Poly-glutamic dendrimer-based conjugates for cancer vaccination - a computational design for targeted delivery of antigens

Computational techniques are useful to predict interaction models and molecular properties for the design of drug delivery systems, such as dendrimers. Dendrimers are hyperbranched macromolecules with repetitive building blocks, defined architecture and functionality. This work evaluated the impact of surface modifications of mannosamine-conjugated multifunctional poly (glutamic acid) (PG)-dendrimers as nanocarriers of the tumor associated antigens (TAA) MART-1, gp100:44 and gp100:209. Their potential to target antigen presenting cells through molecular interactions with mannose receptor (MR1) to promote an efficient and selective antitumor immunotherapeutic effect was also evaluated.
Molecular dynamics (MD) simulations and docking studies were performed. Results showed that nitrobenzoxadiazole (NBD)-PG-G4-dendrimer displayed 64 carboxylic groups, however the frontier molecular orbital theory study has indicated that only 32 of those carboxylic groups present on the backbone were available to form covalent bonds with either mannosamine or TAA. No differences in the gap energy of HOMO of conjugated NBD-PG-G4-dendrimer and LUMO of conjugating agents were observed while increasing conjugation loading. When the number of mannosamines conjugated to dendrimer was increased from 16 to 32, the conjugated dendrimer interacted with the receptor with higher affinity. However, due to absence of available carboxylic end groups of backbone chain for further conjugation in a dendrimer with 32 mannosamine, the 16 mannosamines-NBD-PG-G4-dendrimer was chosen to conjugate TAA for added functionality. Docking results showed that the majority of TAA-conjugated NBD-PG-G4-dendrimer demonstrated a favorable interaction with mannosamine binding site on MR1, thus constituting a promising tool for the targeted delivery of TAA.
Our in silico approach effectively narrows down the selection of the best candidates for the synthesis of functionalized PG-dendrimers with desired functionalities. The results of this study will significantly reduce the time and efforts required to experimentally obtain modified dendrimers for optimal controlled delivery of antigens to targeted DC.