Optimizing Photodynamic Therapy:In vivoPharmacokinetics of Liposomalmeta-(Tetrahydroxyphenyl)Chlorin in Feline Squamous Cell Carcinoma

Abstract

Purpose: The aim of the present study was to optimize and simplify photodynamic therapy using a new liposomal formulation of the photosensitizer meta-(tetrahydroxyphenyl)chlorin [m-THPC (Foscan); liposomal m-THPC (Fospeg)] and to reduce systemic reactions to the photosensitizer. Experimental Design:To examine the pharmacokinetics of liposomal m-THPC, we determined tissue and plasma variables in feline patients with spontaneous squamous cell carcinoma. In vivo fluorescence intensity measurements of tumor and skin were done with a fiber spectrophotometer after i.v. injection of m-THPC or liposomal m-THPC in 10 cats. Blood samples, drawn at several time points after photosensitizer administration, were analyzed by high-performance liquid chromatography. The first reports on photodynamic therapy (PDT) date back to the beginning of the last century, when researchers observed that a combination of light with hematoporphyrin induces cell death (1). In 1995, the U.S. Food and Drug Administration approved PDT as a novel form of therapy against cancer, and since then, PDT has been used more frequently.PDT includes two components combined to induce cellular and tissue effects in an oxygen-dependent manner. The first is a ''light-sensitive'' substance called the photosensitizer. The second is light of a specific wavelength (laser light) to maximally activate the tumor-localized photosensitizer. On activation, a photosensitizer undergoes type I (electron or hydrogen transfer) or type II (local generation of cytotoxic singlet oxygen) photochemical reactions.Tumor destruction associated with PDT involves three principal mechanisms (2): (a) direct tumor cell kill (3), (b) destruction of tumor-associated vasculature (4 -6), and (c) activation of an immune response against tumor cells (7,8). A short drug-light interval allows the photosensitizer to accumulate predominantly in the vascular compartment. PDTmediated vascular effects range from transient vascular spasm, vascular stasis, and thrombus formation to total permanent vessel occlusion and can include enhanced vascular leakiness (5). A longer drug-light interval results in maximal concentration of the photosensitizer in the tumor, causing direct tumor cell destruction. This was shown recently for the secondgeneration photosensitizer meta-(tetrahydroxyphenyl)chlorin [m-THPC (Foscan)] and indicates that the in vivo effects occur via an indirect vascular effect as well as a more direct effect at different drug-light intervals (9, 10).To optimize PDT, liposomes are presently being tested as carrier and delivery systems with the aim of improving the tumoritropic behavior of photosensitizers.

Nanodrug applications in photodynamic therapy

“…One current example of a "nanoformulation" photosensitizer used in PDT is the liposomal formulation of one of the most promising PS 5,10,15,20-tetra(mhydroxyphenyl)chlorin (mTHPC, Foscan, Temoporfin) which has been loaded into dipalmitoyl phosphatidylcholine/dipalmitoyl phosphatidylglycerol (DPPC/DPPG) liposomes, in a ratio of 9:1 [47]. This liposomal formulation of Foscan (Foslip ® ) belongs to the third generation photosensitizers and seems to be a valuable alternative to Foscan in PDT.…”

“…Like for Visudyne  many studies have been published on Foslip. These include studies on the putative absence of side effects [47], efficacy and reduced damage of healthy tissue compared to the non-liposomal formulation Foscan ® [48,49]. Newer studies are related to the potential use of an intratumoral injection of a liposomal formulation of Foslip in a mouse model of local recurrence of breast cancer [129] and its photothrombic activity [130].…”

“…Various studies have been reported on Foslip  , such as on side effects [47], photodynamic efficiency, toxicity, decreased damage of healthy tissue [48,49], tumor selectivity [164] or skin delivery [165]. Not long ago, the potential use of a liposomal formulation of Foslip  was studied in a mouse model for the local recurrence of breast cancer [129].…”

mTHPC – A drug on its way from second to third generation photosensitizer?

“…This alters not only the solubility but also the size and thus results in different tumor:tissue distributions. Pegylated mTHPC derivatives are available with various degree of pegylation (different sizes) and the commercial version is called Fospeg® [14]. A similar strategy utilized the mTHPC compound in chemically unaltered form but incorporates them into vesicles to achieve nanosized formulations.…”

Comparative Oncology Today

“…This includes all traditional treatment modalities such as surgery, radiation therapy, immunotherapy and chemotherapy and novel investigational drugs available through participation in clinical trials. 4,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] …”