Soluble precipitable porphyrins for use in targeted molecular brachytherapy

Abstract

In a new therapy that aims to concentrate and immobilize therapeutic radionuclides in nanoscale assemblies within solid tumors, a soluble precipitable reagent (SPR) is administered as the radionuclide carrier and is converted to non-diffusible precipitate by an enzyme located in tumor tissues. To meet the objective of such an SPR, we have prepared and examined a class of porphyrin-alkyldiphosphates that are soluble in aqueous solution and that are rendered insoluble upon removal of the two phosphate groups. The porphyrins examined herein are of the trans-AB architecture wherein the substituents are a bis(dihydroxyphosphoryloxy)alkyl group and a phenyl (or p-bromophenyl) group. Provisions for later incorporation of radionuclides have been established by preparation of the analogous copper chelate or the meso-iodo free-base porphyrin. Altogether, four porphyrins bearing a bis(dihydroxyphosphoryloxy)alkyl group were examined and found to exhibit satisfactory solubility in water (41 mM). Dephosphorylation reactions have been carried out in vitro using the enzyme shrimp alkaline phosphatase. In each case, enzymeinduced precipitation was observed. The soluble-to-insoluble conversion has been examined by visual inspection, absorption spectroscopy, electrospray ionization mass spectrometry, and nephelometry using non-radiolabeled porphyrins.

Synthetic Chlorins, Possible Surrogates for Chlorophylls, Prepared by Derivatization of Porphyrins

“…For the meso -tetraalkylporphyrins, the tetraisobutylporphyrin 6-H 2 7 gave the mono-β-alkylchlorin ( 6-H 2 10 ) and porphodimethene ( 6-H 2 11 ), whereas the porphyrin with short “swallowtail” substituents (1-ethylpropyl) gave the mono-β-alkylchlorin ( 6-H 2 12 ) and β,β′-dialkylchlorin ( 6-H 2 13 ). A swallowtail groupa symmetrically substituted alkyl grouphas been incorporated previously with a variety of porphyrins − and a few chlorins at one or more meso-substituents. Swallowtail groups are attractive for building steric bulk above and below the plane of the tetrapyrrole macrocycle.…”

Electrochemical and spectroscopic studies of poly(diethoxyphosphoryl)porphyrins

“…Although many synthetic challenges have been overcome over the past decades, including the synthesis of porphyrins containing heteroatoms directly attached to the macrocycle, synthetic routes to phosphorus substituted derivatives involving carbon-phosphorus (CAP) bond formation have been less well studied [1][2][3]. On the other hand, there has been a relatively recent interest in preparing phosphorous containing porphyrins as structural blocks in material chemistry [4][5][6], for studies of molecular-based information storage [7][8][9][10] or to target cancer therapy [11][12][13][14], and this has been demonstrated with different derivatives with phosphorous substituents attached to the porphyrin macrocycle via phenyl or methylene spacers.…”

MRI-Based Detection of Alkaline Phosphatase Gene Reporter Activity Using a Porphyrin Solubility Switch

“…Paramagnetic manganese porphyrins are among the strongest contrast agents for T 1 -weighted MRI (Chen et al, 1984; Koenig et al, 1987), and we showed in another study (Lee et al, 2010) that labile zinc binding by an anionic porphyrin-based molecular imaging agent (Zhang et al, 2007) promotes localization of the probe in tissue, probably because of a change in the charge of the complex. We reasoned that an anionic phosphoporphyrin designed to be a substrate for SEAP could undergo a phosphatase-catalyzed solubility switch (Yao et al, 2007) and accumulate similarly in the presence of SEAP reporter expression (Figure 1). Visualization of the product would then occur following depletion of the soluble starting material, which would be expected to wash out within several hours in vivo (Lee et al, 2010).…”