (PLGA) and poly(lactic acid)-poly(ethylene glycol) systems, although more recent work in our group is focused on development of new biomaterials for drug delivery. We have developed several novel fabrication approaches to improve drug encapsulation or release via polymer blending, size fractionation, on-particle drug precipitation, and generation of double-walled systems. Much of our fabrication work is collaborative, whereby we provided fabrication expertise to facilitate testing of nanoparticles by other laboratories in novel biological systems.

 

Current nanoparticle engineering interests include the following

  • Nanoparticle engineering to optimize loading and release of small molecules

    • Specific focus: histone deacetylase inhibiting (HDACi) molecules

  • Nanoparticle engineering for improved drug delivery to the central nervous system

  • Nanoparticle engineering for compartmental or site-specific drug delivery

 

Drug Delivery in Pediatric Neuro-Oncology

 

Pediatric brain tumors experience a unique form of metastasis, spreading along the leptomeningeal surfaces of the brain and spinal cord. Once leptomeningeal metastasis (LM) occurs, prognosis for the patient is dismal. Chemotherapy is often ineffective, particularly in a recurrent setting, and metastases cannot be surgically resected. Radiation therapy can be effective, but it can also cause devastating damage to the developing brain.

 

To address this problem, we are developing innovative new approaches for delivering drugs to LM via intrathecal injection of drug loaded nanoparticles. Drug administration via the intrathecal route is an approach that is used widely in the clinic. However, drug distribution and clearance remain major obstacles: hydrophilic molecules turn over as cerebrospinal fluid (CSF) clears, and the tissue penetration of hydrophobic molecules is severely limited. These delivery problems have prevented development of intrathecal methods for treatment of disseminated cancer. We hypothesized that drug loaded nanoparticles could distribute through the subarachnoid space and deliver their encapsulated molecules to lesions that develop from infiltrative, recurrent, and metastatic tumors. Our preclinical studies confirm that this is in fact possible, and we are working collaboratively to bring these approaches into the clinic

 

Current projects in drug delivery to pediatric brain tumors include the following:

  • Collaboration with biological partners, including Dr. Robert Wechsler-Reya, to identify drugs of interest and optimize their delivery to metastatic tumors

  • Evaluation of efficacy, pharmacokineticd, pharmacodynamics, and toxicity of nanoparticles in patient derived and genetically engineered models

  • Development of manufacturing approaches to enable production of clinical grade nanoparticle systems and testing in large animal models

  • Collaboration with Dr. David Sandberg to develop new clinical trials at Children’s Memorial Herman

 

Imaging Nanoparticle Drug Delivery

It can be challenging to determine nanoparticle fate in the body. We have shown in published work that nanoparticle and payloads experience different fates in the body, which means that traditional methods for studying nanoparticle biodistribution with fluorescent small molecules yield results that can’t always be generalized to other payloads. The difficulty of tracking nanoparticle movement for direct, mechanistic assessment of drug delivery impediment to progress in the design of nanomedicine.

 

We are interested in understanding the mechanism by which nanoparticles traverse biological barriers in vivo. We are using a variety of novel imaging techniques to tease apart the differential fate of nanoparticle and encapsulated payload in biological systems, toward engineering nanoparticles to enhance localization of drug delivery to target cells and tissues.

Our approaches include the following:

  • Fluorescent, intravital microscopy for real-time imaging of nanoparticle movement within the subarachnoid space

  • Collaboration with Dr. Eva Sevick for quantitative imaging of nanoparticle delivery and clearance with Positron Emission Tomography (PET)

  • Collaboration with Dr. Nathalie Agar for quantitative imaging of the spatial distribution of drugs and polymers with Matrix Assisted Laser Desorption Ionization (MALDI)
     

 

Tissue Engineering Pediatric Neuro-Oncology

One of the major impediments to the development of novel therapies for intrathecal drug delivery is the difficulty of accessing the subarachnoid space in vivo. The membranes, or meninges, that surround the brain and spinal cord are called the pia mater, the arachnoid mater, and the dura mater. Cerebrospinal fluid (CSF) flows between the pia and arachnoid mater, which are known as the leptomeninges. Collagen-rich trabeculae span this space, providing structural support for the leptomeninges, anchoring nerves and blood vessels as they enter and exit the parenchyma, and playing a critical role in driving CSF mixing and flow. This space is the site through which tumors such as medulloblastoma are known to metastasize, and it is our goal to engineer nanoparticles for effective drug delivery to this tissue compartment.

 

To study the process of metastatsis and develop research tools that will enable us to better engineer nanoparticles for effective drug delivery, we are developing electrospun, tissue engineered mimics of the subarachnoid space. Because the subarachnoid space is difficult to access, very little is known about its structure across species or in disease. Thus, a major aspect of our work is focused on characterizing the structure of the subarachnoid space and understanding how CSF movement influences metasis and drug delivery

 

Current tissue engineering projects include the following:

  • Profiling trabeculae structure in humans and large animals

  • Electrospinning natural and synthetic polymers to mimic these structures

  • Studying metastasis as a function of microenvironmental cues

  • Development of flow models to evaluate nanoparticle delivery in subarachnoid mimics

(c) Rachael Sirianni. Content may not be used without permission

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