Preparation And Anti-tumor Research Of Stimulating Response Nanomedicines

Cancer is one of the main diseases that affect human health and threaten human life.The drugs used to treat cancer mainly include small molecule chemotherapeutics and biomacromolecule anticancer drugs.However,due to the poor selectivity of most anti-cancer drugs,they can cause irreversible damage to healthy cells of patients.Therefore,the development of safe and effective anti-tumor drugs is significant.Nanocarriers can not only improve the solubility and bioavailability of poorly soluble drugs,but also protect biomacromolecule drugs from degradation;At the same time,the drug can be endowed with new characteristics,so that it has the characteristics of targeting,slow release and controlled release,so as to reduce adverse reactions,reduce toxic side effects,improve and broaden the application of active drug disease.In this paper,we mainly focused on the anticancer drugs of small molecular drugs,such as sorafenib,paclitaxel,and biological macromolecular tumor suppressor drugs such as RNase A,DNase I,siRNA.We designed and prepared stimuli-responsive self-assembled nanomedicine to efficiently deliver drugs to tumor sites for antitumor research.(1)Quantitative and high drug loading of self-assembled prodrug with defined molecular structures for murine hepatoma 22 therapyAn innovative glutathione(GSH)-sensitive amphiphilic dendritic prodrug(SFP)with quantitative and high drug loading(> 30 wt%)is reported in this chapter.The multi-armed structure of SFP can self-assemble into nanoparticles in aqueous solution without the introduction of any organic solvents.The self-assembled prodrug nanoparticle is composed of the following key components:(i)polyethylene glycol(PEG)outer shell ensuring biocompatibility and prolonging blood circulation,(ii)prodrug inner core responding to GSH for triggered release of intact drug,(iii)multi-armed dendritic structure facilitating self-assembly and enhancing drug loading content,(iv)covalent drug conjugation avoiding drug leakage and improving stability,(v)defined chemical structures and quantitative drug loading easy for reproduction.Both in vitro and in vivo results show that these GSH-responsive prodrug nanoparticle exhibits significant inhibition of tumor cells in the murine hepatoma 22 model,and is expected to achieve efficient and safe delivery of chemotherapeutic drugs.(2)Nucleus-targeted delivery of multi-protein self-assembly for combined cervical cancer therapyWe presented an efficient intranuclear protein delivery nanoplatform which realizes the intracranuclear delivery of ribonuclease A(RNase A)and deoxyribonuclease I(DNase I).Adamantane and RNase A are covalently coupled to form R-A,and then combined with cyclodextrin which modified with lysine to form RNase A-WLC(R-WLC).R-WLC can not only enhance the cellular uptake of RNase A and accumulate it into the nucleus,but also work as nanovehicle to efficiently transport deoxyribonuclease I(DNase I)into the nucleus.Through in vivo imaging of small animals,the accumulation of fluorescent labeled RNase A and DNase I can be seen intuitively at tumor sites,and significant tumor inhibition effect is observed in mouse model of cervical cancer,which provides a strong evidence for combined treatment of multiprotein.This protein co-assembly strategy can be applied to other functional proteins and has great prospects in the treatment of many diseases.(3)Paclitaxel-based stimulus-responsive polymer prodrugs combined with siRNA interference technology for hepatocellular carcinoma therapyIn this chapter,a stimulant response delivery platform was designed and constructed based on chemotherapeutic drug paclitaxel and genetic drug siRNA to achieve synergism in the treatment of liver cancer.First,we used a disulfide bond to bridge paclitaxel and a positively charged lysine derivative molecule,and modified it on the side of β-cyclodextrin by “copper-free click” to form paclitaxel/lysine-cyclodextrin(TMC).Subsequently,the positively charged lysine group in the TMC nanoparticles can encapsulate negatively charged siRNA through electrostatic interaction to form TMC/siRNA.Under the stimulation of GSH in tumor cells,the system can successfully deliver drugs and nucleic acids to tumor cells and release paclitaxel and STAT3-siRNA.It can not only achieve the effect of chemotherapeutic drugs on cancer,but also show remarkable gene silencing effect and hepatocellular carcinoma therapy effect.This combined anticancer strategy provides a good idea for the exploration and development of various anticancer drugs.