Targeted Delivery of Highly Toxic Anti-Cancer Drug to Brain Tumors

Summary: Researchers have developed a Dp44mT nano-carrier that can directly target glioblastoma and other brain cancer cells.

Source: University of Houston

With a survival rate of only five years, the most common and aggressive form of primary brain tumor, glioblastoma multiforme, is notoriously hard to treat using current regimens that rely on surgery, radiation, chemotherapy and their combinations.

“Two of the major challenges in the treatment of gliomas include poor transport of chemotherapeutics across the blood brain barrier and undesired side effects of these therapeutics on healthy tissues,” said Sheereen Majd, assistant professor of biomedical engineering at the University of Houston. “To get enough medicine across the blood brain barrier, a high dosage of medication is required, but that introduces more toxicity into the body and can cause more problems.”

In an article published and featured on the cover of a January issue of Advanced Healthcare Materials, Majd reports a new glioma-targeted nano-therapeutic that will only address tumor cells offering increased effectiveness and reduced side effects.

An iron chelator known as Dp44mT (Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone) is an effective medication known to inhibit the progression of tumors but had not been used against brain tumors prior to this study. The chelator works to pull out the overabundance of iron needed by cancer cells, thus starving them.

Using clues from the tumors themselves, Majd developed a Dp44mT-loaded nano-carrier that would be drawn to glioma tumors, which present many IL13 (Interluken) receptors. Because the IL13 receptors are abundant, she added IL13 ligands onto her FDA-approved biodegradable polymer carrier (with the Dp44mT inside) so the receptors would lure the ligands, thus receiving the medicine.

This shows a finger touching a picture of a brain
The chelator works to pull out the overabundance of iron needed by cancer cells, thus starving them. Image is in the public domain

Prior to her new carrier, the Dp44mT drug would be administered, but could go anywhere in the body, even places it is not meant to go.

“It’s like an envelope with no address on it. It can land anywhere, and with toxins inside it could kill anything. Now, with our targeted delivery, we put an address on the package and it goes directly to the cancer cells,” said Majd.

Aggressive brain tumors also develop high levels of multidrug resistance making them nearly impervious to common chemotherapeutics such as temozolomide or doxorubicin. “There is, hence, an urgent need for more effective therapeutic formulations with the ability to overcome drug resistance in aggressive glioma tumors and to kill these malignant cells without damaging the healthy tissues,” reports Majd.

Majd’s study, which tested the nano-therapeutic both in vivo and in vitro, is the first report on targeted delivery of Dp44mT to malignant tumors.

About this brain cancer research

Source: University of Houston
Contact: Laurie Fickman – University of Houston
Image: The image is in the public domain

Original Research: Closed access.
Tumor Targeted Delivery of an Anti‐Cancer Therapeutic: An In Vitro and In Vivo Evaluation” by Majd et al. Advanced Healthcare Materials


Tumor Targeted Delivery of an Anti‐Cancer Therapeutic: An In Vitro and In Vivo Evaluation

The limited effectiveness of current therapeutics against malignant brain gliomas has led to an urgent need for development of new formulations against these tumors. Chelator Dp44mT (di‐2‐pyridylketone‐4,4‐dimethyl‐3‐thiosemicarbazone) presents a promising candidate to defeat gliomas due to its exceptional anti‐tumor activity and its unique ability to overcome multidrug resistance.

The goal of this study is to develop a targeted nano‐carrier for Dp44mT delivery to glioma tumors and to assess its therapeutic efficacy in vitro and in vivo. Dp44mT is loaded into poly(ethylene glycol) (PEG)ylated poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles (NPs) decorated with glioma‐targeting ligand Interlukin 13 (IL13). IL13‐conjugation enhanced the NP uptake by glioma cells and also improved their transport across an in vitro blood‐brain‐barrier (BBB) model.

This targeted formulation showed an outstanding toxicity towards glioma cell lines and patient‐derived stem cells in vitro, with IC50 values less than 125 nM, and caused no significant death in healthy brain microvascular endothelial cells. In vivo, when tested on a xenograft mouse model, IL13‐conjugated Dp44mT‐NPs reduced the glioma tumor growth by ≈62% while their untargeted counterparts reduced the tumor growth by only ≈16%.

Notably, this formulation does not cause any significant weight loss or kidney/liver toxicity in mice, demonstrating its great therapeutic potential.

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