Photodynamic Efficiency of Diethylene Glycol-Linked Glycoconjugated Porphyrins in Human Retinoblastoma Cells

Abstract

Photodynamic therapy (PDT) is emerging as a new strategy for the conservative treatment of hereditary retinoblastoma. The glycoconjugated porphyrins TPP(p-Deg-O-alpha-GalOH)(3), TPP(p-Deg-O-beta-GalOH)(3), TPP(p-Deg-O-alpha-ManOH)(3), and their S-analogues were synthesized to obtain efficient photosensitizers with some retinoblastoma cell affinity. In these systems, a sugar motif and porphyrin core were linked by a diethylene glycol spacer (Deg). Cellular uptake, localization, and photoactivity have been examined in human retinoblastoma cells (Y79). After preincubation with corresponding glycosylated albumin, the uptake of TPP(p-Deg-O-beta-GalOH)(3) and TPP(p-Deg-O-alpha-ManOH)(3) was 40-45% inhibited, indicating a possible cell-sugar-receptor saturation. High photoactivity was observed for the two alpha-galacto/manno porphyrins 8 and 10 (LD(50) = 0.05 and 0.35 muM, respectively) at 514 nm and low fluence (1 J/cm(2)). Analysis by MALDI-TOF mass spectrometry only indicated a small metabolic cleavage of the O-glycoconjugates and a good stability of the S-glycoside porphyrins. On the basis of these in vitro data, TPP(p-Deg-O-alpha-GalOH)(3) and TPP(p-Deg-O-alpha-ManOH)(3) were selected for in vivo studies.

Nanodrug applications in photodynamic therapy

“…The first step towards nano-sized PS formulations were made through the preparation of dendritic [80,81], glyco [82,83], amino acid [84] and peptide [85] functionalized porphyrins. Initially, many of these studies were just aimed at increasing the water solubility, formulation properties and targeting of the PS [86].…”

Chemical Synthesis and Medicinal Applications of Glycoporphyrins

“…Other linker units may be employed as well. Thus, a library of diethylene glycol linked glycoporphyrins TPP (204)(205)(206) and their S-analogues (207,208) were synthesized and their PDT efficacy tested against retinoblastoma cells [198] . All O-glycosylated diethylene glycol porphyrins and the reference compound (203) were synthesized from 5,10,15-tris(p-phenol)-20-phenylporphyrin and reacted with the bromo-diethylene glycol substituted glycosides followed by deacetylation or with 2-(2-chloroethoxy)ethanol for 203.…”

“…The non-glycosylated dendron was also coupled with 497 affording 512a,b for comparative biological studies. Taking into account their previous work on glycoporphyrins [160,162,198,204,205,255] they concluded that the best compounds appeared to have three α-glycosyl groups on the paraposition of the meso-phenyl ring via a flexible linker. However, the presence of three sugars via a glycodendrimer decreased the phototoxicity [256] .…”

“…Glycophthalocyanines 617 and 618a-c [198] Human retinoblastoma cells Y79 499b-511b, 271 PDT: @ λ > 540 nm, 2 J/cm 2 , 24 h incubation, no dark toxicity, LD50 = 0.43 (206), 2.5-2.7 (499b, 501b, 503b), 3-4.5 (500b, 506b-508b, 511b), 4.9-6 (502b, 504b, 505b, 509b, 512b), >10 (271) μM. 2 (207, 208) μM.…”

“…Octaglucosyl TPP lacked cellular affinity while the galactose derivative displayed significant affinity which was related to saccharide specificity for hepatocytes of the galactose residue [175] . A number of A 3 B-type systems with diethyleneglycol [198] . These cell lines over-express lectins for specific glycosides but the uptake of the glycoporphyrins was independent of such receptors.…”