Antitumor effect of photodynamic therapy with a novel targeted photosensitizer on cervical carcinoma.
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.
State Key Laboratory of Trauma, Burn and Combined Injury, The Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, Sichuan 400042, P.R. China.
Peng-Xi
PX
Li
Department of Pathology, Daping Hospital, Third Military Medical University, Chongqing, Sichuan 400042, P.R. China.
Jiang-Hong
JH
Mu
Department of Pathology, Daping Hospital, Third Military Medical University, Chongqing, Sichuan 400042, P.R. China.
Hua-Lang
HL
Xiao
State Key Laboratory of Trauma, Burn and Combined Injury, The Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, Sichuan 400042, P.R. China.
Dong-Hong
DH
Li
D000818:Animals; D017209:Apoptosis; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011166:Porphyrins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D014018:Tissue Distribution; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D017319:Photosensitizing Agents; D011166:Porphyrins; C000599509:Ps I photosensitizer