In-vivo pharmacokinetics of δ-ALA induced PPIX during photodynamic therapy on mice tumor model

Abstract

In the recent years (delta) -aminolevulinic acid ((delta) -ALA) a precursor for the endogenous production of protoporphyrin IX (PPIX) has gained importance in the Photodynamic Therapy (PDT) of superficial and early-stage cancers. Though (delta) -ALA is present naturally in the cells, systemic administration of exogenous (delta) -ALA leads to the production of intracellular endogenous PP IX in both the tumor and the normal cells, but with varying concentration. However, the PPIX is accumulated more in the tumor tissues as the fast growing tumor cells take up the administered (delta) -ALA more than the normal cells. As the therapeutic efficacy of PDT is dependent on the post (delta) -ALA incubation time, at which the tumor to normal ratio of the PPIX concentration is high, the concentration of the PPIX in the normal and the tumor site were estimated using fluorescence spectroscopy. However, the estimation of the PPIX concentration during/after PDT is mandatory, as the PDT dosimetry is dependent on the sensitizer concentration at the target of interest. The observed variation in the concentration of PPIX in the tumor site with respect to the unexposed normal surrounding tissues, may be attributed to the diffusion of PPIX from the surrounding normal tissues to the tumor site, across the concentration gradient. Based on this a mathematical model has been proposed, to estimate the rate parameter for the diffusion of PPIX from the surrounding normal tissues in to the tumor tissue (K_m), due to photobleaching during PDT at two different fluence. The K_m value at two different fluences, 57.6 and 36 J/cm2 are estimated as 5.444+/- 1.186 and 3.221+/- 0.957, respectively. Further, the rate parameter for the cleavage and efflux of (delta) -ALA (K1), and the rate parameter for the evasion of the PPIX from the tumor tissues during PDT (Kt), were also estimated by fitting the experimental data to the developed mathematical model. The estimated parameters will be utilized to estimate the exact concentration of PPIX in the tumor tissues for a better PDT efficacy.