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Research progress of exclusive original tumor microenvironment responsive nanoscale gel delivery system

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Doctor, Professor, doctoral supervisor. Currently, he is deputy director of pharmaceutical experiment center of China Pharmaceutical University, member of China Bio particle Committee and vice chairman of Nanjing Pharmaceutical Committee; ? editorial board members of many foreign journals such as toxicology, World Journal of drug delivery and more than 10 foreign journal reviewers such as IJP, ddip, molecules, JMPR, ijpp, bjmmr, etc. In the past five years, he has undertaken and participated in 12 national scientific research projects, 5 provincial and ministerial level projects, 7 authorized patents, 12 publicity projects and 1 industrialization project, published more than 40 scientific research papers in core journals at home and abroad, edited and participated in 12 textbook monographs, and won 14 national, provincial and school teaching and scientific research awards. ? main research direction: slow control preparation and microparticle drug delivery system.
Research progress of tumor microenvironment responsive nanoscale gel delivery system
[Abstract] tumor microenvironment responsive nanomaterial has attracted more and more attention in the field of nano drug delivery because of its unique gel three-dimensional network structure, good biocompatibility and long circulating time in vivo. According to different tumor microenvironment, they can be divided into 2 categories: biological microenvironment responsive nanogels and physical microenvironment responsive nanogels. In this paper, the research progress of 2 types of tumor microenvironment responsive nanomaterials in drug delivery is reviewed, in order to provide references for the development of more precise and intelligent nanomaterials delivery system.
Because of its vigorous cell metabolism, uncontrolled division and proliferation, the physiological characteristics of malignant tumors are significantly different from those of normal cells, mainly reflected in weak acidity, high reduction, low oxygen and some specific enzyme overexpression. The special microenvironment of tumor tissue provides a new idea for the study of more targeted and less toxic drugs. Nanotechnology has made significant contributions in the field of drug delivery systems over the past decades, and nanomaterials have shown greater stability than other conventional nanomaterials. Nanogels are nano grade gel particles, and have three dimensional swelling polymer chain cross-linking network. Drugs are contained in them, which can effectively avoid enzyme degradation. It has high water content of hydrogels, which can shrink or expand according to the external environment, and the passive targeting of nanoparticles and the longer blood circulation time. Therefore, the delivery of anti-tumor drugs with nanomaterials has good prospects. Based on the unique microenvironment of tumor cells and the advantages of nanomaterials, the nanomaterials with tumor microenvironment response were designed to make them possess the characteristics of pH, reactive oxygen species, reducing sensitivity, enzyme, temperature and photothermal response. In this paper, the nanomaterials which respond to tumor microenvironment are divided into two categories: bioenvironmental response and physical environmental response from different angles. Based on this, we have refined the research progress in recent years.
1 bioenvironmental responsive nanomaterials
According to the uniqueness of the microenvironment of tumor cells, pH responsive gel, reduced response gel, reactive oxygen responsive response gel and enzyme responsive gel were divided into bioenvironmental responsive nanomaterials.
1.1pH responsive responsive nanomaterials
Too fast metabolism of tumor cells results in too much acid secretion, which makes the pH value of tumor cells lower than that of normal tissues and blood. The significant difference between the pH value of plasma (pH7.4) and tumor extracellular microenvironment (ph6.5-7.2), as well as the pH value of lysosomes (ph4.5-5.5) and endosomes (ph5.5-6.8) provides a good trigger condition for drug release.
One of the strategies for preparing acid responsive nanomaterials is to crosslink drugs through acid unstable functional groups in the polymer backbone. The degradation of these nanomaterials is triggered by the breakdown of acid unstable bonds in the nanomaterials network, such as hydrazone bonds, amide bonds and ortho ester bonds, when pH decreases. The release of encapsulated drugs is caused by the rapid degradation of nanomaterials at low pH. Different acid sensitive groups can be broken in different pH environments, making the drug release in tumor extracellular fluid or lysosome, endosomes play different effects [1,6-7]. Another strategy for pH to respond to nanoscale is the acid side chain and / or main chain functional group forming polymer with polyelectrolyte. These groups are ionized at pH higher than pKa of the polymer network. Because of the electrostatic exclusion of ionization groups, the chain structure of hydrogel extends and increases water absorption and volume expansion.
1.1.1 the pH value of tumor extracellular microenvironment can reach 6.5-7.2 due to the combination of acid by-products produced by tumor tissue metabolism and high glycolysis activity damaged by acid scavenging. Compared with normal cells and blood environment (pH7.4), this lower extracellular pH of tumor cells has been used to promote the uptake of drugs by tumor cells and the release of anti-cancer targeted drugs. A pH responsive charge transfer nanomaterials was prepared by Du et al. The release of bovine serum albumin (BSA) and adriamycin (doxorubicin, DOX) gel in vitro was measured respectively. The experimental results show that under the condition of pH = 6.8, due to the acid response, the amide bond breaks rapidly to release BSA. Only 0.5h was needed to release BSA of 80% of the loading capacity, and the charge conversion induced by acid response promoted the endocytosis of the tumor cells. Oh et al. Peg chitosan was grafted to form 3- two diamino propyl (3-diethylaminopropyl, DEAP). At the physiological pH value, the pH responsive nanomaterials were prepared by self-assembly. When the pH value was reduced to pH value (pH=6.8) of the tumor cells, due to the protonation of DEAP, the structure of nanomaterials was changed and the DOX was released rapidly, thereby improving the therapeutic effect of the pH=6.8. Zhang Ying used dextran modified by acrylic acid as crosslinking agent to react with two methylamino ethyl methacrylate to obtain dextran nanomaterials. The nanomaterials can maintain a smaller particle size under physiological pH conditions, which is beneficial to body circulation, and stimulate particle expansion and increase in particle size under the stimulation of tumor's slightly acidic environment, thus promoting endocytosis of cells to increase intracellular release.
