98P - Cationic dendrimers as prospective vehicles of therapeutic nucleic acids into tumor cells: Approaches, advantages and challenges

Background

Challenges of nanomedicine in oncology require therapeutic tools to affect metabolic pathways in the target cells. Therapeutic nucleic acids (NAs) are promising instruments as siRNAs target them selectively, while microRNAs can reach several targets. However, oligonucleotides suffer from rapid nuclease degradation in biological media. Cationic dendrimers – highly symmetric hyperbranched molecules – can be efficient vehicles. In the current work we studied challenges of using polycationic phosphorus and carbosilane dendrimers and their complexes with oligonucleotides (dendriplexes).

Methods

Different tumor models were used: Jurkat (single-cells suspension culture in serum-containing media), BTSC233, JHH520, NCH644, GBM1 (glioblastoma cancer stem cells (GSCs) as neurospheres in serum-free medium), U87 (“standard” glioblastoma culture). Human PBMCs and iPSCs were used as non-tumor controls. We used miR-34, synthetic inhibitor of miR-21 and siRNA against LYN kinase (siLyn) as therapeutics. Such biological effects as internalization, cytotoxicity (incl. comparison to standard chemodrugs), apoptosis induction, expression of surface markers, related to interactions with immune microenvironment (PD-L1, TIM-3, CD47), LYN-expression were investigated.

Results

Dendrimers have their own cytotoxic effects on tumor cells, which are comparable or superior to standard chemodrugs; in some models the toxic effect on tumor cells was higher than on non-tumor cells. Moreover, GSCs showed higher sensitivity to molecules. Cationic dendrimers efficiently delivered NAs into tumor cells. Dendriplexes showed antitumor effects: decrease of cell viability, apoptosis induction. Dendrimers and dendriplexes affected the expression of PD-L1 and TIM-3, which could be a sign of cell stress. siLyn-dendriplexes decreased tumor cell viability but did not change significantly LYN expression. Patterns of changes strongly depended on the cell type and cultivation mode.

Conclusions

We showed promising antitumor activity of cationic dendrimers and their complexes with therapeutic NAs. However, further investigations of the impact of different cell type and model features in view of pre-clinical testing is to be performed.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

European Cooperation in Science and Technology CA17140.

Disclosure

All authors have declared no conflicts of interest.