Structural and Epimeric Isomers of HPPH [3-Devinyl 3-{1-(1-hexyloxy) ethyl}pyropheophorbide-a]: Effects on Uptake and Photodynamic Therapy of Cancer

Abstract

The tetrapyrrole structure of porphyrins used as photosentizing agents is thought to determine uptake and retention by malignant epithelial cancer cells. To assess the contribution of the oxidized state of individual rings to these cellular processes, bacteriochlorophyll a was converted into the ring "D" reduced 3-devinyl-3-[1-(1-hexyloxy)ethyl]pyropheophorbide-a (HPPH) and the corresponding ring "B" reduced isomer (iso-HPPH). The carboxylic acid analogs of both ring "B" and ring "D" reduced isomers showed several-fold higher accumulation into the mitochondria and endoplasmic reticulum by primary culture of human lung and head and neck cancer cells than the corresponding methyl ester analogs that localize primarily to granular vesicles and to a lesser extent to mitochondria. However, long-term cellular retention of these compounds exhibited an inverse relationship with tumor cells generally retaining better the methyl-ester derivatives. In vivo distribution and tumor uptake was evaluated in the isogenic model of BALB/c mice bearing Colon26 tumors using the respective C-labeled analogs. Both carboxylic acid derivatives demonstrated similar intracellular localization and long-term tumor cure with no significant skin phototoxicity. PDT-mediated tumor action involved vascular damage, which was confirmed by a reduction in blood flow and immunohistochemical assessment of damage to the vascular endothelium. The HPPH stereoisomers (epimers) showed identical uptake (in vitro& in vivo), intracellular retention and photoreaction.

Photodynamic Therapy: A Brief History

“…Kennedy’s group in Canada was among the first to appreciate the potential for use of ALA in clinical PDT [29]. Another agent currently receiving clinical attention in Asia is the pheophorbide HPPH that was synthesized by Pandey’s group at the Roswell Park Cancer Institute [30]. Sales of topical agents now exceed the income derived from Photofrin, demonstrating the success of dermatologic applications.…”

Highly Efficient Water-Soluble Photosensitizer Based on Chlorin: Synthesis, Characterization, and Evaluation for Photodynamic Therapy

“…The PDT effects of HPS were tested in the 4T1- and A549-tumor-bearing mice, and the optimal therapeutic window was chosen on the basis of its biodistribution and pharmacokinetics. The selected illumination conditions and HPS dose (50–120 J/cm 2 , 0.08–0.64 mg/kg) approximate those previously studied for the structurally similar chlorin-based HPPH, S-PS mediated PDT. , The 4T1 model was treated with 0.6 mg/kg HPS or 0.6 mg/kg HPPH, whereas the nude mice bearing A549 tumors were administered different concentrations of HPS (0.08–0.64 mg/kg) or HPPH (0.32 mg/kg). The tumors were exposed to different lasers 6 h later, and the tumor volume and survival were recorded.…”

Nanosonosensitization by Using Copper–Cysteamine Nanoparticles Augmented Sonodynamic Cancer Treatment

“…Similar to photosensitizers for PDT, sonosensitizers are important for SDT, and various organic sonosensitizers including photofrin, hematoporphyrin, chlorophyll derivatives, have been studied and reported for SDT. However, these sonosensitizer molecules suffer from low chemical or biological stability, low accumulation in tumor, and low SDT efficacy .…”