| Changes in people’s living environment,their own physical causes and the aging of the population have led to a sharp increase in the incidence of cancer.At present,cancer is usually treated by chemotherapy.However,due to the increased resistance of tumors,toxic and side effects of drugs,tumor tissue permeability and other problems,the anti-tumor efficacy is poor.Therefore,the development of a suitable drug delivery system to increase the load and delivery management of anticancer drugs has become a new way to solve these problems.In this paper,using natural polysaccharide chitin as the matrix,two chitin-based nano-drug controlled release systems with biodegradability and tumor drug-responsive delivery were developed,and the drug loading capacity and responsiveness of the anti-tumor drug doxorubicin hydrochloride were studied Drug slow-control behavior,evaluate the intracellular delivery performance and drug uptake accumulation capacity of anti-tumor nano-drugs,construct a mouse liver cancer model,and evaluate the biocompatibility and anti-tumor activity of nano-drugs.The following conclusions are obtained:1)Study on Controllable Preparation and Antitumor Drug Delivery of pH / Enzyme Dual Response Nanochitin / Gelatin Hybrid NanogelFirst,to address the problems of poor water solubility of natural chitosan,poor colloid stability,and insufficient controlled release of drug response,a nano-drug delivery system with dual responsiveness to pH and enzyme was designed.We use self-assembly technology to physically assemble the metalloproteinase(MMP2)responsive gelatin onto the surface of the nano-chitin particles,and use glutaraldehyde as a cross-linking agent to effectively treat the gelatin shell layer after the gelatin shell layer is treated.Sex.Optimized preparation of nano-hybrids with a size of 178.7 ± 2.4 nm,the loading rate of the nano-drug on doxorubicin reached 73.1 ± 3%,compared with pure nano-chitin,the loading efficiency of doxorubicin increased by 1.2 times,The cumulative release efficiency of doxorubicin in normal pH 7.4 physiological environment is only ～ 46%,while under the stimulation of tumor weak acidity and high expression enzyme microenvironment signal,the cumulative release rate of the drug is increased to 83% and 82%,respectively,1.8 times and 1.7 times the original.It shows that chitin / gelatin nanogel has excellent anti-tumor drug loading capacity,and exhibits good pH and enzyme dual-responsive delivery function.Through the zoology evaluation of co-cultured with human lung cancer cells(A549),we found that nanogels have good cell compatibility,can effectively enhance the delivery of anti-tumor drugs in the cell and the long-term accumulation in the package,and can significantly inhibit the growth of tumor cells.(The IC50 value inhibits tumor cells by 2.15 times that of doxorubicin).After that,we constructed a mouse liver cancer model and evaluated the anti-tumor activity of the nanogel drug in vivo.The results showed that the nanogel material has good biological safety and can effectively inhibit the growth of tumor volume.2)Controllable Construction and Antitumor Activity of Multifunctional Nanogels with Both pH / Redox / Enzyme Multiple Response and Cascade Drug Delivery FunctionNanomedicines currently in clinical use(such as liposomes,micelles,etc.)generally have poor colloidal stability and lack of active response controlled-release performance,and the size of these nanomedicines is generally large(100-200 nm),and there is a large The size steric hindrance effect greatly reduces the deep penetration of the tumor tissue of the drug,and the clinical cure effect is limited.In response to these problems,on the basis of our previous research,we designed and prepared a multifunctional nano-drug delivery system with both pH / redox / enzyme multi-responsiveness and tumor drug cascade delivery function.Firstly,for the problems of natural hydrophilicity and poor colloidal stability of natural chitosan,the hydrophilic carboxymethyl chitosan was introduced into the chitosan matrix through the principle of self-assembly,and sodium tripolyphosphate was introduced to physically perform the nano-assembly system Pre-crosslinking,and then using the Michael addition technology to carry out secondary chemical crosslinking of N,N bisacryloyl cystamine and amino groups on chitosan to construct a double-network cross-linked structure with positively charged nano-hybrid coagulation Glue(CTCB).In order to regulate the surface potential of the nanogel,we further assembled the negatively charged low molecular weight polyacrylic acid molecules onto the surface of the CTCB nanogel by electrostatic assembly technology,which effectively controlled and controlled the surface charge of the nanogel from positive to negative.Selective management of drugs(negatively charged DNA and positively charged doxorubicin).The CTCP nanogel with a negatively charged surface of95.8 ± 1.5 nm in size was successfully prepared through process optimization,and the loading of doxorubicin hydrochloride was 92.1 ± 3.6%.The nano-drug was weakly acidic /lysozyme / reducible Under the micro-environmental conditions,it has a long-term drug release capability(48 h).Simulating the weak acidity of the tumor microenvironment and the multiple corresponding signals of high expression of lysozyme greatly stimulates the drug release efficiency(～ 90%).When the tumor microenvironment with high expression of glutaminase and lysozyme can cleave the nano-drug to release ～ 1000 drug-loaded small-sized nano-subunits(4 ± 1 nm),and continue under the tumor pathological micro-environment The release of DOX can effectively reduce the toxic and side effects of sudden release of DOX.In vitro cell experiments show that nanomedicines have excellent biocompatibility / biosafety and enhanced antitumor efficacy(compared to free drugs,IC50 for cancer cells is reduced by 2.6 times.In vivo mouse liver cancer constructed The model study found that mice treated with nano-drugs can maintain a 100% survival rate,and the vital organs of mice treated with free DOX drugs are severely damaged and all died after 7 days of treatment.The tumor size increased significantly,and the tumor size of mice in the nano-administration group continued to decrease within 15 days,indicating that CTCP nanogel has good anti-tumor activity. |
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