Targeted Photodynamic Killing Of Breast Cancer Cells Employing D-Mannose-modified Nanoparticle Loaded With Photosensitizers

Chemotherapy is one of the most widely applied therapies in cancer treatment.However,traditional chemotherapeutic drugs distribute in the body non-specifically,resulting in problems like low bioavailability of anticancer drugs,undesired toxicity to normal cells as well as multidrug resistance of cancer cells,which have severely limited the application of chemotherapy in cancer treatments.To solve these problems,various targeted drug delivery systems were studied.A new safe treatment,photodynamic therapy,had been developed and achieved good results.It apply targeted delivery carriers to enrich the low dark toxic photosensitive drugs in the tumor site.When exposed to a specific wavelength of light,these drugs can produce strong oxidative singlet oxygen,which would kill cancer cells.Worthy of note is that because of nice biocompatibility of photosensitive drugs,the nano-materials usesd to photodynamic therapy is of great potential in research and application.In this study,D-mannose-modified hydrophilic β-cyclodextrin(CD-Man7)and a three-arm adamantine-conjugated BODIPY photosensitizer(denoted as BTA)were synthesized respectively.Because of the presence of supramolecular host-guest interactions between β-cyclodextrin and adamantane,the BTA-loaded nanoparticles BTA@CD-Man7 were prepared through co-assemble between CD-Man7 and BTA.Structures of CD-Man7 and BTA was confirmed by 1H NMR and MALDI-TOF etc.The sizes,morphologies and stability of the special nanoparticle BTA@CD-Man7 were characterized by transmission electron microscopy and dynamic light scattering.The results showed D-mannose had palyed an important role in maintaining nanostructures and solvent-stability of BTA@CD-Man7.The singlet oxygen(1O2)generation efficiency of BTA@CD-Man7 in water or DMSO also was evaluated by fluorescence spectrophotometer.And the results showed 1O2 generation need molecular state of BTA and 665 nm LED irradiation.Using mannose-receptor-over-expressing human breast cancer cells MDA-MB-231 as model tumor,the in vitro cellular uptake and photodynamic therapy effect of BTA@CD-Man7 were evaluated by confocal laser scanning microscopy.The results showed that BTA@CD-Man7 are selectively internalized by mannose-receptor-over-expressing MDA-MB-231 breast cancer cells via receptor-mediated endocytosis,and cancer cells apoptosis occurred due to 1O2 generated by BTA@CD-Man7 under NIR irradiation,while mannose-receptor-poor MCF-10 A cells showed much lower photodynamic therapy effect.Compared with BTA@CD,BTA@CD-Man7 have a great tumor growth-inhibition effect in vitro and in vivo on MDA-MB-231 tumor cells.In conclusion,our prepared BTA@CD-Man7 showed excellent targeted photodynamic therapy efficacy and low dark toxicity,thus this new strategy for photodynamic therapy system has the potential to develop as an effective system with few side effects and high efficacy and applied in targeted photodynamic therapy for breast cancer.