Evaluation the synergistic antitumor effect of methotrexate–camptothecin codelivery prodrug from self‐assembly process to acid‐catalyzed both drugs release: A comprehensive theoretical study

Abstract

Therapeutic efficiency of amphiphilic methotrexate-camptothecin (MTX-CPT) prodrug compared to free drug mixture (MTX/CPT) has been investigated using allatom molecular dynamics simulation and first principles density functional theory calculations. This comparison revealed that MTX-CPT prodrug tends to form spherical self-assembled nanoparticle (NP), while free MTX/CPT mixture forms rod-shape NP. These observations are attributed to a structural defect in the MTX-CPT prodrug and solvation free energies of MTX, CPT and MTX-CPT molecules. The results provided evidence that noncovalent interactions (NCIs) among the pharmaceutical drugs play a very important role in anticancer agents aggregation process, leading to enhanced stability of the self-assembled NPs. It is found that the stability of MTX-CPT self-assembled NP is greater than the MTX/CPT NP due to the synergistic effect of hydrogen bonding between monomers and solvent (water). Moreover, the noncatalyzed as well as catalyzed hydrolysis reactions of MTX-CPT prodrug are theoretically studied at the PCM(water)//M06-2X/6−31G(d,p) computational level to shed additional light on the role of acidic condition in tumor tissues. We found that the ester hydrolysis in mild acidic solutions is a concerted reaction. In an agreement between theory and experiment, we also confirmed that the activation energies of the catalyzed-hydrolysis steps are much lower than the activation energies of the corresponding steps in the noncatalyzed reaction. Thus, the MTX-CPT prodrug reveals very promising properties as a pH-controlled drug delivery system. K E Y W O R D Sacid-catalyzed ester hydrolysis,

Multicomponent carrier-free nanodrugs for cancer treatment

“…Otherwise, hydrophilic drugs and hydrophobic drugs are linked through acid-sensitive amide bonds, Schiff base bonds, and disulfide bonds, which have also been widely studied. 45,52–60…”

“…Otherwise, hydrophilic drugs and hydrophobic drugs are linked through acid-sensitive amide bonds, Schiff base This journal is © The Royal Society of Chemistry 2022 bonds, and disulfide bonds, which have also been widely studied. 45,[52][53][54][55][56][57][58][59][60] The conjugates of drugs and other small bioactive molecules (carbohydrates, peptides) have also attracted attention, besides pure DDC. 54,[61][62][63][64][65] The carbohydrate modification on the surface of NPs can facilitate tumor specific recognition.…”

Interactions of boron nitride nanosheet with amino acids of differential polarity

“…Since molecular dynamics (MD) simulation is a science that studies the evolution of chemical systems at the nanoscale, it can provide us with a nanoscopic frame of view into the biochemical reactions 8 – 10 . On the other hand, nanotechnology deals with the production and usage of materials at the nanoscale, therefore, its convergence with MD simulations will considerably contribute to the advancement of nano-biomedicine 11 – 14 .…”

Emerging Trends in Nanotechnology-based Delivery Approaches: Hexakis (m-PE) Macrocycles as a Novel Therapeutics

“…However, their quality problems (i.e., the inability to tune the pore diameters and difficult production), carrier-related toxicity, and poor drug loading capacity issues have restricted their clinical utilization [1][2][3] . Nevertheless, the research interest has shifted to focus on the design and fabrication of novel drug-delivery vehicles [4][5][6][7][8][9] . Among the different ring-shaped macrocycles, those with non-deformable cavities and rigid backbones are of particular interest.…”