A Nanomedicine Consisted Of Natural Polyphenol And Bortezomib Preparation And Biomedical Applications

Bortezomib（BTZ）,which has been approved as a borate proteasome inhibitor for clinical treatment,is less effective against solid tumors.The main reasons are the severe toxic side effects and poor tumor penetration ability during chemotherapy.Two major strategies to deliver BTZ are physically encapsulating drugs within a nanocarrier or chemically conjugating the drug to polymeric scaffolds.However,the current delivery systems for BTZ still possess some limitations such as low BTZ loading,poor tumor penetration and polymer degradation.There is still an urgent need to develop a green and facile delivery system for BTZ to reduce the toxic side effects of BTZ and achieve a better therapeutic effect in clinic treatments.The dissertation focuses on proposing a novel carrier-free drug delivery system for BTZ.This thesis consists of three chapters.Chapter 1 introduced the categories,principles and applications of several drug delivery systems.We also provided a summary about the research progress of boronic medicines and natural polyphenols.Finally,the content of this dissertation was described.In chapter 2,a strategy of carrier-free delivery system for bortezomib was proposed and investigated from the following three aspects:（1）A nanoparticle consisted of bortezomib,tannic acid,and iron（BTI）was synthesized.The amphiphilic complex formed by bortezomib and tannic acid could form nanoparticles by self-assembly in water and then the BTI nanoparticles that are stable under physiological conditions are fabricated by mixing iron ions with the bortezomib/tannic acid nanoparticles.Transmission electron microscopy（TEM）and dynamic light scattering（DLS）measurements showed that the BTI nanoparticles can present in physiological conditions with a uniform particle morphology.（2）The release behavior and cytotoxicity of BTI nanoparticles were studied in vitro.This nanoparticle showed a significant acid-responsive drug releasing profile that is gradually increased according to decreasing pH value.BTI nanoparticles pre-incubated with acids can significantly kill cancer cells.Under physiological conditions,BTI nanoparticles showed no obvious toxicity towards normal cells.（3）We further investigated the therapeutic effect of BTI nanoparticles in vivo.The nanoparticles had excellent T₁ magnetic resonance imaging capability.By analyzing the therapeutic outcomes of BTI nanoparticles in two tumor models,we found that BTI nanoparticles have a more efficient tumor inhibition efficiency compared with the free BTZ.By further analyzing the histopathology and blood parameters,BTI nanoparticles can significantly reduce the toxic side effects of naked BTZ and have a better biological safety.The third chapter summarized the research results and gave a prospect of the polyphenol mediated carrier-free delivery system for boric acid containing drugs.We believe that as more and more natural polyphenolic compounds and boric acid containing drugs are discovered,this delivery strategy will achieve more attention and exploration,and will be utilized to the treatment of multiple tumors.