Development of Drug-loaded Nanoparticles for Targeted Chemotherapy.

drug delivery system;chemotherapy;cancer;nanoparticle;cisplatin;Biomedical Engineering;Health Sciences;Biophysics

Shirakura, TeppeiGafni, Ari ;

University of Michigan

关键词: drug delivery system;    chemotherapy;    cancer;    nanoparticle;    cisplatin;    Biomedical Engineering;    Health Sciences;    Biophysics;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/111622/tshira_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Cancer is the second highest cause of death in the US, and chemotherapy is one of the common cancer therapies. In order to reduce side effects and avoid cancer’s resistance to antitumor drugs, we use nanoparticle (NP)-assisted chemotherapy. This strategy can selectively deliver high concentrations of antitumor drugs to the tumor area, because NPs can encapsulate antitumor drugs, target the tumor area by active and passive targeting mechanisms, and release the drugs inside the cancer cells. This work focuses on three aspects of such NPs: high loading with antitumor drugs, controlled release of antitumor drugs, and high cellular uptake by the NPs. As a model system, polyacrylamide-based NPs were loaded with cisplatin. The effects of functional groups in the NPs, and the effects of matrix densities, were evaluated in terms of the NPs’ drug-loading, their release profile, and their cellular uptake. The carboxyl-functionalized NPs achieved 2 times higher loading and faster release of cisplatin than the amine-functionalized NPs. In contrast, the amine-functionalized NPs had 3.5 times better cellular uptake than the carboxyl-functionalized NPs. Tuning the matrix density of those NPs could control the release of cisplatin. Also, cisplatin-loaded, temperature-responsive NPs were synthesized so as to incorporate a trigger for cisplatin release in the cancer cells. The elevated temperature successfully enhanced the release of cisplatin from the synthesized NPs, especially under acidic conditions simulating lysosomes, which were the destination of the NPs inside the cells. Also, the in vitro cytotoxicity of the NPs is accelerated at high temperature. Finally, polyethylenimine (PEI) was incorporated into cisplatin-loaded PAA-NPs. Incorporation of PEI enhanced the cellular uptake of the PAA NPs 7 times, and resulted in significantly higher cytotoxicity. Other properties of these NPs, such as enhanced loading, enhanced release, and endosomal escape may contribute to their higher cytotoxicity. These results confirmed the importance of the following three factors when designing NPs for NP-assisted chemotherapy: (1) high loading with antitumor drugs, (2) controlled release of antitumor drugs, and (3) high cellular uptake of the NPs.