Introduction to 0
After intravenous, oral or local injection, conventional drugs are distributed all over the body, and the amount of drugs that really reach the treatment target area is only a small part of the dose, while most drugs distributed in non-target areas not only have no therapeutic effect, but also bring toxic and side effects. Therefore, the development of new dosage forms of drugs has become a direction of the development of modern pharmacy, in which the targeted drug delivery system (TDDS) has become a hot spot in pharmaceutical research [1]. TDDS refers to a new drug delivery system, which can concentrate and locate drugs in diseased tissues, organs, cells or cells. Targeted preparation has the advantages of high curative effect, less dosage and less toxic and side effects. The ideal TDDS should release drugs in the target organ or site of action, and at the same time, the systemic intake is very small, which can not only improve the curative effect, but also reduce the toxic and side effects of drugs. TDDS requires drugs to reach target organs, target cells and even intracellular structures, and requires a certain concentration of drugs to stay for a long time to exert their efficacy. A successful TDDS should have three elements: local accumulation, drug controlled release, non-toxicity and biodegradability. Targeting agents include passive targeting agents, active targeting agents and physical and chemical targeting agents. At present, the main methods to achieve targeted drug delivery are vector-mediated method and receptor method.
1 vector-mediated targeted drug delivery
The commonly used targeted drug delivery carriers are various particles. Particle delivery system has passive targeting performance. Organic drugs can improve their bioavailability, uniformity, dispersibility and absorbability by micronization, and change their distribution in vivo. Microparticle delivery systems include liposomes (LS), nanoparticles (NP) or nanocapsules (NC), microspheres (ms) or microcapsules (MC). Cells, emulsions, etc. The mechanism of particles targeting various organs is that reticuloendothelial system (RES) is rich in phagocytes, and particles with a certain size (0. 1~3.0 microns) can be absorbed into liver and spleen as foreign bodies. Larger particles (7~30 microns) can't be filtered through the capillary bed, and they are mechanically retained in the lungs. Particles smaller than 50 nanometers can enter the bone marrow through capillary tips.
Liver diseases, such as liver cancer and hepatitis, are common and frequently-occurring diseases, but the therapeutic effect of drugs is not ideal at present. The reason is that the drug itself is not ideal in pharmacology, and it is also an important reason why the drug can not be effectively delivered to the liver lesion. Some anti-tumor and anti-hepatitis drugs can be made into particles, which can increase the liver targeting of drugs after administration. The study on the distribution of mitoxantrone albumin microspheres (DHAQ BSA MS) in vivo found that the distribution of DHAQ BSA MS and mitoxantrone (DHAQ) in mice was significantly different when administered for 20 minutes. About 80% of DHAQ BSA MS is concentrated in the liver, while more than 85.9% of DHAQ is in the blood [2]. Zhang Li et al [3] studied the morphology, particle size distribution and biological safety of norcantharidin (NCTD) microemulsion. The tissue distribution of NCTD microemulsion and its injection in mice was studied. The results showed that compared with NCTD injection, NCTD microemulsion enhanced the drug's liver targeting to some extent, reduced the drug's distribution in the kidney of mice, and prolonged the drug's circulation time in mice. There have been many reports about liver targeting nanoparticles and nanocapsules. Anti-cancer drugs such as fluorouracil, adriamycin, hydroxycamptothecin, Stellera chamaejasme B and cyclosporine have been made into nano-targeted preparations [4]. Wang Jianhong et al. [5] prepared mitoxantrone gelatin microspheres by two-step method, accounting for 87.36% of the total, with a particle size range of 5.1~ 25.0μ m. Compared with the original drug, the release time in vitro was prolonged by four times. The distribution test in mice showed that mitoxantrone gelatin microspheres had obvious lungs. The targeting efficiency is improved by 3~35 times, and the pharmacokinetic behavior in lung can be described by one-compartment open model, and the average residence time is prolonged by 65438±00h hours. Coating hydrophilic surfactant or chemically connecting polyethylene glycol or its derivatives on the surface of nanoparticles can reduce the affinity with reticuloendothelial cell membrane, thus avoiding the phagocytosis of reticuloendothelial cells. Improve the targeting of nanoparticles to brain tissue. Gulyaev et al [6] prepared adriamycin nanoparticles with biodegradable butyl cyanoacrylate as carrier and Tween 80 as wrapping material. The results showed that the concentration of adriamycin in the brain was 60 times higher than that in the control group. Some easily decomposable peptides or drugs (such as darragon, loperamide and curculine) that cannot pass through the blood-brain barrier have achieved certain targeted therapeutic effects in animals by making biodegradable nanoparticles coated with Tween 80 [7]. Studies have shown that the particle size is the key factor affecting the particle entering the bone marrow. The smaller the particles, the easier it is to enter the bone marrow. Peng et al. [8] prepared daunorubicin nanoparticles with different particle sizes and administered them through the tail vein of mice. The concentration of daunorubicin in bone marrow of small particle size group was 65438 0.58 times higher than that of large particle size group (425±75)nm. Tumor infiltration, chemotherapy drugs or severe infection can inhibit bone marrow. Research shows that. For example, human granulocyte colony stimulating factor (GCSF) and granulocyte macrophage colony stimulating factor (GMCSF) can promote the self-renewal, division and proliferation of bone marrow cells and improve their activity. The use of bone marrow targeting carriers can improve the distribution of drugs in bone marrow and avoid adverse reactions of hemogram. Gibaud et al [9] used isobutyl cyanoacrylate and isohexyl nanoparticles as carriers to carry GCSF, which improved its distribution in bone marrow.
