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Exosome is a kind of vesicle secreted by a variety of cells with lipid bilayer membrane structure， which has good biocompatibility， high targeting and high stability， and is a natural nanoscale drug carrier with great development potential in drug delivery system. In this paper， exosomes and their properties， exosome drug delivery pathways and methods， the design strategy of engineered exosome drug delivery systems for targeted disease therapy， and the application of exosome drug delivery systems in the treatment of a variety of diseases were reviewed. Exosome drug delivery pathways could be divided into two categories： exogenous and endogenous. Common exosome drug delivery methods included electroporation， co-incubation， and ultrasound. Engineered exosome drug delivery system can further improve drug loading and enhance drug targeting. The main way of engineering is to modify exosome surface through genetic engineering technology， physical modification， chemical modification， etc. Exosome drug delivery system provides a new idea for targeted therapy of arthritis， tumor， brain and other diseases.
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@#Chitosan-based microspheres use chitosan as the main material to obtain particles with special structures through microsphere processing technology. They have the ability of slow and controlled release of drugs and the role of scaffolding, which have great application prospect in stomatology, but the application of chitosan-based microspheres is still in the research stage and has not yet been applied in clinical practice. This article reviews progress of domestic and foreign research on chitosan-based microspheres, in aspects of treatment of oral and jawbone tissue defects, periodontal diseases, dental pulp diseases and nerve tissue injury, in order to provide reference for follow-up research.
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@#In recent years, bio-metal organic frameworks (Bio-MOFs) synthesized with biocompatible ligands have been widely investigated as a potential drug delivery carrier due to their large specific surface area and porosity, rich host-guest intermolecular interactions, and good biocompatibility.In this review, we summarized the design methods of Bio-MOFs including structural and toxic factors, as well as a variety of drug loading methods including click chemistry, with particular focus on recent research advances in Bio-MOFs for pulmonary drug delivery systems, improving pharmaceutical properties of drugs, sustained and controlled drug release, stimulation response and targeted drug delivery systems.Finally, we summarized the bottlenecks that constrain the development of Bio-MOFs in clinical studies of actual pharmaceutical formulations and their future directions for approved formulations, aiming to provide some theoretical reference for promoting the application of Bio-MOFs in drug delivery systems.
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Objective:To prepare polyvinyl alcohol (PVA) and hydroxyapatite (HA) composite embolization microspheres and investigate their physicochemical properties.Methods:PVA/HA composite embolization microspheres were prepared by reverse suspension polymerization, using PVA and HA as dispersed phases, liquid paraffin containing sorbitan fatty acid ester as the continuous phase, and glutaraldehyde as the cross-linking agent. The morphology, particle size distribution, and microscopic morphology of PVA/HA composite embolization microspheres were observed by optical microscopy and scanning electron microscopy. The chemical structure of PVA/HA composite embolization microspheres and the elasticity, drug loading, and drug release properties of PVA/HA composite bolus microspheres were characterized by Fourier infrared spectroscopy.Results:The PVA/HA composite embolization microspheres were internal, porous round spheres with a particle size distribution of 50-300 μm. The elastic properties of PVA/HA composite embolization microspheres were(13.6±0.145) kPa, which was 2.28 times that of PVA microspheres, and the drug loading capacity and encapsulation efficiency were (76.80±1.22) mg/g and (38.4±12.7)%, respectively. The maximum cumulative release rate of the microspheres within 7 days was (7.37±0.101)%, and the maximum cumulative release was (256.2±9.8) μg.Conclusions:PVA/HA composite embolization microspheres have good mechanical properties and drug-loading and drug-releasing properties, which provide an important reference for their use as medical devices.
