Molecular Modeling of Shockwave-Mediated Blood-Brain Barrier Opening for Targeted Drug Delivery.

Bubble-enhanced shock waves induce the transient opening of the blood-brain barrier (BBB) providing unique advantages for targeted drug delivery of brain tumor therapy, but little is known about the molecular details of this process. Based on our BBB model including 28 000 lipids and 280 tight junction proteins and coarse-grained dynamics simulations, we provided the molecular-level delivery mechanism of three typical drugs for the first time, including the lipophilic paclitaxel, hydrophilic gemcitabine, and siRNA encapsulated in liposome, across the BBB. The results show that the BBB is more difficult to be perforated by shock-induced jets than the human brain plasma membrane (PM), requiring higher shock wave speeds. For the pores formed, the BBB exhibits a greater ability to self-heal than PM. Hydrophobic paclitaxel can cross the BBB and be successfully absorbed, but the amount is only one-third of that of PM; however, the absorption of hydrophilic gemcitabine was almost negligible. Liposome-loaded siRNAs only stayed in the first layer of the BBB. The mechanism analysis shows that increasing the bubble size can promote drug absorption while reducing the risk of higher shock wave overpressure. An exponential function was proposed to describe the relation between bubble and overpressure, which can be extended to the experimental microbubble scale. The calculated overpressure is consistent with the experimental result. These molecular-scale details on shock-assisted BBB opening for targeted drug delivery would guide and assist experimental attempts to promote the application of this strategy in the clinical treatment of brain tumors.

Shock Hugoniot Calculations of Newly Designed Thermoplastic Elastomers and Comparison with Classical Binder Estane.

Our purpose is to design excellent binder candidates used in polymer-bonded explosives (PBX) according to the calculated shock of Hugoniot. Here, we mainly examined the thermoplastic elastomer (TPE) binders commonly used in PBX formulations. Equilibrium molecular dynamics (MD) simulation and mixing rule methods were used to calculate the shock Hugoniot values of 180 newly designed TPEs. We focused on the influence of the polymerization degree, contents, and types of soft and hard segments composed of TPEs on the shock Hugoniot and compared them with the classic PBX binder, Estane. The results show that the hard segment has an effect on the Hugoniot curve, which gradually diminishes as the degree of polymerization increases. The underlying physical mechanism can be attributed to the presence of a large number of hydrogen bonds in hard segment domains. The shock Hugoniot of TPEs also depends on the type of soft segments. The volume compression rate of TPEs decreases with increasing content of hard segments under a given shock. By comparing with Estane, a TPE binder commonly used in PBX, we ultimately chose several new TPEs with the potential to serve as PBX binders in terms of shock performance.

Molecular modelling of shockwave-mediated delivery of paclitaxel aggregates across the neuronal plasma membrane.

Shock-assisted paclitaxel (PTX) transport across the blood-brain barrier offers a promising treatment strategy for brain tumors. Here, based on a realistically complex human brain plasma membrane (PM) model, we investigated the dynamic transmembrane behavior of a PTX cluster by shock induced bubble collapse, focusing on the effect of impulse (I), bubble diameter (D) and arrays. The results show that all three factors can control the transport depth (ΔDPM) of PTX. For a fixed D, the ΔDPM grows exponentially with I, ΔDPM ∼ exp (I), and eventually reaches a critical depth. But the depth, ΔDPM, can be adjusted linearly in a wider range of D. This mainly depends on the size of jets from bubble collapse. For bubble arrays, the bubbles in series can transport PTX deeper than a single bubble, while the parallel does the opposite. In addition, only PTX clusters in the range of jet action can be successfully transported. Finally, the absorption of PTX clusters was examined via recovery simulation. Not all PTX clusters across the membrane can be effectively absorbed by cells. The shallow PTX clusters are quickly attracted by the membrane and embedded into it. The critical depth at which PTX clusters can be effectively absorbed is about 20 nm. These molecular-level mechanisms and dynamic processes of PTX clusters crossing the PM membrane may be helpful in optimizing the application of shock-induced bubble collapse for the delivery of PTX to tumor cells.