Molecularly Imprinted Nanoparticles towards MMP9 for Controlling Cardiac ECM after Myocardial Infarction: A Predictive Experimental-Computational Chemistry Investigation

Abstract

The recent advances in nanotechnology are revolutionizing preventive and therapeutic approaches to treating cardiovascular diseases. Controlling the extracellular matrix metalloproteinase (MMP) activation and expression in the failing human left ventricular myocardium represents a significant therapeutic target for heart disease. In this study, we used molecularly imprinting polymers (MIPs) to restore the correct balance between MMPs and their tissue inhibitors (TIMPs), and explored the potential of this technique exhaustively through chemical synthesis, physicochemical and biological characterizations, and computational chemistry methods. By molecular dynamics simulations based on classical force fields, we simulated the early stages of the imprinting process in solution disclosing the pivotal interaction established between the monomers and the MMP9 protein template. The average interaction energies of methacrylic acid (MAA) and poly (ethylene glycol) ethyl ether methacrylate (PEG) units were in the ranges 17–22 and 30–37 kcal/mol, respectively. At low coverage, the PEG monomers seemed firmly anchored to the protein surface and were not displaced by water, while only about 20% of MAA was replaced by water. The synthesis of MIPs was successfully with a monomer conversion higher than 99 % and the production of spherical particles with average diameter of 344 ± 33 nm. HPLC analysis showed a specific recognition factor of MMP9 on MIPs of about 1.3. FT-IR Chemical Imaging confirmed the mechanisms necessary to generate a “selective memory” of the MIPs towards the enzyme. HPLC results indicated that the rebound amount of both TIMP1 and MMP2 to MIPs is lower than that of the template, showing a selectivity factor of 2.1 and 2.3, respectively. Preliminary tests on the effect of MIPs on H9C2 cells revealed that this treatment has no cytotoxic effects.

An integrated signature of clinical metrics and immune-related genes as a prognostic indicator for ST-segment elevation myocardial infarction patient survival

“…In this study, we found that MMP9 and GNLY , as two immune-related genes with the most significant differences in expression, showed consistent trends of expression changes in early serum of STEMI patients with previous research conclusions [ 16 , 17 ]. Matrix metalloproteinases(MMPs) constitute a group of enzymes responsible for extracellular matrix degradation, significantly impacting myocardial remodeling [ 18 ]. Specifically, MMP9 plays a role in the inflammatory response, fibrosis, and angiogenesis following AMI [ 18 ].…”

“…Matrix metalloproteinases(MMPs) constitute a group of enzymes responsible for extracellular matrix degradation, significantly impacting myocardial remodeling [ 18 ]. Specifically, MMP9 plays a role in the inflammatory response, fibrosis, and angiogenesis following AMI [ 18 ]. Previous research has consistently demonstrated elevated MMP9 levels in the serum of AMI patients, correlating with an unfavorable prognosis [ 17 , 19 ].…”

Assessment of RANTES, MIP4A, MMP7, MMP9, MMP14, TIMP 1, TIMP 2 and TIMP 3 concentration in the follicular fluid of patients undergoing in vitro fertilization/embryo transfer procedure

“…In some presented studies the population of patients was larger, but in others it was comparable. There are many factors that can contribute to differences in MMP expression, including underlying disease, medication, acute illnesses, and carcinoma [24,25]. The expression of MMPs and TIMPs would require further investigation on a wide population of patients.…”

Rational Design and Evaluation of Photoactive Molecularly Imprinted Nanoparticles for Tetracycline Degradation Under Visible Light

“…Short or in vacuum MD simulations have been used to evaluate monomer arrangements in pre-polymerization complexes for diverse molecular targets, such as creatinine, microcystin-LR, carbamate moieties, melamine, acetamide, 17-β-estradiol, , and norfloxacin, among others. Recently, more realistic settings for MD simulations, including explicit solvent molecules, counterions, and multiple monomer compositions, have been applied to address the recognition of various biomolecular targets, including monosaccharides, hormones, and proteins. , These advances raise the opportunity of using MD simulations to optimize the design of molecularly imprinted materials for TC recognition, using more complex and diverse monomer mixtures than those so far reported experimentally to achieve binding sites with an enhanced affinity toward the target.…”