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Beyin Kanseri Tedavisi İllüstrasyonu

Bilim adamları, yüksek dereceli glioma beyin tümörlerini besleyen kan damarlarında yüksek seviyelerde LDL reseptörleri keşfettiler. Bu bulgular, şu anda geliştirilmekte olan ilaçların bu reseptörleri hedeflemek ve tümörlere saldırmak için kullanılmasına kapı açıyor.

Yeni bulgular, agresif beyin tümörlerini besleyen kan damarlarının, yeni bir tür ilaç salan nanopartikül tarafından hedeflenebilen reseptörler içerdiğini göstermektedir. Bu parçacıklar, tümörün enerji beslemesini etkili bir şekilde kesebilir, büyümesini ve yayılmasını engelleyebilir ve ayrıca uyarlanmış varoluşunda başka bozulmalara, hatta kendi kendini öldürmesine neden olabilir.

Nottingham Üniversitesi ve Duke Üniversitesi’nden araştırmacılar, yüksek dereceli glioma beyin tümörlerini besleyen kan damarlarında yüksek seviyelerde Düşük Yoğunluklu Lipoprotein (LDL) reseptörleri (LDLR) ortaya çıkardılar. Bu keşif, her iki kurumda hâlihazırda geliştirilmekte olan ilaçların bu reseptörleri hedeflemek için kullanılması ve böylece ilaçların tümörler tarafından alınmasına izin verilmesi olasılığının önünü açmaktadır.

Bulgular yakın zamanda dergide yayınlandı Eczacılık.

Gliomalar en yaygın primer beyin tümörleridir ve beynin glial hücrelerinden kaynaklanır. Yavaş büyüyenden çok agresif infiltre tümörlere kadar heterojen bir spektrumdur. Tüm Glioma’ların yaklaşık yarısı yüksek dereceli gliomalar (HGG) olarak sınıflandırılır ve oldukça agresif yapıları nedeniyle, tedavisiz ortalama hayatta kalma süresi yalnızca 4,6 ay ve günümüzün optimal multimodal tedavileri ile yaklaşık 14 ay olan kötü bir prognoza sahiptir.

Araştırmacılar, LDLR’yi terapötik bir hedef olarak doğrulamak için 36 yetişkin ve 133 pediatrik hastanın tümör içi ve tümörler arası bölgelerinden alınan doku mikrodizilerini incelediler. Üç temsili hücre hattı modelindeki ifade seviyeleri, LDLR hedefli nanopartikül alımını, tutulmasını ve sitotoksisiteyi test etmek için gelecekteki faydalarını doğrulamak için de test edildi. Yetişkin ve pediatrik kohortlarda yaygın LDLR ekspresyonu gösterdiler ve daha da önemlisi, yetişkin Yüksek Dereceli Gliomalar’ın çekirdek ile kenar veya invaziv bölgeleri arasında gözlemlenen tümör içi varyasyonu da kategorize ettiler.

Ruman Rahman[{” attribute=””>University of Nottingham’s School of Medicine led the study and said: “Brain tumors can be very hard to treat with the current techniques available, this is because many of the drugs or nanoparticles that have been shown to work in cells, when used in tests of clinical treatments cannot penetrate the blood-brain barrier that many tumors sit behind. So, it’s vital we look for new ways to treat them. These findings are a significant step in understanding the biology of tumors and how they gather energy to grow and spread from the body’s own fat and protein-containing lipoprotein particles. The key now is to use drug and prodrug nanoparticles to target these receptors and cut off the energy supply of the cancer cells.”

David Needham, Professor of Translational Therapeutics in the School of Pharmacy at the University of Nottingham and Professor of Mechanical Engineering and Materials Science at Duke University has been working on developing new, more clinically-effective, formulations of a common metabolic inhibitor (niclosamide) that cuts off the energy of cells and could be modified as a treatment for a number of diseases – including cancer.

In its original anti-parasitic application, niclosamide has been used for over 60 years, taken as oral tablets, killing tapeworms on contact in the gut by inhibiting their crucial metabolic pathway and shutting down their energy supply. This same ability to lower the energy supply in a cell, has shown that niclosamide can also reduce the energy a virus needs to replicate (another formulation Needham has recently been developing as a nasal spray and early treatment throat spray for COVID-19 and other respiratory virus infections. For the sprays, Needham figured out how to increase the solubility of niclosamide in simple pH-buffered solutions (Needham 2022, Needham 2023). However, niclosamide’s poor solubility in water makes it very difficult to use elsewhere, such as in an intravenous (i.v.) injection or infusion.

Professor Needham, who has been investigating this drug as a possible treatment for cancer for a number of years and has been driving research in this area and is a co-author on this study, said: “We know that niclosamide works by turning down the dimmer switch on host cells in the body, like in the nose as a preventative for COVID19 and other infections. Cancers’ though have developed additional strategies to survive and so have very different metabolic processes than normal cells. Niclosamide targets not only the energy production in the cells but also triggers other processes that result in what is called, Apoptosis, (self-killing) in the cells.”

He continues, “And now we know that brain tumors have LDL receptors that we think are used to feed their growth and metastatic spread we can work to modify the drug to target these and starve the cancer cells of their energy. Given that cancers feed on LDLS our strategy is to make the drug look like the cancer’s food.”

Professor Needham and the team at Duke have developed the “Bricks to Rocks Technology” (B2RT) that makes this common low solubility drug (commonly called “brick dust”) into even less soluble “rocks” for the expressed purpose of making pure prodrug nanoparticles. They converted niclosamide into a new less soluble (niclosamide stearate) prodrug that allows the formation of the injectable or implantable nanoparticles.

With data already obtained showing that the, so-called “niclosamide stearate prodrug therapeutic” (NSPT) can stop the formation of lung metastases in a mouse model of Osteosarcoma (Reddy, Kerr et al. 2020), and also actually cure some dogs in a small canine feasibility study (Eward, Needham et al. 2023).

Professor Needham continues: “This technology is now ready to be applied in other cancers, and Nottingham is ideally placed to develop this with the expertise at the Children’s Brain Tumour Research Centre. The next step will be to test the B2RT with Ruman and colleagues specifically in brain tumor cells, animal models and, if it shows promise, move it into patients as fast as feasibly and safely as possible. We want to determine if and to what extent LDLR-targeted anti-cancer drug and prodrug nanoparticles can have activity in brain cancer, both injected intravenously and/or as post-surgical deposits.”

Such LDLR-targeted nanoparticles have already been developed as a feasible formulation by another School of Pharmacy researcher, Jonathan Burley, and his recent Ph.D. graduate George Bebawy who showed that they improved tumor cell uptake.

Professor Needham adds: “We are now actively seeking industry and also government and infectious disease institute partners to help pursue preclinical and eventually clinical trials. We’re keen to hear from anyone who thinks they can help to further the testing and development of this new technology.”

Reference: “Low-Density Lipoprotein Pathway Is a Ubiquitous Metabolic Vulnerability in High Grade Glioma Amenable for Nanotherapeutic Delivery” by Adenike O. Adekeye, David Needham and Ruman Rahman, 10 February 2023, Pharmaceutics.
DOI: 10.3390/pharmaceutics15020599

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