Purpose Boron neutron capture therapy (BNCT) is an emerging binary radiotherapy, which is limited for application due to the challenge of targeted delivery into tumor nowadays. Here, we propose the use of iRGD-modified polymeric nanoparticles for active targeted delivery of boron and doxorubicin (DOX) in BNCT.Methods 10B-enriched BSH was covalently grafted to PEG-PCCL to prepare 10B-polymer, then surface-modified with iRGD. And, DOX was physically incorporated into polymers afterwards. Characterization of prepared polymers and in vitro release profile of DOX from polymers were determined by several methods. Cellular uptake of DOX was observed by confocal microscope. Accumulation of boron in cells and tissues was analyzed by ICP-MS. Biodistribution of DOX was studied by ex vivo fluorescence imaging and quantitative measurement. Tumor vascular normalization of Endostar for promoting delivery efficiency of boron on refractory B16F10 tumor was also studied.Results The polymers were monodisperse and spheroidal in water with an average diameter of 24.97 nm, which were relatively stable at physiological pH and showed a sustained release of DOX, especially at endolysosomal pH. Enhanced cellular delivery of DOX was found in iRGD-modified polymer group. Cellular boron uptake of iRGD-modified polymers in A549 cells was remarkably raised fivefold (209.83 ng 10B/106 cells) compared with BSH. The polymers represented prolonged blood circulation, enhanced tumor accumulation of 10B against BSH, and favorable tumor:normal tissue boron concentration ratios (tumor:blood = 14.11, tumor:muscle = 19.49) in A549 tumor-bearing mice 24 hrs after injection. Both fluorescence imaging and quantitative measurement showed the highest tumor accumulation of DOX at 24 hrs after injecting of iRGD-modified polymers. Improvement of vascular integrity and reduction of vascular mimicries were found after Endostar injection, and raised tumor accumulation of boron as well.Conclusion The developed nanoparticle is an inspiring candidate for the safe clinical application for BNCT.
The multi-modal combination therapy is proved powerful and successful to enhance the antitumor efficacy in clinics as compared with single therapy modes. In this study, the potential of combining chemotherapy with antiangiogenic therapy for the treatment of non-small-cell lung cancer is explored. Towards this aim, OEGylated carboxymethyl cellulose–(2-(2-(2-methoxyethoxy)ethoxy)methyl)oxirane (CMC–ME 2 MO) is prepared by treating CMC with ME 2 MO in the alkaline aqueous solution, and used to efficiently carry doxorubicin (DOX) with high drug-loading content (16.64%) and encapsulation efficiency (99.78%). As compared to free DOX, the resulting nanoparticles show not only the favorable stability in vitro but also the prolonged blood circulation, improved safety and tolerability, optimized biodistribution, reduced systemic toxicity, and enhanced antitumor efficacy in vivo, indicates a potential utility in cancer chemotherapy. Furthermore, the combination of the DOX-loaded polysaccharide nanoparticles and antiangiogenic drug endostar provides synergistic effects of chemotherapy and antiangiogenic therapy, which shows the highest efficiency in tumor suppression. The combination approach of the DOX-containing nanomedicine and endostar for efficient treatment of non-small-cell lung cancer is first proposed to demonstrate the synergistic therapeutic effect. This synergistic combination proves to be a promising therapeutic regimen in cancer therapy and holds great potential for clinical application.
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