Antitumor effect of photodynamic therapy with a novel targeted photosensitizer on cervical carcinoma

Abstract

The antitumor effect of photodynamic therapy (PDT) mediated by a novel photosensitizer I (Ps I; {γ-[N-poly(ethyleneglycol)]folic acid}-5,10,15-tris(3-hydroxyphenyl)-20-(4-carboxyphenyl)chlorin), in which chlorin was used as a photoactive unit, folic acid as a tumor‑targeting warhead, and polyethylene glycol as a linker, on cervical carcinoma was studied in vitro and in vivo. Ps I exhibited a considerably higher cellular uptake by HeLa cells than folic acid-free analogue Ps A (tert-butyl N-poly(ethyleneglycol)ethylcarbamate-5,10,15-tris(3-hydroxyphenyl)-20-(4-carboxyphenyl)chlorin), and the cellular uptake by HeLa cells of Ps I could be competitively inhibited by excess folic acid. Moreover, at different time points after the intravenous (i.v.) injection of Ps I and A, Ps I produced a >2-fold higher tumor to normal tissue ratio in tumor-bearing nude mice as compared to Ps A. MTT assay indicated that the HeLa cell proliferation inhibition ratio was increased 34% after Ps I-PDT compared with Ps A-PDT with a photosensitizer concentration of 15.2 µmol/l. Administration of Ps I (7 mg/kg, i.v.) followed by light exposure (80 J/cm2) markedly suppressed the growth of xenograft tumors, and the tumor volume was 10-fold smaller than that of the control group. Tumor growth inhibition in vitro and in vivo had an obvious dependency on the Ps I concentration and irradiation dose. The mode of cell death post-Ps I-PDT was analyzed by flow cytometry, confocal laser scanning microscopy, and electron microscope, and the results suggested that apoptosis was the primary mode of HeLa cell death induced by Ps I-PDT. The results also demonstrated that tumor targeting of Ps I was clearly improved because of the endocytosis mediated by the folate receptor. As a result, Ps I-PDT exhibited higher antitumor activity than Ps A-PDT and has potential as an alternative treatment modality for cervical cancer.

Advances in targeting the folate receptor in the treatment/imaging of cancers

“…This technology involves light-mediated activation of a photosensitiser in the presence of oxygen and the subsequent generation of reactive oxygen species that neutralise the cells that have been exposed to the photosensitiser. 48 Moreover, the advantages of light-based techniques include non-invasive activation and added selectivity from the ease of this medium's spatial and temporal manipulation. 49 An example of a promising class of photosensitisers are boron dipyrromethene (BODIPY) derivatives that possess attractive optical and photophysical properties as well as displaying high stability in aqueous media.…”

“…Other examples of FA–SMDCs whose cell-killing action is triggered by light include combretastatin A-4 prodrugs activated by visible/near IR, 51 a folate–doxorubicin conjugate that liberates doxorubicin when irradiated with UV-light 49 and a folate–chlorin conjugate where the photosensitising ability of the chlorin unit is activated upon irradiation of red light. 48 …”

Photodynamic Efficiency: From Molecular Photochemistry to Cell Death

“…Some specific biomarkers overexpressed in tumor cells have also been used to further concentrate PS in tumors. In addition, PSes conjugated to antibodies, peptides ligands, and proteins exhibits special targeting, as well as PSes conjugated to non-protein ligands (e.g., folic acid) have been proposed [ 180 , 186 , 187 , 188 , 189 , 190 ]. Another strategy is to use pH-activatable PSes, which respond to the higher acidity of cancer cells, and glutathione-activated PS, since glutathione concentration is also higher in these cells [ 191 , 192 , 193 , 194 ].…”

Folate receptor-targeted near-infrared photodynamic therapy for folate receptor-overexpressing tumors

“…It binds to extracellular folate with very high affinity and can physically deliver folate into the cell through endocytosis[ 17 ]. Therefore, FR is a good candidate for tumor-specific PS targeting[ 9 , 18 ]. Specific active targeting of PS to FR present on the cancer cell surface can be achieved by conjugation with the folate moiety[ 19 ].…”