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Objective:To investigate the relationship between phase behavior of curcumin （CUR） from self-nanoemulsion drug delivery system （SNEDDS） and stability of the formed nanoemulsion in artificial gastrointestinal fluid. Method:The growth rate of precipitation after dispersion of CUR-SNEDDS was expressed by the change tendency of CUR supersaturation-time curve. The effect of drug loading on crystal nucleation and growth was investigated by ultraviolet-visible spectrometry and polarized light microscope， respectively. X-ray powder diffraction （XRD） and differential scanning calorimetry （DSC） were used to analyze the precipitation forms of CUR-SNEDDS with different drug loading in artificial gastrointestinal fluid. At the same time， the effect of drug loading on the quality stability of nanoemulsion formed by CUR-SNEDDS in artificial gastrointestinal fluid was investigated. Result:In the artificial gastrointestinal fluid， with the increase of drug loading， the area under the supersaturation-time curve of CUR was increased （100% drug loading≈90% drug loading>75% drug loading）， the crystallization nucleation and growth rate were accelerated （100% drug loading>90% drug loading>75% drug loading）， the amorphous proportion in the precipitation composition decreased， the nanoemulsion droplets adhered and distributed unevenly， the particle size and dispersivity were increased. Conclusion:High drug loading promotes the nucleation and growth of crystals， and increases the proportion of crystal forms in the precipitation composition， which leads to the decrease in the stability of the formed nanoemulsion. Therefore， it is suggested that the drug loading of CUR-SNEDDS needs to be controlled below 90%.
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Cyclodextrin metal-organic framework (CD-MOF) as a highly porous supramolecular carrier could be one of the solutions to the insolubility of isosteviol (STV). The solubility of STV was lower than 20.00 ng/mL at pH 1.0 and pH 4.5, whilst its solubility increased to 20,074.30 ng/mL at pH 6.8 and 129.58 ng/mL in water with a significant pH-dependence. The
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Metal-organic frameworks (MOFs), comprised of organic ligands and metal ions/metal clusters
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With Sangtang Yin granule as model drug,and based on the strategy of " unification of medicines and excipients",the feasibility of preparing high drug loading granules with traditional Chinese medicine( TCM) raw powder as carrier was explored. The powder yield,particle size and particle size distribution,fillibility,flowability,hygroscopicity,reconstituability and other key physical properties relating to preparations of 8 herbs( Dioscoreae Rhizoma,Euryales Semen,Atractylodis Macrocephalae Rhizoma,Coicis semen,Poria,Puerariae Lobatae Radix,Puerariae Thomsonii Radix and Coicis Semen by stir-frying with bran) were studied after being smashed,and the feasibility of taking them as excipients of TCM granules was evaluated by co-spray drying,dry granulation and other preparation techniques. According to the results of the physical properties of raw powders,raw powders of Dioscoreae Rhizoma,Euryales Semen and Puerariae Thomsonii Radix had a high powder yield,uniform particle size distribution,good fillibility,poor hygroscopicity and good reconstitutability,with the feature of assisting granule forming. Compared with the prescription of spray dry powder Sangtang Yin without any excipient,the co-sprayed powder had a high yield,good fillibility and compressibility. The yield of dry granules prepared by co-spraying dry powder was increased by more than 10%,and the particles had a uniform color,good fluidity and dissolubility with the drug-loading rate up to 100%. Based on the physical characteristics of TCM raw powder combined with the analysis of the preparation process,Dioscoreae Rhizoma and Puerariae Thomsonii Radix raw powder were selected as the carriers of granule preparations,and Sangtang Yin granule without any excipient was successfully prepared. The findings provide a feasible idea for the preparation of TCM granules with a high drug loading capacity.
