The Product of Matrix Metalloproteinase Cleavage of Doxorubicin Conjugate for Anticancer Drug Delivery: Calorimetric, Spectroscopic, and Molecular Dynamics Studies on Peptide–Doxorubicin Binding to DNA

Abstract

Matrix metalloproteinases (MMPs) are extracellular matrix degradation factors, promoting cancer progression. Hence, they could provide an enzyme-assisted delivery of doxorubicin (DOX) in cancer treatment. In the current study, the intercalation process of DOX and tetrapeptide–DOX, the product of the MMPs’ cleavage of carrier-linked DOX, into dsDNA was investigated using stationary and time-resolved fluorescence spectroscopy, UV-Vis spectrophotometry and isothermal titration calorimetry (ITC). The molecular dynamics (MD) simulations on the same tetrapeptide–DOX…DNA and DOX…DNA systems were also performed. The undertaken studies indicate that DOX and tetrapeptide–DOX can effectively bond with dsDNA through the intercalation mode; however, tetrapeptide–DOX forms less stable complexes than free DOX. Moreover, the obtained results demonstrate that the differences in DNA affinity of both forms of DOX can be attributed to different intercalation modes. Tetrapeptide–DOX shows a preference to intercalate into DNA through the major groove, whereas DOX does it through the minor one. In summary, we can conclude that the tetrapeptide–DOX intercalation to DNA is significant and that even the lack of non-specific proteases releasing DOX from the tetrapeptide conjugate, the presence of which is suggested by the literature for the efficient release of DOX, should not prevent the cytostatic action of the anthracycline.

[Retracted] Exosome: Function and Application in Inflammatory Bone Diseases

“…Exosomes derived from monocytes and T cells stimulated by inflammatory factors, such as TNF- α , induce high production of MMP-1, MMP-3, MMP-9, and MMP-13 by rheumatoid arthritis fibroblasts [ 86 ]. Matrix metalloproteinases (MMPs) are a family of 23 structurally related proteolytic enzymes, which can degrade almost all components of the extracellular matrix [ 87 ]. MMP-9 promotes bone resorption by degrading extracellular matrix macromolecules around and on the surface of bone trabeculae and mediates osteoclast adhesion and migration to resorption sites [ 88 ].…”

On the Effect of pH, Temperature, and Surfactant Structure on Bovine Serum Albumin–Cationic/Anionic/Nonionic Surfactants Interactions in Cacodylate Buffer–Fluorescence Quenching Studies Supported by UV Spectrophotometry and CD Spectroscopy

“…The value of K a is particularly relevant for the understanding of the distribution of the drug in plasma, since weak binding can lead to a short lifetime or a poor distribution, while strong binding is responsible for the reduction in the plasmatic distribution of free drug [ 69 , 70 ]. The K a values obtained for the studied BSA complexes suggest relatively high/medium binding affinity to the protein for ionic surfactants (mainly at higher pH) and significantly lower binding affinity for nonionic ones when compared to other known strong biomolecule–ligand complexes with binding constants ranging from 10 5 to 10 8 M −1 [ 71 , 72 , 73 ]. However, lower binding constants (10 2 −10 4 M −1 ), which indicate a very weak interaction between the ligand and the protein, have been reported for several other protein–ligand complexes as well [ 74 , 75 , 76 ].…”

The Physical Chemistry and Chemical Physics (PCCP) Section of the International Journal of Molecular Sciences in Its Publications: The First 300 Thematic Articles in the First 3 Years

“…In this Thematic Area, 56 articles have been published [ 48 , 64 , 104 , 108 , 110 , 124 , 195 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 , 270 , 271 , 272 , 273 , 274 , 275 , 276 , 277 , 278 , 279 , 280 , 281 , 282 , 283 , 284 , 285 , 286 , 287 , 288 , 289 , 290 , 291 , 292 , 293 , 294 , 295 , 296 , 297 , 298 , 299 , 300 ], an...…”

“…A more detailed examination shows that, in this direction, as well as in the previous ones, articles in which the objects of research are organic materials clearly prevail over articles in which the objects of research are inorganic materials (36 and 20, respectively). Wherein, the overwhelming majority of articles of the “organic” profile are, in one way or another, connected with the participation of the objects with a biological origin; these include [ 64 , 124 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 274 , 277 , 278 , 282 , 284 , 289 , 291 , 292 , 293 , 294 , 295 , 296 , 298 , 299 , 300 ] and the processes in abiogenic organic materials were considered only in [ 48 , 195 , 266 , 271 , 272 , 273 , 283 , 288 , 290 ]. The thematic focus of these works, as well as the chemical compounds studied in them, is also very diverse, and even a simple listing of them here is clearly beyond the scope of this article, too.…”