Photodynamic Therapy of Intracranial Tissues: A Preclinical Comparative Study of Four Different Photosensitizers

Abstract

For clinical PDT of most adult intracranial neoplasms ALA-induced PpIX appears to be promising, and SnET2 (liposomal) has potential for selective tumor destruction with relative sparing of white matter. Other normal brain structures and, for the other photosensitizers, also white matter are at risk of collateral damage, if exposed to light during PDT.

Photodynamic therapy in the treatment of intracranial gliomas: A review of current practice and considerations for future clinical directions

“…For a normal brain tissue, the e®ective attenuation coe±cient eff varies from 4.1 to 2.0 cm À1 for wavelength in the 630-690 nm range. 36,[50][51][52] The photodynamic threshold model, 44 …”

“…Hence, the selective uptake/retention of the photosensitizers provides the primary source for PDT treatment selectivity for GBM microinvasion within normal tissue. 36,[63][64][65] At a¯xed depth, d, beyond the bulk tumor resection, or distance from an interstitial light source with T t , T n , ½PS t , and ½PS n denoting the threshold values and photosensitizer concentrations for tumor and normal tissue respectively, selectivity requires the ratio of T t =½PS t to be smaller than the respective ratio of normal neuronal tissues.…”

“…34,35 For ALA, glioblastoma shows a larger synthesis and retention of PpIX compared to the normal surrounding brain tissue. [36][37][38][39] PpIX is synthesized via the heme biosynthesis pathway and preferentially retained in tumor cells which are decient in Fe 2þ and ferrochelatase, the enzyme responsible for the conversion of PpIX into heme (Fig. 2).…”

“…This suggests that personalized cancer medicine concepts are equally applying to PDT for GBM. The pharmacokinetic-based selectivity of the various photosensitizers translate at least partially into a clinical impact and prolong the survival times in early clinical trials, but not to the extent anticipated based on the large di®erences in photosensitizer uptake initially observed in preclinical studies for ALA induced PpIX 36,37 and also in some clinical studies for Photofrin, 26 HpD 25 and ALA induced PpIX 30 reporting speci¯c uptake ratio (SUR) of less than 10. In part, this is due to the intrinsic high sensitivity or low resilience of the normal tissue structures, particular astrocytes and neurons within the PDT treatment¯eld as shown by Lilge and Wilson.…”

“…In part, this is due to the intrinsic high sensitivity or low resilience of the normal tissue structures, particular astrocytes and neurons within the PDT treatment¯eld as shown by Lilge and Wilson. 44,42 Neurological de¯cits due to high radiant exposure [J cm À2 ] and hence high PDT dose, see below, are a limiting factor within the current PDT delivery concepts. Thus, most trials selected a more moderate light dose at the expense of tumor resection, to provide for a high quality of life for these patients post therapy, particularly when photosensitizer photobleaching is not a PDT-dose limiting e®ect.…”