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Excipients , Medicine, Chinese Traditional , Particle Size , Powders , Pueraria , RhizomeABSTRACT
Objective:To investigate the antitumor effect of shikonin loaded milk derived exosomes on hepatoma cells.Methods:The experimental study was conducted. Exosomes were isolated from milk by differential centrifugation and be loaded by shikonin to constructed a nano drug loading system. The shikonin content of this nano drug loading system was determined and calculated by spectrophotometry. The cytotoxicity of shikonin loaded milk derived exosomes was evaluated by sulfonyl rhodamine B colorimetry and cell apoptosis was determined by annexin V-FITC/propidium iodide assay. Western blotting was used to detect the Bax and Bcl-2 protein expression level in hepatoma cells. Human HepG2 hepatoma cells treated with shikonin were set as the shikonin treated group and human HepG2 hepatoma cells treated with shikonin loaded milk derived exosomes were set as the shikonin loaded milk derived exosomes treated group. Observa-tion indictors: (1) the loading percentage of shikonin in shikonin loaded milk derived exosomes; (2) the cytotoxicity of shikonin loaded milk derived exosomes on human HepG2 hepatoma cells; (3) cell apoptosis of human HepG2 hepatoma cells; (4) Bax and Bcl-2 protein expression level in human HepG2 hepatoma cells. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups were analyzed using the t test. Results:(1) The loading percentage of shikonin in shikonin loaded milk derived exosomes: the loading percentage of shikonin in shikonin loaded milk derived exosomes was 22.8%. (2) The cytotoxicity of shikonin loaded milk derived exosomes on human HepG2 hepatoma cells: the survival rates of hepatoma cells were 53.9%±2.9% and 45.4%±1.9% in the shikonin treated group and the shikonin loaded milk derived exosomes treated group, respectively, showing a significant difference ( t=46.27, P<0.05). (3) Cell apoptosis of human HepG2 hepatoma cells: the early apoptosis rates of hepatoma cells were 11.3%±1.5% and 14.8%±2.2% in the shikonin treated group and the shikonin loaded milk derived exosomes treated group, respectively, showing no significant difference ( t=1.37, P>0.05). The late and overall apoptosis rates of hepatoma cells were 32.3%±1.3% and 43.6%±4.3% in the shikonin treated group, versus 38.7%±3.2% and 53.5%±4.4% in the shikonin loaded milk derived exosomes treated group, showing significant differences ( t=37.39, 30.97, P<0.05). (4) Bax and Bcl-2 protein expression level in human HepG2 hepatoma cells: Bax and Bcl-2 protein expre-ssion level were 232.0±2.6 and 32.0±1.6 in the shikonin treated group, versus 286.0±3.8 and 17.0±1.5 in the shikonin loaded milk derived exosomes treated group, showing significant differences ( t=69.83, 53.32, P<0.05). Conclusion:The shikonin loaded milk derived exosomes have cytotoxic and apoptosis inducing effects on human HepG2 hepatoma cells, which can inhibit the growth of hepatoma cells.
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In order to improve the supersaturation and maintenance time of drug dispersion in curcumin self-nanoemulsion(CUR-SNEDDS), precipitation inhibitors(PPIs) were introduced to prepare curcumin supersaturated self-emulsion(CUR-SSNEDDS). The composition of CUR-SNEDDS prescriptions was selected through the solubility test, the compatibility of oil phase and surfactant, the investigation of the emulsifying ability of the surfactant and the drawing of the pseudo-ternary phase diagram. Analytic hierarchy process was used in combination with central composite design-response surface method to optimize the prescription. The type and dosage of precipitation inhibitors(PPIs) were selected to maintain the supersaturated concentration and duration of CUR in artificial gastrointestinal fluids. At the same time, polarizing microscope was used to evaluate the crystallization inhibition effect and the quality and in vitro release behavior of CUR-SSNEDDS. The prepared CUR-SSNEDDS prescription was capryol 90-kolliphor RH40-transcutol HP-Soluplus(7.93∶66.71∶25.36∶5), with the drug loading of(65.12±1.25) mg·g~(-1). CUR-SSNEDDS was transparent yellow, and the nanoemulsion droplets were spherical with uniform distribution. The emulsification time was(21.02±0.13) s, the average particle size was(57.03±0.35) nm, the polydispersity index(PDI) was(0.23 ± 0.01), and the Zeta potential was(-18.10±1.30) mV. CUR-SSNEDDS significantly inhibited the generation and growth of crystals after in vitro dilution. The supersaturation could be maintained above 10 within 2 h, and the dissolution rate and degree of CUR in artificial gastrointestinal fluid were significantly increased. Soluplus could effectively maintain the supersaturated state of CUR and enhance CUR dissolution in vitro.
