Camptothecin-based Dendrimersome For Drug-Gene Combination Therapy: Template Design For Treatment of Drug-resistant Cancer Cells

Background: Despite significant advances in detection and therapy, cancer remain some of the leading causes of unnatural deaths due to poor response to available therapeutic modalities and drug resistance. To remediate, drug-gene combination therapy has the potential to provide a synergistic therapeutic effect, to overcome drug resistance while limiting the severe side effects. However, the lack of such smart delivery systems able to simultaneously carry anti-cancer drugs and nucleic acids and to selectively deliver them to cancer tissues without secondary effects still limits the application of this therapeutic strategy. Methods: Here, a pro-drug dendrimer have been successfully synthesized by conjugating the PEGylated positively charged generation 3-diaminobutyric polypropylenimine (DAB) dendrimer to the anti-cancer drug camptothecin with a redox-sensitive disulphide linkage (-S-S-),via in situ two-step reaction, and validated using various biophysical, analytical and in vitro functional assays as a tumor relevant redox-responsive nanocarrier to facilitate successful drug and gene combination therapy against cancer. Results: The amphiphilic prodrug-dendrimer was found to spontaneously self-assemble into cationic stable dendrimersomes in water(pH 7.4), where the drug forms vesicular bilayer with negative chirality and left-handed helical arrangement. The dendrimersome was not only able to release camptothecin at tumor-relevant intracellular higher redox conditions with the breakage of vesicle-structure, but also can condense DNA, leading to an enhanced cellular uptake of DNA and gene transfection in prostate cancer cells. Conclusions: Early promising in vitro results using such a novel redox-responsive drugdendrimer delivery system proved its potential as a template towards successful applications in drug-gene combination therapy against various cancers