Effect of Metalation on Porphyrin-Based Bifunctional Agents in Tumor Imaging and Photodynamic Therapy

Abstract

Herein we report the syntheses and comparative photophysical, electrochemical, in vitro, and in vivo biological efficacy of 3-(1'-hexyloxy)ethyl-3-devinylpyropheophorbide-cyanine dye (HPPH-CD) and the corresponding indium (In), gallium (Ga), and palladium (Pd) conjugates. The insertion of a heavy metal in the HPPH moiety makes a significant difference in FRET (Förster resonance energy transfer) and electrochemical properties, which correlates with singlet oxygen production [a key cytotoxic agent for photodynamic therapy (PDT)] and long-term in vivo PDT efficacy. Among the metalated analogs, the In(III) HPPH-CD showed the best cancer imaging and PDT efficacy. Interestingly, in contrast to free base HPPH-CD, which requires a significantly higher therapeutic dose (2.5 μmol/kg) than imaging dose (0.3 μmol/kg), the corresponding In(III) HPPH-CD showed excellent imaging and therapeutic potential at a remarkably low dose (0.3 μmol/kg) in BALB/c mice bearing Colon26 tumors. A comparative study of metalated and corresponding nonmetalated conjugates further confirmed that STAT-3 dimerization can be used as a biomarker for determining the level of photoreaction and tumor response.

A Pyropheophorbide Analogue Containing a Fused Methoxy Cyclohexenone Ring System Shows Promising Cancer‐Imaging Ability

“…The decay of 124 I( b + 23 %, EC 77 %) is followed by emission of an umber of high-energy g photons:6 03 keV (61 %), 723 (10 %), and 1691 (10 %), in addition to 511keV annihilation photons. The quantitative phantom studies of 124 Ii maging with different scanners [29,30] have shown that, compared with 18 Fi maging, there is only as mall loss in image resolution and contrast due to as mall increase in background from high-energy g photons from 124 I.…”

“…Ex vivo biodistribution (PET imaging and relative uptake volume (RUV)):F or the biodistribution study,t hree female BALB/c mice for [ 18 [14] and determined to be 94 mCi mmol À1 with 95 %r adiospecificity for [ 124 I]4. [ 18 F]FDG in 0.9 %s aline at 1mCi mL À1 was purchased from Cardinal Health (Rochester,N Y, USA).…”

“…[10][11][12] However,i ts hows limitations in imaging tumors in organs where glucosem etabolism is high, it is not ag ood candidate for imaging renal carcinomas, [13] and has shown both potential as well as pitfalls for imaging pancreatic malignancy. [14] The short half-life (110 min) of the 18 Fi sotope alsop recludes its shipment over long distances, and necessitatesa3-to 4-fold highera mountt han the requiredd ose. To overcome this, the cyclotron facility would have to be closer to the imaging facilities, but the cost and maintenance of such facilities is very expensive.…”

“…It works well for imaging superficial tumors,b ut due to limitation of light penetration in tissue at the excitation wavelength of 660 nm, it is not an ideal fluorophore for imagingl arge and deeply seated tumors. [17,18] For quite some time, one of the objectives of our research group has been to develop as ingle near-infrared (NIR) multimodalitya gent which, in combination with radioactive and non-radioactive analogues,c ould be used for PET imaging of tumors with an option of PDT;t herefore, as eries of chlorin and bacteriochlorin analogues were evaluated. Some of these compounds showed significant PDT efficacy with desired photophysical properties, but also produced high uptake in spleen, kidney, and liver,w hich cleared with time, and were not suitable candidates for whole-body PET imaging.…”

Modulating cellular cytotoxicity and phototoxicity of fluorescent organic salts through counterion pairing

“…Additionally, visible light absorbance by endogenous biological fluorophores such as heme and flavin groups 6 causes autofluorescence and weak signal intensity. On the other hand, NIR light is minimally absorbed by biological material, drastically reducing background noise and increasing penetrance 7,8 . FDA-approved NIR-responsive fluorescent dyes including indocyanine green, 5-aminolevulinic acid, and methylene blue are available and used in medical diagnostics 9 , but are limited due to their low level of brightness.…”