FLTX2: A Novel Tamoxifen Derivative Endowed with Antiestrogenic, Fluorescent, and Photosensitizer Properties

Abstract

Tamoxifen is the most widely used selective modulator of estrogen receptors (SERM) and the first strategy as coadjuvant therapy for the treatment of estrogen-receptor (ER) positive breast cancer worldwide. In spite of such success, tamoxifen is not devoid of undesirable effects, the most life-threatening reported so far affecting uterine tissues. Indeed, tamoxifen treatment is discouraged in women under risk of uterine cancers. Recent molecular design efforts have endeavoured the development of tamoxifen derivatives with antiestrogen properties but lacking agonistic uterine tropism. One of this is FLTX2, formed by the covalent binding of tamoxifen as ER binding core, 7-nitrobenzofurazan (NBD) as the florescent dye, and Rose Bengal (RB) as source for reactive oxygen species. Our analyses demonstrate (1) FLTX2 is endowed with similar antiestrogen potency as tamoxifen and its predecessor FLTX1, (2) shows a strong absorption in the blue spectral range, associated to the NBD moiety, which efficiently transfers the excitation energy to RB through intramolecular FRET mechanism, (3) generates superoxide anions in a concentration- and irradiation time-dependent process, and (4) Induces concentration- and time-dependent MCF7 apoptotic cell death. These properties make FLTX2 a very promising candidate to lead a novel generation of SERMs with the endogenous capacity to promote breast tumour cell death in situ by photosensitization.

Photodynamic therapy: Innovative approaches for antibacterial and anticancer treatments

“…114,[413][414][415][416][417] Similarly, tamoxifen or estradiol binding with PSs led to the targeted drug delivery towards estrogen-dependent tumor cells. [418][419][420][421][422][423][424] Generally, a saccharide attachment to PS promotes enhanced targeting to cancer cells due to their deregulation of glycosylation pathways and fast metabolism. 120,[425][426][427][428] Since hyaluronan is the main ligand for CD44, a nonkinase transmembrane glycoprotein overexpressed in many types of cancer, HA has been widely used in targeted cancer cells elimination via PDT.…”

“…Gram-positive bacteria Gram-negative bacteria Anionic, cationic or neutral PS 328,336,337 Conjugation of anionic/neutral PS with cationic antimicrobial peptides 337 Fullerenes combined with electron donors 358 Zinc pthalocyanine with membrane pertubing agent 344 Hypericin combined with N-acetylcysteine 364 Conjugation of PS with polymixin B, 405 poly-L-lysine, 406 and PEI 407 Rose bengal with polycationic chitosan, 391 cationic phosphorus dendrimer, 392 or a positively charged peptide 393 Gram-positive and Gram-negative bacteria Curcumin enclosed in colloidal systems 380 Rose bengal (free or conjugated with an exopolysaccharide) 395 Methylene blue and toluidine blue O (free or incorporated in mesoporous silica nanoparticles) 398,400 T A B L E 2 A list of photosensitizers with particular modification for strategies listed in this review to enhance effects of anticancer PDT. Conjugation with a FA moiety Target of cancer cells in brain, lungs, or ovary tumors Rose bengal 418 ; zinc (II) phthalocyanine, 419 ruthenium (II) polypyridyl complex, 420 polythiophene, 421 pyropheophorbide 422 Tamoxifen binding Target of estrogen receptors in estrogen-dependent tumor cells to enhance PDT Tetraphenylporphyrin, 423 chlorin e6 dimethyl ester 424 Estradiol binding Target of estrogen receptors in estrogen-dependent tumor cells to enhance PDT Zn(II) porphyrin, 425 pyropheophorbide-α, 426 psoralen, 427 porphyrins, and phthalocyanines 428…”

“…For example, a conjugation with a FA moiety led to the targeted delivery of PS to brain, lung, or ovary cancer cells 114,413–417 . Similarly, tamoxifen or estradiol binding with PSs led to the targeted drug delivery towards estrogen‐dependent tumor cells 418–424 . Generally, a saccharide attachment to PS promotes enhanced targeting to cancer cells due to their deregulation of glycosylation pathways and fast metabolism 120,425–428 .…”

The Potency of Alkaloid Derivates as Anti-Breast Cancer Candidates: In Silico Study

“…(Hollingsworth & Dror, 2018). Molecular docking results are combined with molecular dynamics simulation techniques to obtain more reliable results (Mario et al, 2021). molecular dynamics simulations were performed on the substances daurisoline, solasodine, sambutoxin, 7-ethyl-10-hydroxycamptothecin, 7ethylcamptothecin, tamoxifen and 1-[4-[4-[[3,5-bis(chloranyl)-4-([ 1,2,4]triazolo[1,5a]pyridine-7yloxy)phenyl]amino]pyrimido [5,4d]pyrimidin-6-yl]piperazine-1-yl]-4-(3fluoranylazetidin-1-yl)butan-1-one (70I) as a comparison.…”