Charged dendrimers reduce glioblastoma viability by modulating lysosomal activity and HMGB1-RAGE interaction
Natali Joma1, Marten Kagelmacher2, Issan Zhang1
1Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada.
Abstract:
Dendrimers and dendrimer-based self-assembly systems have emerged as promising nanocarriers for a variety of applications, including anti-cancer therapies, modulation of the tumor microenvironment, and imaging. Here, we explored the therapeutic potential of two charged dendrimers, dendritic polyglycerol sulfate (dPGS) and dendritic polyglycerol amine (dPGA), in the context of glioblastoma multiforme (GBM). Docosahexaenoic acid (DHA) has shown potential in GBM. We therefore examined dPGS and dPGA effects alone and in combination with DHA. Using 2D cell models and 3D tumoroids, we showed that DHA with dPGA reduced tumor integrity and cell viability. dPGS reduced oxidative stress, whereas dPGA reduced lysosomal acidification, contributing to cellular dysfunction. Both dendrimers influence the interaction between high mobility group box 1 (HMGB1) and the receptor for advanced glycation end products (RAGE). The surfaces of the HMGB1-RAGE complex provide binding sites for interactions of charged molecules like dPGS and dPGA, suggesting the contribution of these interactions to cytotoxicity. In summary, our findings show that combining DHA with charged dendrimers (dPGS and dPGA) enhances GBM cytotoxicity through several mechanisms, involving lysosomal alkalinization, lipid peroxidation and modulation of the HMGB1-RAGE complex.
Insights
Charged dendrimers, dendritic polyglycerol sulfate (dPGS) and dendritic polyglycerol amine (dPGA), combined with docosahexaenoic acid (DHA) show enhanced glioblastoma multiforme (GBM) cytotoxicity through multiple mechanisms.
Area of Science:
- Nanomedicine
- Cancer Biology
- Biochemistry
Background:
- Dendrimers are versatile nanocarriers with potential in anti-cancer therapies.
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options.
- Docosahexaenoic acid (DHA) has demonstrated therapeutic promise against GBM.
Purpose of the Study:
- To investigate the therapeutic potential of charged dendrimers, dendritic polyglycerol sulfate (dPGS) and dendritic polyglycerol amine (dPGA), in GBM.
- To evaluate the combined effects of dPGS and dPGA with DHA on GBM models.
Main Methods:
- Utilized 2D cell cultures and 3D tumoroid models of GBM.
- Assessed the impact of dPGS, dPGA, and DHA on tumor integrity, cell viability, oxidative stress, and lysosomal acidification.
- Investigated the interaction between high mobility group box 1 (HMGB1) and the receptor for advanced glycation end products (RAGE).
Main Results:
- DHA combined with dPGA significantly reduced GBM tumor integrity and cell viability.
- dPGS mitigated oxidative stress, while dPGA reduced lysosomal acidification, leading to cellular dysfunction.
- Both dendrimers modulated the HMGB1-RAGE complex interaction, contributing to enhanced cytotoxicity.
Conclusions:
- Combining DHA with charged dendrimers (dPGS and dPGA) potentiates GBM cytotoxicity.
- The enhanced anti-GBM effects involve lysosomal alkalinization, lipid peroxidation, and modulation of the HMGB1-RAGE pathway.
