Conjugation of 2-(1′-Hexyloxyethyl)-2-devinylpyropheophorbide-a (HPPH) to Carbohydrates Changes its Subcellular Distribution and Enhances Photodynamic Activity in Vivo

Abstract

The carbohydrate moieties on conjugating with 3-(1′-hexyloxyethyl)-3-devinyl pyropeophorbide-a (HPPH) altered the uptake and intracellular localization from mitochondria to lysosomes. In vitro, HPPH-Gal 9 PDT showed increased PDT efficacy over HPPH-PDT as detectable by the oxidative cross-linking of nonphosphorylated STAT3 and cell killing in ABCG2-expressing RIF cells but not in ABCG2-negative Colon26 cells. This increased efficacy in RIF cells could at least partially be attributed to increased cellular accumulation of 9, suggesting a role of the ABCG2 transporter for which HPPH is a substrate. While such differences in the accumulation in HPPH derivatives by tumor tissue in vivo were not detectable, 9 still showed an elevated light dose-dependent activity compared to HPPH in mice bearing RIF as well as Colon26 tumors. Further optimization of the carbohydrate conjugates at variable treatment parameters in vivo is currently underway.

Chemical Synthesis and Medicinal Applications of Glycoporphyrins

“…HPPH, like Photofrin ® , is lipophilic with slow clearance from the body [286] . 3-Devinyl-3-(1'-hexyloxyethyl) pyropheophorbide-a (HPPH) was conjugated with mono-, di-, or tetra-saccharides to determine the effect the carbohydrate unit had on the PDT efficacy of the basic macrocycle [287] . To determine the effect β-galactose carbohydrates have on tumor-selectivity and its dependence on galectin 3 binding both galactose conjugates (galactose and lactose) and non-galactose conjugates (glucose and cellobiose) of HPPH were synthesized.…”

“…The first series of HPPH derivatives were synthesized by coupling HPPH with 1-aminotetra-acetogalactose, 1-aminotetra-acetoglucose, 1-aminohepta-acetolactose and 1-aminoheptaacetocellobiose and deacetylated affording 558a-d. The second series synthesized incorporated mono-and multivalent rigidified lactose units which were coupled to HPPH with an extended amine linker (558e) followed by deacetylation afforded 558f-h. All were tested for their affinity for galectins overexpressed on cancer cells [287] . Similar systems were also employed in a study on the effect of the carbohydrate unit had on PET imaging and PDT efficacy a range of glycosylated phytochlorin derivatives were synthesized.…”

“…Similar systems were also employed in a study on the effect of the carbohydrate unit had on PET imaging and PDT efficacy a range of glycosylated phytochlorin derivatives were synthesized. Galactose conjugated HPPH had previously shown higher photosensitizing efficacy than HPPH in mice bearing RIF tumors [285,287] . I.…”

“…Here, the dependence on galectins-3 binding was evaluated on both galactose conjugates (558a, 558c) and nongalactose conjugates (558b, 558d) of HPPH [287] . All in vitro tests were carried out in murine radiation-induced fibrosarcoma (RIF) and colon carcinoma (Colon26) cell lines; both express similar levels of the β-galactose-recognizing galectin-1 and galectin-3.…”

Supramolecular stacking motifs in the solid state of amide and triazole derivatives of cellobiose

“…Both groups give rise to supramolecular stacking motifs with potential for exploitation in crystal engineering. (7) were prepared from the corresponding azide (2) 15 which was in turn obtained from the bromide (1) as outlined in Scheme 1. Hydrogenation of azide (2) over Pd/C at 200 psi gave the amine (3) as a single epimer.…”