1.1.2 tumor cell endoplasmic / lysosomal microenvironment response lysosome is an intracellular organelle with a variety of hydrolases in an internal acidic environment (ph4.5-5.5), which plays a key role in cell membrane repair, pathogen defense, autophagy and signal transmission, and intracellular drug release. Lysosomes in tumor cells are more and larger than those in normal tissue cells. Endoplasmic body (pH5.5 ~ 6.8) is a vesicular organelle in cells. When cells and some of their own cell membranes swallow a substance (can be virus, protein, etc.), such endoplasmic body will be produced. It exists in the cytoplasm, but its internal substances can transmit signals to the nucleus through the cell specific transport system. Responsive nanoscale gel is usually internalized by endocytosis, and intracellular release can be achieved through the low pH environment of endosome / lysosome. However, it should be noted that the endosomes and lysosomes of all cells (tumor cells or normal cells) are acidic, which requires high tumor targeting and selective tumor cell uptake to prevent potential side effects of the drug.
Ju and other nano gel carrier systems with volume expansion and contraction under different pH conditions were prepared. It is made up of all polymer biopolymer based nanomaterials with polyelectrolyte core and cross-linked protein shell, and is used in the delivery study of DOX. Through free radical polymerization, poly N- isopropylacrylamide, N- lysine -N'succinyl chitosan (N-lysinal-N'-succinyl chitosan, NLSC) and N-N' methylene bis acrylamide form the polyelectrolyte core, and the outer layer adsors BSA to form stable nanomaterials. Under lysosomal acidic conditions, the amino groups of NLSC are protonated, resulting in electrostatic repulsion. The nanomaterials are highly expanded and the drug is released. Meanwhile, lysosomes expand and split, and the nanomaterials enter the cytoplasm. However, the pH in cytoplasm is higher, the volume of carrier shrinks back to the original size, and it can enter into adjacent tumor cells to play a role. The drug carrier system can penetrate into tumor tissue and increase the efficacy of the drug.
Seyfoori et al. Combined with the advantages of carbon nanotube (CNT) and pH sensitive nanomaterials, a multifunctional magnetic /pH response nanohybrid system was developed, which contained DOX as a general cancer chemotherapy drug model. Chitosan nanomaterials were coated on the surface of MnFe2O4 magnetic nanoparticles, and then deposited on the surface of functionalized CNT to form covalent bonded pH/ magnetic response CNT. By analyzing the properties of nano carriers, drug loading efficiency and drug release characteristics, it is found that functional CNT has the characteristics of lysosomal micro acid environmental response (ph5.3). The results showed that Chitosan Coated Magnetic Nanocomposites could produce higher pH response and higher drug release in one week. The nano carrier based on tumor microenvironment response has higher drug loading and more intelligence. Julio et al. Synthesized poly (N- isopropylacrylamide co acrylic acid) nanomaterials (nanogel, NG) with different N- isopropylacrylamide / acrylic acid by precipitation / dispersion polymerization as drug delivery system (drug delivery system, DDS) and amphotericin hydrochloride as a model drug. Dynamic light scattering (DLS) shows that ng has good biological dispersion under the simulated physiological environment.
In addition, due to the interaction between cationic drugs and anionic ng, ng shows high drug loading capacity and efficiency. At 37 ℃, the drug leakage was the smallest in plasma simulation medium (pH = 7.4 and 0.14mol · L-1NaCl), and drug release was triggered in lysosomal environment simulation medium (pH = 5 and 0.14mol · L-1NaCl).
However, due to the presence of a large number of hydrolases in the endosomes / lysosomes, in order to avoid the hydrolysis of the encapsulated small molecule drugs, gene drugs and proteins after their release in the endosomes / lysosomes, how to enhance the escape of lysosomes by means of the formation of holes on the lysosomal membrane, the proton sponge effect and other mechanisms remains a very worthy problem.
1.2 reduced responsive nanomaterials
The concentration of glutathione (GSH) in tumor cells is 7-10 times higher than that in normal cells, and the concentration of GSH in normal cells is 200 times higher than that in extracellular cells, so tumor cells are a highly reductive environment. Redox responsive nanomaterials possess excellent drug loading capacity; selective accumulation of enhanced permeability and retention effect (EPR) in tumor tissues; adjustable and stable chemical and physical structures and rapid drug release under intracellular reduction conditions. Most redox responsive nanomaterials have two sulfur bonds and succinimide thioether bonds.
Tian and so on prepared hyaluronic acid (HA) crosslinked poly (ethylene glycol) two glycidyl ether and cystamine (cystamine, CYS) gel formed. The two sulfur bonds in CYS provide a reduction response characteristic. The DOX loaded in the gel is released rapidly. While the two sulfur bond breaks, the size of the nanoscale gel increases significantly, thereby damaging the actin filament and further preventing its proliferation and assembly in the cytoplasm, resulting in the increased apoptosis of tumor cells. such

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