summary: In a recent study, scientists found high levels of LDL receptors (LDLR) in the blood vessels that feed high-grade glioma brain tumors. The study found that using drug-containing nanoparticle-based therapies that target these receptors could be a new way to treat cancer. Glioma is the most common primary brain tumor and has a poor prognosis due to its highly aggressive nature, with a median survival of only 4.6 months without treatment and approximately 14 months with optimal multimodality therapy. It’s the moon. This research may pave the way for treating glioma brain tumors with nanoparticle-based therapies that target the LDL receptor, thereby shutting off the cancer cell’s energy supply.
sauce: University of Nottingham
New research shows that there are receptors on blood vessels that feed aggressive brain tumors. This could lead to other disruptions, using new types of drug-laden nanoparticles to deprive tumors of the energy they use to grow and spread. Adapted beings, even suicidal.
Scientists at the Universities of Nottingham and Duke have found that many of the blood vessels that feed high-grade glioma brain tumors have high levels of low-density lipoprotein (LDL) receptors (LDLR). This finding paves the way for drugs already in development at both institutions that target these receptors and have the potential to be taken up by tumors.
The result is pharmacy.
Glioma is the most common primary brain tumor and originates from glial cells in the brain. They are a heterogeneous spectrum, from slow-growing to highly aggressive invasive tumors.
Nearly half of all gliomas are classified as high-grade gliomas (HGG) and due to their highly aggressive nature, the median survival without treatment is only 4.6 months, today’s optimal Combined modality treatment has a dismal prognosis of approximately 14 months.
The researchers examined tissue microarrays of intratumoral and intertumoral regions in 36 adult and 133 pediatric patients to confirm that LDLR is a therapeutic target. We also tested expression levels in three representative cell line models to confirm their future utility for testing the uptake, retention and cytotoxicity of LDLR-targeted nanoparticles.
They showed widespread LDLR expression in adult and pediatric cohorts and, importantly, also classified the intratumoral variation observed between core and rim or infiltrating regions of adult high-grade gliomas.
Ruman Rahman, Ph.D., of the University of Nottingham School of Medicine, led the study. When used in clinical therapeutic tests, many tumors are unable to cross the underlying blood-brain barrier. Therefore, it is important to look for new ways to treat them.
These findings are an important step in understanding tumor biology and how tumors harvest energy to grow and spread from the body’s own fat- and protein-containing lipoprotein particles. It’s a step. The key now is to use nanoparticles of drugs and prodrugs to target these receptors and cut off the energy supply of cancer cells. “
David Needham, Professor of Translational Therapeutics at the University of Nottingham School of Pharmacy and Professor of Mechanical Engineering and Materials Science at Duke University, is developing new, more clinically effective formulations of a common metabolic inhibitor (niclosamide). I have been working on the development. It blocks cellular energy and may be modified as a treatment for many diseases, including cancer.
In its original antiparasitic use, niclosamide has been used as an oral tablet for over 60 years to kill tapeworms in the gut by inhibiting key metabolic pathways and cutting off energy supplies.
This same ability to lower intracellular energy supplies has shown that niclosamide can also lower the energy required for viruses to replicate Another formulation we are developing as a spray and early treatment throat spray) for viral infections.
For spraying, Needham devised a method to increase the solubility of niclosamide in a simple pH buffer (Needham 2022, Needham 2023). However, niclosamide’s low water solubility makes it very difficult to use elsewhere, such as for intravenous (iv) injection or infusion.
Niclosamide has been investigated as a potential cancer treatment for many years, driving research in this area, said co-author of the study, Professor Needham. Like your nose, it lowers the dimmer switch of host cells in your body as a preventive against COVID19 and other infections.
“Cancer has a very different metabolic process than normal cells because it is thought that they have developed additional strategies to survive. However, it also triggers other processes within the cell that lead to so-called apoptosis (self-killing).
“And now we know that brain tumors have LDL receptors, which are thought to be used to drive their growth and spread of metastases. Given that cancer feeds on LDLS, our strategy is Make medicine look like cancer food. ”
Professor Needham and his team at Duke University turned this common low-solubility drug (commonly called ‘brick dust’) into an even less soluble ‘brick dust’ for the express purpose of creating pure prodrug nanoparticles. Developed “Bricks to Rocks Technology” (B2RT) to make “rocks”. .
They transformed niclosamide into a new sparingly soluble (niclosamide stearate) prodrug that allows the formation of injectable or implantable nanoparticles. We have already obtained data that the so-called ‘niclosamide stearate prodrug treatment’ (NSPT) can stop the formation of lung metastases in mouse models of osteosarcoma (Reddy, Kerr et al. 2020). It can actually cure some dogs. Small dog feasibility study (Eward, Needham et al. 2023).
Professor Needham continues:
“The next step is to test B2RT with Luhmann and colleagues in animal models, especially in brain tumor cells, and if it shows promise, introduce it into patients as quickly and safely as possible. would like to investigate whether and to what extent LDLR-targeted anticancer drugs and prodrug nanoparticles act as intravenous injections and/or post-surgical deposits on brain tumors.”
Such LDLR-targeted nanoparticles have already been developed as viable formulations by another pharmacy researcher, Jonathan Burley, and his recent Ph.D. was shown to improve the uptake of
Professor Needham adds: We would love to hear from anyone who thinks we can help them further test and develop this new technology. “
See also
A summary generated with the help of Chat GPT AI technology
About this Brain Tumor Research News
author: Jane Ike
sauce: University of Nottingham
contact: Jane Ike – University of Nottingham
image: image is public domain
Original research: open access.
“The low-density lipoprotein pathway is a ubiquitous metabolic vulnerability in high-grade gliomas suitable for nanotherapeutic delivery” by David Needham et al. pharmacy
overview
The low-density lipoprotein pathway is a ubiquitous metabolic vulnerability in high-grade gliomas suitable for nanotherapeutic delivery
Metabolic reprogramming through increased cholesterol uptake in the form of low-density lipoproteins (LDL) is one way cancer cells, including high-grade glioma (HGG), sustain rapid growth.
In this study, immunohistochemistry was used to determine LDL receptor (LDLR) expression in HGG on tissue microarrays from intratumoral and intertumoral regions of 36 adult and 133 pediatric patients, and LDLR was treated with Confirmed to be the target.
In addition, we analyzed expression levels in three representative cell line models to confirm their future utility for testing the uptake, retention and cytotoxicity of LDLR-targeted nanoparticles.
Our data demonstrate widespread LDLR expression in adult and pediatric cohorts, although significant intratumor variation has been observed between core and rim or infiltrated regions of adult HGG.
Expression was independent of childhood tumor grade or identified clinicopathologic factors. LDLR-expressing tumor cells were preferentially localized within the perivascular niche, with significant intratumor variability in adults. All cell lines demonstrated varying levels of LDLR expression, confirming their suitability as a model for testing the delivery of LDLR-targeted nanotherapy.
Overall, our study reveals that the LDLR pathway is a ubiquitous metabolic vulnerability in high-grade gliomas of all ages, potentially circumventing tumor heterogeneity. suitable for future investigation of LDL-mediated nanoparticle/drug delivery.
