Enhancement of methyl-aminolevulinate photodynamic therapy by iron chelation with CP94: an in vitro investigation and clinical dose-escalating safety study for the treatment of nodular basal cell carcinoma

Abstract

Purpose:Methyl-aminolevulinate (MAL) photodynamic therapy (PDT) is a cancer therapy that combines the selective accumulation of a photosensitizer in tumor tissue with visible light (and tissue oxygen) to produce reactive oxygen species. This results in cellular damage and ablation of tumor tissue. Combining iron chelators with MAL has the potential to increase the accumulation of the photosensitizer protoporphyrin IX (PpIX) by reducing its bioconversion to heme. This paper investigates this method of enhancement both in vitro and for the first time clinically for the treatment of nodular basal cell carcinoma (BCC). Methods:Enhancement of MAL-induced PpIX accumulation by the iron chelator CP94 was quantified fluorometrically in human cultured cells (including three dermatological cell types). An open, dose-escalating, pilot study was then conducted in patients with nodular BCC, to determine the safety of this pharmacological modification. Results:Large enhancements in PpIX accumulation were observed in the cultured cells when coincubated with the iron chelator CP94. Clinically the addition of CP94 was found to be feasible and safe. In addition greater reductions in tumor depth were observed in the CP94 coincubated tumors. Conclusion:Iron chelation by CP94 is an effective enhancer of MAL-induced PpIX accumulation in vitro.

Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

“…S8). The lack of NHEK susceptibility to PpIX-based photodynamic cell killing under different conditions has previously been reported [40,41].…”

The importance of iron chelation and iron availability during PpIX-induced photodynamic therapy

“…[48,49]. Although these clinical investigations were only designed to assess safety, enhancements in tumour clearance were observed both clinically and histologically when CP94 was included within the photosensitising cream.…”

Monitoring the accumulation and dissipation of the photosensitizer protoporphyrin IX during standard dermatological methyl-aminolevulinate photodynamic therapy utilizing non-invasive fluorescence imaging and quantification

“…This finding indicated that greater PpIX accumulation increases the potential of the therapy as more PpIX is available for activation during irradiation. Therefore one of the main modalities of treatment enhancement focuses around increasing the level of PpIX within cells utilizing a variety of different techniques including lesion preparation (34), alternative prodrugs (35), penetration enhancers (36) and iron chelators (24,37).…”