Mesoscale Simulations and Experimental Studies of pH-Sensitive Micelles for Controlled Drug Delivery

Abstract

The microstructures of doxorubicin-loaded micelles prepared from block polymers His(x)Lys10 (x = 0, 5, 10) conjugated with docosahexaenoic acid (DHA) are investigated under different pH conditions, using dissipative particle dynamics (DPD) simulations. The conformation of micelles and the DOX distributions in micelles were obviously influenced by pH values and the length of the histidine segment. At pH >6.0, the micelles self-assembled from the polymers were dense and compact. The drugs were entrapped well within the micellar core. The particle size increases as the histidine length increases. With the decrease of pH value to be lower than 6.0, there was no distinct difference for the micelles self-assembled from the polymer without histidine residues. However, the micelles prepared from the polymers with histidine residues shows a structural transformation from dense to swollen conformation, leading to an increased particle size from 10.3 to 14.5 DPD units for DHD-His10Lys10 micelles. This structural transformation of micelles can accelerate the DOX release from micelles under lower pH conditions. The in vitro drug release from micelles is accelerated by the decrease of pH value from 7.4 (physiological environment) to 5.0 (lysosomal environment). The integration of simulation and experiments might be a valuable method for the optimization and design of biomaterials for drug delivery with desired properties.

Mechanistic Understanding From Molecular Dynamics Simulation in Pharmaceutical Research 1: Drug Delivery

“…Protein structures can be downloaded and their potentials have already been parameterized; attach a polymer to the protein, solvate in water and you can study its behavior. Both PASylated (Hedayati et al, 2017) and PEGylated (Cohan et al, 2011) (Guo et al, 2010;Zheng et al, 2011;Nie et al, 2013Nie et al, , 2014Wang et al, 2015a, Luo Z. et al, 2016Rungrotmongkol and Poo-arporn, 2016;Min et al, 2017;Wang Y. et al, 2017Wolski et al, 2017bWolski et al, , 2018Quan et al, 2017;Gao et al, 2019;Wu W. et al, 2019;Maleki et al, 2020) Optical (Lajunen et al, 2016(Lajunen et al, , 2018Massiot et al, 2017) Magnetic (Panczyk et al, 2013;Yang C. et al, 2020;Zhang X. et al, 2020) Thermal (Dhawan et al, 2004;Pérez-Sánchez et al, 2020) TABLE 2 | Drug delivery vehicles studied using molecular modeling methods.…”

Integration of target discovery, drug discovery and drug delivery: A review on computational strategies

“…Drug molecules could be encapsulated well in the micellar core at pH pH > 6.0 pH > 6.0 pH < 6.0 pH < 6.0 pH > 6.0 pH < 6.0 >6.0. When the pH decreased to <6.0, the conformation of micelles transforms from dense to swollen structures, and this structural transformation is influenced by the length of histidine residues (Figure 4; Wang et al, 2015).…”

In SilicoSelf-Assembly of Nanoparticles with Applications in Drug Delivery

“…62 A similar study was carried out later using doxorubicin-loaded micelles prepared from block polymers His(x)Lys10 (x = 0, 5, 10) conjugated with docosahexaenoic acid. 63 The nanoparticles can accommodate simultaneously several drugs and release them specifically in different experimental conditions, as shown in a recent study in which a dual-drug-loaded micelle was designed and constructed by self-assembly from a mixture of poly(propylene oxide)-b-poly(γ-benzyl-Lglutamate)-b-poly(ethylene glycol) (PPO-b-PBLG-b-PEG) triblock terpolymers and two model drugs, doxorubicin (DOX) and naproxen (Nap). In the micelles, the DOX is covalently linked to PBLG through an acid-cleavable hydrazone bond, whereas the Nap is physically encapsulated in the cores.…”