Design And Properties Of Multifunctional Manganese Dioxide-based Nano-drug Carriers

Nano drug delivery system(NDDS)have attracted more and more attention because of their potential for cancers targeted and multimodal combination therapy.Nano-manganese dioxide(MnO₂)has high drug loading,good biocompatibility and responsive degradation performance.After surface modification,it can avoid drug release in advance,realize targeted drug delivery and precise cancer treatment,and has become one of the important drug carriers.Based on biomimetic and mineralization methods,three MnO₂-based drug carriers were synthesized in this paper:The first part of the research work explores a new method of drug visual loading in order to solve the tedious process of drug loading monitoring.In the second part,the visual loading technology of various drugs was established,and the anticancer activity of drug synergistic therapy was studied.In the third part,we focus on a greener and healthier method of starvation-gas synergistic treatment,realize the loading of glucose oxidase(GOX)and L-arginine(L-Arg),and systematically study the mechanism of apoptosis.All three works have achieved good cancer treatment results,and the specific contents are as follows:In order to improve the drug loading efficiency and solve the tedious process of drug loading monitoring,the first part of the work realized the visual monitoring of drug loading and release.To build this system,highly fluorescent carbon quantum dots(CQDs)were firstly synthesized and served as an effective indicator and carrier to achieve visual doxorubicin(DOX)loading by the strong fluorescence resonance energy transfer(FRET)interactions between them.Biodegradable nano-MnO₂was then synthesized by biomineralization with folic acid(FA)modified bovine serum albumin(BSA),which was employed as the other fluorescence quencher for CQDs and DOX and established the other FRET system to visually monitor drug loading.The double-FRET nanosystem could be specifically ingested by cancer cells and responsively degraded by intracellular H⁺/H₂O₂or glutathione(GSH).Meanwhile,this triggered drug release behavior was visually detected after gradual dissociation of the two FRET systems by monitoring the fluorescence and magnetic resonance changes.Both in vitro and in vivo experiments demonstrated that the novel nanosystem exhibited much better cancer therapy effects than pure DOX,and this paper also reported its first experimental example to treat cancer migration,demonstrated its good performance in cancer therapy and anti-migration.In the second part of the work,inspired by the structure of leaves,a novel MnO₂-based biomimetic nanosystem was constructed to overcome the cells resistance during treatment.Leaf-like MnO₂with hollow tubes and wrinkled sheets was first synthesized,and further modified by dopamine(DA)for effective loading both hydrophilic and hydrophobic drugs.The degradation of MnO₂can be well controlled by adjusting the thickness of poly-dopamine(PDA)film,and the strong?-?interactions between them also establish an strong FRET system,which allows us unprecedentedly to conveniently monitor drug loading process under naked eyes just by judging solution color changes.Additionally,in vitro experimental results demonstrate that the co-drug loaded system exhibits outstanding anti-cancer and anti-cancer migration therapy effect than single therapy,showing great potential application value.The third part of the work developed a new concept of starvation therapy pattern that employs biodegradable carriers with special selectivity and exhibits excellent anti-migration and therapy effect without using any invasive chemotherapy drugs.A facile biomineralization method is first chosen to synthesize human serum albumin(HSA)and folic acid(FA)modified MnO₂to guarantee active targeting,long-term stability and responsive degradation in tumor microenvironment.Designed degradation remarkably reduce GSH contents and hugely elevate intracellular O₂levels,both of which significantly improve the catalytic efficiency of glucose oxidase(GOX).Furthermore,the by-product of H₂O₂is intelligently used to oxidize L-arginine(L-Arg)and the generated nitric oxide(NO)results into effective gas therapy.The first anti-migration case of starvation therapy has been reported in this work,and detailed molecular mechanism study uncovers that lysosome damage and changes of mitochondria membrane potential contribute to cell apoptosis.This work opens up new ideas to construct novel green yet noninvasive methods to treat cancer and inhibit migration by using degradable carriers and endogenous substances to minimize adverse effect.