Disulfur-bridged polyethyleneglycol/DOX nanoparticles for the encapsulation of photosensitive drugs: a case of computational simulations on the redox-responsive chemo-photodynamic drug delivery system.

Tumor redox stimulus-responsive nanoparticulate drug delivery systems (nano-DDSs) have attracted considerable attention due to their thermodynamically stable microstructures and well-controlled drug release properties. However, drug-loading nanoparticle conformation and redox-triggered drug release mechanisms at the molecular level remain unclear. Herein, doxorubicin-conjugated polymers were constructed using disulfide bonds as linkages (PEG-SS-DOX), which loaded photosensitizer chlorin e6 (Ce6). We integrated multiple scale dynamic simulations (density functional theory (DFT) calculation, atomistic molecular dynamics (MD) simulation and dissipative particle dynamics (DPD) simulations) to elucidate the assembly/drug release dynamic processing. First, it was revealed that the emergence of the calculated bond flexible angle of disulfide bonds facilitated the assembly behavior and improved the stability of conformation. Sorted by the binding model, hydrogen bonding accounted for the major interactions between polymers and photosensitive drugs. DPD simulations were further delved into to acquire knowledge regarding the drug-free self-aggregation and Ce6-loaded assembly mechanism. The results show that nano-assembly conformation not only depended on the concentration of polymers, but also were associated with the polymer-drug ratio. Different from dicarbon bond-bridging polymers, disulfide bonds would contribute to the breakage of the polymer and the rapid release of DOX and Ce6. Our findings provide deep insights into the influence of redox-responsive chemical linkages and offer theoretical guidance to the rational design of specific stimulus-responsive nano-DDSs for cancer therapy.

Structure-aided ACEI-capped remdesivir-loaded novel PLGA nanoparticles: toward a computational simulation design for anti-SARS-CoV-2 therapy.

The sudden arrival of novel coronavirus disease 2019 (COVID-19) has stunned the world with its rapidly spreading virus. Remdesivir, a broad spectrum anti-viral drug, is now under in vitro and in vivo investigation as a potential agent against SARS-CoV-2. However, the results of this therapy were recently equivocal due to no significant benefit in the clinical trial. Herein, combination molecular docking with dissipative particle dynamics (DPD) simulations is used to theoretically design angiotensin-converting enzyme inhibitor (ACEI)-containing remdesivir-loaded PLGA nanoparticles (NPs) for anti-SARS-CoV-2 therapy. Based on the therapeutic and lung protective effect of ACEI, the classical lisinopril molecule covalently grafted onto PLGA (L-PLGA) has been used to encapsulate remdesivir. A binding model is used to confirm the interactions between lisinopril and ACE on the surface of cells, as well as remdesivir and its intracellular targeting protein (RNA-dependent RNA polymerase (RdRp)). Furthermore, DPD simulations are applied to study the nano-aggregation of drug-free L-PLGA, and remdesivir loaded in L-PLGA. The lisinopril molecules were directly demonstrated to be on the surface of L-PLGA NPs. Molecular docking proved that hydrogen bonding was decisive for the encapsulation of remdesivir. With an increase in concentration, remdesivir loaded L-PLGA formed spherical NPs, and then underwent precipitation. Similar to the above conditions, high remdesivir loading was also observed to cause precipitation formation. Thus, the optimized remdesivir NPs in our study give insights into a rational platform for formulation design against this global pandemic.