Gene therapy is a specific targeted therapy. Gene therapy is to introduce foreign recombinant genes or nucleic acids into human target cells through gene transfer technology to correct gene defects or abnormal expression. As a gene carrier, nanoparticles have some remarkable advantages. Nanoparticles can encapsulate, concentrate and protect nucleotides from degradation by nucleases. Large specific surface area, biological affinity, easy to couple specific targeting molecules on its surface, and realize the specificity of gene therapy; The circulation time in the circulatory system is obviously longer than that of ordinary particles, and it will not be removed by phagocytes as quickly as ordinary particles in a certain period of time; Slowly release nucleotides, effectively prolong the action time, maintain effective product concentration, improve transfection efficiency and bioavailability of transfected products; Less metabolites, less side effects and no immune rejection.
2 receptor-mediated targeted drug delivery
It is the most common active targeted drug delivery system to design a targeted drug delivery system using receptors on the cell surface. ASGPR is a transmembrane glycoprotein, which exists in mammalian liver parenchyma cells. Its main function is to remove saliva glycoprotein and apoptotic cells and lipoprotein. It was found that ASGPR can specifically recognize N- acetylgalactosamine, galactose and lactose. Using these characteristics, some exogenous functional substances can be directionally transferred to hepatocytes after being modified by galactose. Lee et al. synthesized a three-branched N- acetylgalactosamine sugar cluster YEE, and its binding capacity to hepatocytes was 654.38+100000 times that of acetylgalactosamine monosaccharide. We studied the liver targeting of galactoside modified lamivudine palmitate solid lipid nanoparticles. Its targeting efficiency is 4.66, which is 3.7 times higher than that of unmodified nanoparticles [10]. The drug can produce better liver targeting effect by connecting with macromolecular carrier and then galactosizing it. If the drug can be directly galactosylated, the coupling link can be simplified and the targeting efficiency can be improved. For protein drugs, it is easy to achieve. Protein or polypeptide (molecular weight is within a certain range) may become receptor-bound liver targeting substances after being linked to galactose. Whether small molecules can target the liver through similar channels depends on many factors, such as the density, molecular weight and uptake barrier of sugar and drugs. Small molecule drugs are linked to lactose or galactose with valence of * * *, which initially reveals that their targeting is not good, and the mechanism and feasibility need to be further explored.
Galactosylated chitosan (GC) was mixed with plasmid pEGFPN 1 to prepare nanocapsule complex, which was transfected into SMMC772 1 cell in vitro. Nanocapsules containing 1 mg plasmid were injected into dogs via hepatic artery and portal vein. The experimental results show that galactosylated chitosan has high transfection efficiency in vitro and targeting to canine liver. It can be used as a carrier for liver targeted gene therapy [1 1]. The number and activity of folate receptors on the surface of most tumor cells are significantly higher than those of normal cells. Folic acid has been widely studied as a carrier of radionuclide targeting lymphatic system or tumor cells, and folic acid has also been used as a carrier of anti-tumor drugs targeting tumor cells [12].
Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein, which is encoded by proto-oncogene cerbB 1 and is one of the erbB receptor families. EGFR is highly expressed in many tumors, such as glioblastoma, prostate cancer, breast cancer, gastric cancer, colorectal cancer, ovarian cancer and thymic epithelial cancer. Fang Huasheng et al. [13] aimed at malignant tumors rich in EGFR.
Antibody-mediated targeted drug delivery
Monoclonal antibody is a good drug targeting carrier, which can be crosslinked or adsorbed on drug carriers (such as liposomes, nanoparticles, microspheres, magnetic carriers, etc.). ) or drugs or antibodies with autoantibodies (such as red blood cells) combine with cytotoxic molecules to avoid their toxicity to normal tissues and selectively play an anti-tumor role. Xu Fenghua et al [14] used adipic dihydrazide to prepare hydrazone-linked polyglutamic acid epirubicin. Then cross-link it with monoclonal antibody to prepare conjugate. The conjugate retains the antibody activity well, and its cytotoxicity in vitro is slightly lower than that of free drugs, but it shows the selective killing effect of monoclonal antibodies on target cells, which lays a foundation for its further preparation of cell-targeted tumor chemotherapy drugs.