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Biological Availability , Curcumin , Emulsions , Nanoparticles , Particle Size , Solubility , Surface-Active AgentsABSTRACT
Objective: To prepare glycyrrhizic acid (GL)-Pluronic F127 (F127)/polyethylene glycol 1000 vitamin E succinate (TPGS) mixed nanomicelles (MMs) and improve oral absorption of GL. Methods: GL-F127/TPGS-MMs was prepared by thin film dispersion method. The encapsulation efficiency and drug loading of MMs were used as evaluation indexes. The formulation and process, including the ratio of F127 to TPGS, the concentration of polymer and GL, hydration temperature and time, were optimized by the single factor experiment. The morphology of MMs was investigated by transmission electron microscopy. The single-pass perfusion model was established in rats to investigate the intestinal absorption characteristics of GL-F127/TPGS-MMs with absorption rate constant (Ka) and apparent absorption coefficient (Papp) as evaluation indexes. Results: The optimal formulation and process of GL-F127/TPGS-MMs were as follows: TPGS 180 mg, F127 270 mg, GL 70 mg, hydration temperature 50 ℃ and hydration time 3 h. The prepared GL-F127/TPGS-MMs had good clarity and the particle size, polydispersity index, and Zeta potential were (28.20 ± 5.63) nm, 0.20 ± 0.06, and (-5.24 ± 1.55) mV, respectively. The encapsulation efficiency and drug loading were (97.57 ± 5.29) % and (13.13 ± 0.71) %, respectively. The MMs were spherical with distinct vesicle structure. The absorption of GL in the jejunum segment was significantly higher than that in the ileum segment (P < 0.05). Compared with raw GL, GL-F127/TPGS-MMs had a statistically significant higher absorption rate in the intestinal segment (P < 0.05). Conclusion: The prepared GL-F127/TPGS-MMs could significantly improve the absorption of GL in vivo.
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Objective: To prepare and characterize puerarin chitosan/sodium alginate oral nanoparticles (Pur-CS/SA-NPs) and conduct its pharmacokinetics studies. Methods: Pur-CS/SA-NPs were prepared by self-assembly method, the morphology, particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, drug loading and microstructure of Pur-CS/SA-NPs suspension and lyophilized powder were characterized. To determine the concentration of puerarin in plasma after oral administration of nanoparticles to rats, an LC-MS/MS analysis method for puerarin was established, and its pharmacokinetic characteristics were investigated. Results: The morphology, structure and texture of Pur-CS/SA-NPs suspension and lyophilized powder were complete and fine, no new chemical bonds and crystals were formed. The particle size, PDI, Zeta potential, encapsulation efficiency, and drug loading of Pur-CS/ SA-NPs suspension were (208.327 ± 1.870) nm, 0.131 ± 0.006, (89.056 ± 1.680)% and (44.528 ± 0.840)%, respectively. The particle size, Zeta potential, encapsulation efficiency and drug loading of Pur-CS/SA-NPs lyophilized powder were (260.000 ± 0.475) nm, (47.300 ± 0.208) mV, (86.234 ± 0.873)% and (43.117 ± 0.234)%, respectively. The AUC0-24, AUC0-∞, tmax and Cmax of Pur-CS/SA- NPs were (833.067 ± 132.546) mg∙h/L, (844.919 ± 154.768) mg∙h/L, (1.000 ± 0.098) h and (236.318 ± 36.864) mg/L, respectively. The AUC0-24, AUC0-∞, tmax and Cmax of puerarin were (250.087 ± 32.156) mg∙h/L, (250.091 ± 28.398) mg∙h/L, (0.500 ± 0.031) h and (191.830 ± 17.963) mg/L, respectively. The AUC0-24, AUC0-∞, tmax and Cmax of Pur-CS/SA-NPs were 3.331, 3.378, 2.000, and 1.232 times of puerarin, respectively. Conclusion: The structure of Pur-CS/SA-NPs prepared by self-assembly method is stable. After oral administration, the AUC0-24, AUC0-∞ and tmax of the drug in the body are significantly increased, and the circulation time is relatively extended, which significantly improve bioavailability of puerarin.
