Summary: MIT researchers have engineered drug-loaded nanoparticles that cross the blood-brain barrier more effectively than conventional drugs. In a realistic human tissue model, these particles reached tumor tissue and killed glioblastoma cells.
Source: MIT
Glioblastoma is an aggressive brain cancer with limited treatment options and a high mortality rate. One major obstacle to effective therapy is the blood-brain barrier, a tightly regulated network of blood vessels that prevents most chemotherapy agents from reaching tumors within the brain.
A multidisciplinary team at MIT has developed surface-engineered nanoparticles that more effectively traverse the blood-brain barrier and deliver chemotherapy directly to tumor cells. Using a human tissue model that replicates key features of the brain’s vasculature and tumor microenvironment, the researchers demonstrated that targeted nanoparticles penetrate tumor-associated vessels and kill glioblastoma cells more selectively than untargeted drug formulations.
Many treatments that perform well in animal studies fail in clinical trials, highlighting the need for better preclinical models. Joelle Straehla, a clinical investigator at MIT’s Koch Institute and pediatric oncologist at Dana-Farber Cancer Institute, explains that more realistic tissue models could reduce the time and resources spent pursuing therapies that ultimately do not work in patients.
The study’s lead authors are Joelle Straehla and Cynthia Hajal, with senior authors Paula Hammond and Roger Kamm. The findings are published in the Proceedings of the National Academy of Sciences.
Modeling the blood-brain barrier
To simulate the blood-brain barrier, the team used a microfluidic platform that grows human brain microvessels around a central mass of patient-derived glioblastoma cells. The model incorporates endothelial cells, pericytes, and astrocytes to recreate the cellular interactions that control transport across the barrier. This system provides a human-relevant environment to study nanoparticle trafficking and drug delivery to brain tumors.
Layer-by-layer assembly, a technique pioneered in Paula Hammond’s laboratory, enables precise control over nanoparticle surface chemistry. For this study, the researchers applied a peptide coating called AP2 to the particle surface. Previous work suggested AP2 can enhance transport across the blood-brain barrier; the new tissue model allowed the team to observe how that peptide affects passage through vessel walls and entry into tumor cells.
When AP2-coated nanoparticles were introduced into the model, they penetrated the vessels surrounding tumor tissue far more effectively than uncoated particles or free drug. Transport of these particles was mediated by binding to the LRP1 receptor, which the team found to be more abundant in tumor-associated vasculature than in normal brain vessels. This receptor-mediated uptake helped the particles cross the barrier and reach tumor cells.
The researchers loaded the nanoparticles with cisplatin, a widely used chemotherapy agent. In the tissue model, AP2-targeted cisplatin nanoparticles produced greater tumor cell death than either free cisplatin or non-targeted particles. Importantly, the targeted particles caused less damage to healthy vasculature, indicating improved specificity for tumor tissue.
“We observed increased tumor cell death with peptide-targeted nanoparticles compared to bare particles or free drug,” says Cynthia Hajal. “The coating provided more selective killing of tumor cells while sparing healthy tissue.”
Validation in live animals and next steps
To validate the model’s predictions, the team tracked the nanoparticles in mice using intravital imaging through a specialized surgical microscope. The particles’ capacity to cross the blood-brain barrier in vivo closely matched the behavior observed in the human tissue model. In mice bearing glioblastoma tumors, AP2-coated cisplatin nanoparticles slowed tumor growth, although the effect was less pronounced than in the tissue model—possibly because the animal tumors were more advanced when treatment began.
Building on these results, the researchers plan to test additional drug cargos and nanoparticle formulations to identify combinations with the strongest therapeutic effect. They also intend to expand the tissue model to represent different brain tumor subtypes, including rare tumors that are difficult to study due to limited sample availability.
Straehla emphasizes the model’s potential for designing more effective, selective nanoparticle therapies: “This platform allows us to evaluate how different particles interact with human brain vasculature and tumors, so we can prioritize candidates most likely to succeed in patients.”
The methodology for creating the brain tissue model has been described in a Nature Protocols paper so that other laboratories can adopt and build on the approach.
Funding: The research received support from a Cooperative Agreement Award from the National Cancer Institute, a Horizon Award from the Department of Defense Peer Reviewed Cancer Research Program, a Cancer Research UK Brain Tumour Award, a Ludwig Center for Molecular Oncology Graduate Fellowship, the Rally Foundation for Childhood Cancer Research/The Truth 365, the Helen Gurley Brown Presidential Initiative, and the Koch Institute Support (core) Grant from the National Cancer Institute.
About this nanotech research news
Author: Anne Trafton
Source: MIT
Contact: Anne Trafton – MIT
Image: The image is credited to Cynthia Hajal and Roger D. Kamm (MIT), edited by Chris Straehla
Original Research: The findings appear in PNAS