CMA676 is used to treat leukemia, which is formed by coupling humanized monoclonal antibody hp 67.6 and N- acetyl γ derivative, a new anti-tumor antibiotic of calicheamicin [15]. After CMA676 binds to CD33 antigen, the antigen-antibody complex internalizes rapidly, and after entering the cell, calicheamicin derivatives are released by water interpretation. By combining with the groove of DNA double helix in a sequence-specific way, the hydrogen atom in the deoxyribonucleic ring is transferred, thus breaking the DNA double strand and inducing cell death [16]. EGFR MAB can directly act on the extracellular ligand binding region of EGFR, blocking ligand binding, such as IMCC225, ABXEGFR, EMD55900, and can inhibit cell growth and survival rate. Tratuzumab can induce apoptosis and inhibit angiogenesis. Tratuzumab acts on the extracellular domain of erbB2 and has been approved by FDA for the treatment of metastatic breast cancer [17]. IMCC225 can enhance the effect of cytotoxic drugs and radiotherapy. The combination of IMCC 225 and TPT can be used in nude mice transplanted with human colon cancer. It can improve its survival rate [18]. A new drug I [[13li] Metoczumab injection for the treatment of liver cancer, which was jointly developed by the Fourth Military Medical University and Chengdu Huashen Group Co., Ltd., has recently obtained the production number issued by the State Food and Drug Administration of the United States and will be listed soon. It is the world's first monoclonal antibody-oriented isotope drug specially used to treat primary liver cancer.
4. Make prodrugs.
Some drugs react with appropriate carriers to prepare prodrugs. After administration, the drug will be released at a specific site, thus achieving the goal of targeted administration. The brain is the command center of higher nervous activity and the most complex part of the nervous system. However, due to the existence of the blood-brain barrier, most therapeutic drugs cannot effectively penetrate the blood-brain barrier. It contains OH and NH2. Drugs with poor fat solubility in COOH structure can be made into pro-drugs with high fat solubility through chemical reactions such as esterification, amidation, aminomethylation, etherification and cyclization. After entering the central nervous system, its lipophilic groups release active drugs through biotransformation. Zhang Zhirong et al. [19] synthesized 3 ′, 5 ′ dioctyl fluoroglycoside and prepared its drug body. After intravenous injection in mice, the drug content was determined by HPLC.
There are a large number of bacteria in the colon, which can produce many unique enzyme systems. Many polymer materials are degraded by these enzymes in colon, but due to the lack of corresponding enzymes, these polymer materials cannot be degraded in stomach and small intestine, which ensures that drugs are not released in stomach and small intestine. For example, polysaccharide, pectin, guar gum, azo polymer and α, β, γ cyclodextrin can all be used as carrier materials for colon drug delivery system. Azo prodrugs are prepared by reducing azo bonds. Sulfasalazine is composed of 5 aminosalicylic acid (5ASA) and sulfapyridine by azo bond. It is released in colon after oral administration, which plays the role of 5ASA in treating ulcerative colitis. It can reduce the systemic adverse reactions caused by gastrointestinal absorption. 5ASA is also a prodrug made from azo double bonds and non-physiologically active polymers [20]. Glucocorticoid is linked to polysaccharide [2 1] and cyclodextrin [22], which can release drugs in colon after oral administration and can be used to treat colitis. We synthesized pectin ketone [23, 24]. In vitro and in vivo evaluations were conducted. The results showed that the structure of the prodrug was stable in different pH environments, and it could only be specifically degraded by colonic pectinase, releasing KP and playing a therapeutic role. The colon-specific drug delivery system can also be designed by using the difference of colon pH value and time lag effect [25].
5 chemical transfer system
Chemical delivery system (CDS) is a drug delivery system that transports drugs to the target site through physiological barriers and then releases drugs through biotransformation. CDS usually connects the valence of drugs containing OH, NH2 and COOH structures to dihydropyridine carrier (Q), and drug (D) combines with dihydropyridine to form a DQ conjugate. A dihydropyridine-dihydropyridine salt redox brain targeted drug delivery system was established. Chen et al. [26] designed Tyr Lys brain-targeted CDS and evaluated its efficacy. TyrLys is made from L- amino acid bridging targeting agent 1, 4- dihydrofenugreek (containing pyridine structure) at the C- terminal and its whole body. Through passive diffusion mechanism, 1, 4-dihydrofenugreek base was converted into quaternary ammonium salt by enzyme catalysis and remained in the brain. The tail-flick experiment in mice proved that the action time of Tyr Lys CDS was obviously prolonged. Mahmoud et al. [27] linked the electron-withdrawing carboxymethyl group to the nitrogen atom, and constructed a new dihydropyridine carrier-mediated brain targeted drug delivery system (N carboxymethyl group 1 4 dihydro).
The research of targeted drug delivery still faces many substantive challenges: improving the bioavailability of drugs in target tissues; Improve the specificity of TDDS to target tissues and cells; So that biological macromolecules can be released at the action target and enter the target cells more effectively; Metabolic kinetic model in vivo; Quality evaluation items and standards, physiological functions in vivo and other issues are the focus of research. With the in-depth study of targeted drug delivery system, new targeted drug delivery routes and new drug delivery methods will continue to appear, and the problems encountered will be gradually solved. The study of targeted drug delivery is not only of theoretical significance, but also will produce obvious economic and social benefits.
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