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Objective: To prepare resveratrol (Res) nanoparticles grafted with polyamide-amine dendrimer (PAMAM) modified by lactose acid (LA) and evaluate them in vitro. Methods: After partial carboxylation of G3.0 PAMAM terminal (PAMAM-COOH) which synthesized by divergence method. Res was bonded through esterification reaction and LA was grafted on the surface of the carrier through amidation reaction. Nuclear magnetic resonance (1H-NMR) and infrared spectroscopy (IR) were used for characterization. La-PAMAM-Res/Res nanoparticles were prepared by physical encapsulation using LA-PAMAM-Res and Res, and the encapsulation rate was detected by dialysis method. The drug load of the two kinds of nanoparticles was detected by high performance liquid chromatography (HPLC), the particle size was investigated by laser particle size analysis method, the drug release performance in vitro was determined by dialysis method, and the biosafety was evaluated by hemolytic experiment. The cytotoxicity and anticancer activity of PAMAM, PAMAM-COOH, Res, LA-PAMAM-Res and LA-PAMAM-Res/Res were investigated by MTT assay. Results: LA- PAMAM-Res and La-PAMAM-Res/Res nanoparticles were prepared. The encapsulation rate of LA-PAMAM-Res/Res was (75.1 ±2.2) %, the drug loading rates of LA-PAMAM-Res and LA-PAMAM-Res/Res were (7.2 ± 0.9) % and (18.4 ± 1.1) %, respectively. The particle size was (126.3 ± 3.4) nm and (251.0 ± 15.7) nm, respectively. After 72 h, the drug release in vitro was (23.83 ± 0.43)% and (35.28 ± 0.72)%, respectively. The hemolysis rate of both nanoparticles was less than 5%, and the carrier PAMAM-COOH showed less cytotoxicity than PAMAM, and both LA-PAMAM-Res and LA-PAMAM-Res/Res maintained anti-tumor proliferative activity. Conclusion: LA-PAMAM-Res and LA-PAMAM-Res/Res nanoparticles with sustained drug release, good biocompatibility, low cytotoxicity and anticancer activity were prepared, and LA-PAMAM-Res/Res increased the drug load of Res.
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Objective: To establish a vitamin K1(VK1)-delivery system with red blood cells as carrier. Methods: The VK1 self-emulsifying nano-emulsion, micelle and plasma solution were prepared to investigate the VK1 loading on red blood cells. The VK1- chitosan(CS)nanoparticles were prepared with different particle size by the 3 different preparation methods, and the effect of the particle size and charge property on the VK1-loading on red blood cells was investigated with the prepared VK1-CS nanoparticles. The encapsulation efficiency and drug loading were used as main indicators to investigate the appropriate drug loading method. Results: Due to the solubility of VK1 or the charge properties of nanoparticles, the drug loading and encapsulation efficiency of the red blood cell-encapsulated VK1 were quite low, and a large amount of drugs could not be loaded on the red blood cells. The ability of red blood cells to load VK1 was likely related to its Zeta potential. The VK1-CS nanoparticles prepared by the ion condensation method showed a good drug loading performance. Each milliliter of red blood cells could load 174.46 μg VK1 in the nanoparticles, and the loading rate was 85.11%. Conclusion: The VK1 loading by the red blood cells could be achieved by the electrostatic interaction between the positively charged chitosan nanoparticles and the negatively charged erythrocyte membrane.
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Alternative drug delivery for the treatment of resistant bacterial infections is necessary to bypass existing antibioticresistance mechanism and ensure direct delivery of the drug to the targeted site using locally sourced materialsto minimize cost in the long term. In this study, cockle shell-derived calcium carbonate aragonite nanoparticles(CS-CaCO3NP) was synthesized, loaded with oxytetracycline (OTC), and characterized using Zeta analysis,Transmission electron microscopy (TEM), FESEM, X-ray Diffraction (XRD), Fourier Transform Infrared (FTIR) andBrunauer–Emmett–Teller analysis. The loaded OTC-CS-CaCO3NP was further characterized after which the in vitrorelease of OTC was studied. A homogenously spherical CS-CaCO3NP was observed on TEM with a mean diameter of29.90 nm and −19.9 zeta potential which increased to 62.40 nm and −23.5, respectively, after OTC loading. XRD andFTIR analysis of OTC-CS-CaCO3NP revealed that OTC maintained its functionality and crystallinity. The formulationof OTC:CS-CaCO3NP in ratio 1:4 with drug encapsulating efficiency (71%) was used for in vitro release studies.OTC was sustainably released from OTC-CS-CaCO3NP over a period of 96 hours. Our results suggest that OTC-CSCaCO3NP is a promising nanoparticle antibiotic delivery system with efficient physicochemical and pharmacologicalproperties whose antibiotic properties should be further investigated.
