Abstract
The aim of this study was to fabricate a reactive oxygen species (ROS)-sensitive and folate-receptor-targeted nanophotosensitizer for the efficient photodynamic therapy (PDT) of cervical carcinoma cells. Chlorin e6 (Ce6) as a model photosensitizer was conjugated with succinyl β-cyclodextrin via selenocystamine linkages. Folic acid (FA)-poly(ethylene glycol) (PEG) (FA-PEG) conjugates were attached to these conjugates and then FA-PEG-succinyl β-cyclodextrin-selenocystamine-Ce6 (FAPEGbCDseseCe6) conjugates were synthesized. Nanophotosensitizers of FaPEGbCDseseCe6 conjugates were fabricated using dialysis membrane. Nanophotosensitizers showed spherical shapes with small particle sizes. They were disintegrated in the presence of hydrogen peroxide (H2O2) and particle size distribution changed from monomodal distribution pattern to multimodal pattern. The fluorescence intensity and Ce6 release rate also increased due to the increase in H2O2 concentration, indicating that the nanophotosensitizers displayed ROS sensitivity. The Ce6 uptake ratio, ROS generation and cell cytotoxicity of the nanophotosensitizers were significantly higher than those of the Ce6 itself against HeLa cells in vitro. Furthermore, the nanophotosensitizers showed folate-receptor-specific delivery capacity and phototoxicity. The intracellular delivery of nanophotosensitizers was inhibited by folate receptor blocking, indicating that they have folate-receptor specificity in vitro and in vivo. Nanophotosensitizers showed higher efficiency in inhibition of tumor growth of HeLa cells in vivo compared to Ce6 alone. These results show that nanophotosensitizers of FaPEGbCDseseCe6 conjugates are promising candidates as PDT of cervical cancer.
Highlights
To synthesize the FaPEGbCDseseCe6 conjugates, the Chlorin e6 (Ce6) was conjugated with selenocystamine and these conjugates were conjugated again with succinyl β-cyclodextrin to produce succinyl β-cyclodextrin-selenocystamine-Ce6 conjugates, as shown in Figure S1 and Figure 1
These results mean that the nanophotosensitizers must have been swollen by H2 O2 and, after that, they disintegrated at a high concentration of H2 O2. These results indicated that nanophotosensitizers of the FaPEGbCDseseCe6 conjugates displayed reactive oxygen species (ROS) sensitivity and their physicochemical properties could be altered in the presence of ROS
These results indicate that nanophotosensitizers of FaPEGbCDseseCe6 conjugates have ROS-sensitivity
Summary
Treatment of cervical cancer includes surgery, radiotherapy and chemotherapy according to the pathological stage [4,5,6]. Pre- or postoperative adjuvant therapy was tried to treat primary or recurred cervical cancer [10,11,12,13,14]. Wang et al reported that neoadjuvant chemotherapy of cervical cancers is effective in reducing the sizes of tumors and in potentiating the resectability of tumors [11]. These approaches may effectively reduce the risk of pathologic progress in cervical cancer. Kim et al reported that postoperative adjuvant therapy with chemoradiation decreases the recurrence rate [12]
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