Synthesis And Application Of Stimulus Response Nano-drug Delivery

This study designed and synthesized three multifunctional drug delivery systems based on drug delivery and response release requirements.The results of the study indicate that the drug delivery system which we designed have the functions of response release,fluorescence imaging,photodynamic therapy and anti-aging treatment.It is expected that our work can provide beneficial applications for the wide application of nanomedicine-based drug delivery systems in biomedical applications.The main research work and results of this paper are as follows:(1)Design and preparation of a photodynamic therapy nano-system(CD-ALA-TPP)with a mitochondria-targeted and photo-controllable release system.The system containing a carbon quantum dot with strong fluorescence emission and good water solubility(C-dot)as a carrier,5-ALA as a precursor for photosensitizer PpIX and a hydrophobic cation compound triphenylphosphine(TPP).Photo-controlled release was achieved by a coumarin group.The nano drug-loading system can rapidly release 5-ALA under single-photon or two-photon illumination,and the latter undergoes biotransformation in the cell to form a photosensitizer PpIX,which generates singlet oxygen after light irradiation,so as to achieve inhibition of cancer cells.The system also has the function of cell imaging.Nanoparticles can be traced by monitoring the fluorescence of C-dot and coumarin.The intracellular release of 5-ALA can also be obtained by observing the fluorescence of endogenous PpIX.This strategy can not only avoid the side effects of common photodynamic therapy,but also improve the bioavailability of 5-ALA.(2)A photodynamic therapy nano-drug delivery system(LIP-ALA-As-TPP)with mitochondrial targeting and responsive to dithiol proteins was designed and prepared.In the synthesis of the drug-loading system,we used the reaction of p-aminophenylarsine and dimercaptopropanol to obtain the intermediate linkage,and connected the photosensitizer precursor 5-ALA and the hydrophobic cation TPP.When the drug system enters cancer cells,the drug is enriched in the vicinity of the mitochondria with the help of the mitochondria-targeting function of TPP,and 5-ALA is released under the action of intracellular dithiol proteins.After biotransformation,PpIX is formed and generates singlet oxygen after light irradiation for anti-cancer therapeutic effects.Illumination of PpIX can also be traced by the release process.After liposome-encapsulated drugs were used to form nano drug delivery systems,they also showed good anti-tumor effects in tumor mice model.This drug system with targeted and intracellular controlled release functions demonstrates its potential for application in the field of photodynamic therapy.(3)Design and preparation of a PLL-g-PEG-QA@siRNA based on quercetin and siRNA for anti-oxidative stress nano drug delivery system.We combined genetic and chemical drugs to achieve better anti-oxidative stress effects.We first connected the quercetin to the hydrophilic poly(L-lysine)molecular chain by electrostatic interaction,and formed a nanoprodrug by electrostatic interaction with a p66 ShcA interfering RNA in the aqueous phase.Under acidic conditions in the cell,the electrostatic interaction between quercetin and poly(L-lysine)in the nanoprodrug breaks down,the structure of the micelle breaks down,and at the same time the two active drugs which are quercetin and siRNA are released simultaneously.Quercetin can regulate the level of reactive oxygen species as an activator of SIRT1 protein.The release of interfering RNA can not only silence the expression of p66 ShcA gene,but also up-regulate the level of p66 ShcA at the protein level to achieve better anti-oxidative stress effects.We also preliminarily explored the application of the nano-drug system in anti-aging.In the D-galactose-induced aging mice model,nano-drug loading system can effectively increase the content of multiple oxidative stress proteins in mice and reduce the toxic compound MDA.The results show that the nanoprodrug system has a certain effect of delaying aging.In summary,the drug delivery system we designed and prepared,combined with cell imaging and responsive release,which have the characteristics of enhancing disease treatment,reducing toxic and side effects,and increasing bioavailability,and it has good anti-cancer and antioxidant properties.The therapeutic effect is expected to provide some new ideas and basis for the future design and preparation of nano drug delivery systems.