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In this study, magnetic nanoparticles (MNPs) coated with a combination of oleic acid and chitosan were synthesizedby ex situ and in situ coprecipitation methods. Morphology and particle size, crystal structure and crystallite size,chemical structure, and magnetic saturation were characterized by scanning electron microscope (SEM), X-raydiffraction (XRD), Fourrier transform infrared, and vibrating sample magnetometer (VSM), respectively. SEMimages showed that better spherical morphology is obtained by ex situ co-precipitation method. The XRD patternidentified that nanoparticles containing Fe3O4 and γ-Fe2O3. The particles and crystallite size of the nanoparticles tendedto decrease with increasing oleic acid to the optimum composition. Further functionalization through the chitosanaddition (crosslinked by Tripolyphosphate/sulfate) is contributed to the hydrophilicity properties of nanoparticles.Through VSM analysis, MNPs-oleic acid-chitosan showed superparamagnetic behavior with magnetic saturationreaching 32.63 emu/g. There was a linear correlation between magnetic saturation and Fe3O4 content of nanoparticles.Drug loading and drug release were carried out by using Doxorubicin. These nanoparticles showed a high drug loadingefficiency with lower chitosan composition. Loading efficiency of Doxorubicin is related to the conjugation withcarboxylic groups and hydrophobic sites from oleic acid and MNPs
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In this work, the potential of using microspherical aerogel particles based on commercial carrageenan as a drug vehiclewas evaluated. Carrageenan hydrogel microparticles were prepared following the emulsion gelation approach. Afterthe successive solvent exchange, supercritical CO2 drying procedure was employed to obtain aerogel microsphericalparticles. Meloxicam and atorvastatin (class II drug) were loaded into the aerogel matrix by adsorption from theircorresponding supercritical CO2 solution. All preparations were characterized by their physicochemical properties. Invitro drug released was investigated for the drug-aerogel formulation to assist the effect of aerogel technology on therelease profile of the targeted drug. Meloxicam and atorvastatin model drugs maintained their crystalline structure.Significant enhancement in the release profile of meloxicam after loading in the carrageenan aerogel can be related tode-aggregation of meloxicam inside the particle, while no enhancement in atorvastatin release was observed. Resultswere indicative of a failure in the loading of atorvastatin inside the carrageenan particle at the selected experimentalprocessing parameters.
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Objective To evaluate the effects of chitosan microspheres as the ball wall,pre pared by emulsion cross-linked VEGF chitosan microspheres.Methods 1 ％ chitosan aqueous solution as the aqueous solution and genipin as a cross-linking agent were used to detect the drug loading rate and cumulative release rate of drug-loaded microspheres by ELISA.Results VEGF chitosan microsphere size was about 5.25-20.34 μm;electron microscopy showed that microspheres surface was smooth,decentralized,and had small adhesions each other.The highest encapsulation efficiency was (56.33±3.42) ％ and the highest drug loading rate was (18.75±0.32) ng/mg.In vitro release experiments showed that the concentration of VEGF increased gradually with the passage of time.The release rate of microspheres was (32.32±2.31)％ on the first day and (86.42±1.68)％ on the 21st day.The cumulative release rate was 88.7％.Conclusions Genipin can be used to prepare chitosan microspheres loaded with different concentrations of VEGF with good performance and simple preparation process.The drug-loading rate and entrapment efficiency of the obtained microspheres are both high.
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Malignant tumors are the second most important cause of death after cardiovascular and cerebrovascular diseases. Chemotherapeutic drugs for tumor treatment have strong toxic side effects. The common solution is to use nanoparticle as a carrier that can deliver drugs to tumor issues so as to kill the tumor cells. However, most of the current drug-carriers have a serious drug loss before reaching the tumor area, which makes the difficult control of drug release. Multi-stimulus responsive nano-carrier systems can overcome these drawbacks and make drug release controllable. pH/redox dual sensitive nano-carrier systems are currently hot research direction. In this paper, the research progress of pH/redox dual sensitive nano-carrier systems in recent years was reviewed in order to provide reference for relative researches.
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@#Carbon nanomaterials are one of the hotspots in the research of drug delivery systems for cancer. Compared with the traditional drug delivery systems for cancer treatment, carbon nanomaterials can be used as drug carriers after modification based on their advantages of large specific surface area and unique optical properties. They have the characteristics of high drug loading, good biocompatibility, tumor targeting and lasting action time, indicating great potential and development space. In this paper, the properties and functions of quantum dots, carbon nanotubes, graphene oxide and mesoporous carbon nanospheres are introduced in the order of dimensional quantum properties. The current research focus and existing problems of carbon nanomaterials are discussed in order to provide a reference for the safe and effective application of carbon nanomaterials in tumor therapy.