Modulation of Biodistribution, Pharmacokinetics, and Photosensitivity with the Delivery Vehicle of a Bacteriochlorin Photosensitizer for Photodynamic Therapy

Abstract

Intravenous (i.v.) formulations with various amounts of organic solvents [PEG400 , propylene glycol (PG), cremophor EL (CrEL)] were used to deliver a fluorinated sulfonamide bacteriochlorin to mice, rats, and minipigs. Biodistribution studies in mice showed that a low-content CrEL formulation combines high bioavailability with high tumor-to-muscle and tumor-to-skin ratios. This formulation was also the most successful in the photodynamic therapy of mice with subcutaneously implanted CT26 murine colon adenocarcinoma tumors. Pharmacokinetic studies in mice and minipigs revealed that with the same low CrEL formulation, the half-life of the photosensitizer in the central compartment was longer in minipigs. Differences in biodistribution with the various formulations, and in pharmacokinetics between the two animal species with the same formulation, are attributed to the interaction of the formulations with low-density lipoproteins (LDLs). Skin photosensitivity studies in rats showed that 30 min exposure of the skin to a solar simulator 7 days after i.v. administration of the fluorinated sulfonamide bacteriochlorin at 1 mg kg(-1) did not elicit significant skin reactions.

Elimination of primary tumours and control of metastasis with rationally designed bacteriochlorin photodynamic therapy regimens

“…Although the concentration of redaporfin in the tumour equals that in the plasma at DLI = 12 h [16], this did not improve PDT efficacy. The therapeutic index of the regimes using DLI = 12, 24 and 48 h is narrow, with no cures and lethality.…”

“…The protocols with DLI between 12 and 48 h have a narrow phototherapeutic index that is related with pharmacokinetics because $80% of redaporfin is cleared from the plasma within 12 h post-iv administration [16]. PDT with DLI = 72 h (1.5 mg/kg, 100 J/cm 2 ) is the most selective, but considering that the final goal must be eliciting a favourable long-term tumour response, vascular-PDT (0.75 mg/kg, DLI = 0.25 h, 50 J/cm 2 , tumour margin of 4 mm) is preferable because it provides the highest cure rates and long-lasting systemic anti-tumour immunity.…”

“…We recently described a photostable bacteriochlorin (redaporfin) with intense infrared absorption, high yield of ROS generation, high phototoxicity [15], low skin photosensitivity and favourable pharmacokinetics [16,17]. This work uncovers relationships between PDT regimens, cure rates, antitumour immune memory and resistance to metastasis using redaporfin.…”

Engineering of relevant photodynamic processes through structural modifications of metallotetrapyrrolic photosensitizers

“…Redaporfin presented in Figure 9 is a fully synthetic bacteriochlorin especially designed to combine the spectroscopic properties of bacteriochlorins with their photostability [53]. It interacts with molecular oxygen through type I and II mechanisms, which makes it highly effective in the treatment of a variety of cancer cells and tumors [5,[98][99][100]. Redaporfin is a bacteriochlorin, not a metallobacteriochlorin, but it is included in Table 3 to allow for a direct comparison with the photophysical and photochemical properties of the recently developed metallobacteriochlorins.…”

Mechanistic studies on versatile metal-assisted hydrogen peroxide activation processes for biomedical and environmental incentives

“…It is an example of how the dynamics of the interaction between light, a photosensitizer and oxygen can be tuned to increase therapeutic efficacy. The fact that redaporfin interacts with molecular oxygen both through type I and type II photoreactions makes it versatile in the treatment of a variety of cancer cells and tumors, such as melanoma [233,234,242], lung adenocarcinoma [230,232] and colon carcinoma [275][276][277]. It is currently in phase II clinical trials for head and neck tumors.…”