The preparation and characterization of folate-conjugated human serum albumin magnetic cisplatin nanoparticles

Objective： Nanoparticles are becoming an important method of targeted drug delivery. To evaluate the importance of folate-conjugated human serum albumin （HSA） magnetic nanoparticles （Folate-CDDP/HSA MNP）, we prepared drug-loaded Folate-CDDP/HSA MNPs and characterized their features. Methods： First, folate was conjugated with HSA under the effect of a condensing agent, and the conjugating rate was evaluated by a colorimetric method using 2, 4, 6 - trinitrobenzene sulfonic acid. Second, under N., gas, Fe：~O1 magnetic nanomaterials were prepared and characterized by using transmission electron microscopy （TEM）, SEM-EDS and X-ray diffraction （XRD）. Finally, Folate-CDDP/HSA MNP was prepared by using a solvent evaporation technique. TEM was used to observe particle morphology. The particle size and distribution of the prepared complexes were determined by a Laser particle size analyzer. Drug loading volume and drug release were investigated by a high performance liquid chromatography method （HPLC） in vitro. Results： We successfully prepared folate-conjugated HSA and its conjugating rate was 27.26 μg/mg. Under TEM, Fe2O4 magnetic nanoparticles were highly electron density and had an even size distribution in the range of 10-20 nm. It was confirmed by SEM-EDS and XRD that Fe304 magnetic nanoparticles had been successfully prepared. Under TEM, drug-loaded magnetic nanoparticles were observed, which had a round shape, similar uniform size and smooth surface. Their average size was 79 nm which was determined by laser scattering, and they exhibited magnetic responsiveness. Encapsulation efficiency was 89.75% and effective drug loading was calculated to be 15.25%. The release results in vitro showed that the half release time （ta/2） of cisplatin in cisplatin Solution and Folate-CDDP/HSA MNP was 65 min and 24 h respectively, which indicated that microspheres had an obvious effect of sustained-release. Conclusion： Folate-CDDP/HSA MNPs were prepared successfully. The preparation process and related characteristics data provided a foundation for further study, including the mechanism of the nanoparticles distribution in vivo and their intake by tumor cells.

Preparation and distribution of 5-fluorouracil ^(125)I sodium alginate-bovine serum albumin nanoparticles

AIM To prepare 5 FU sodium alginate 125 I bovine serum albumin nanoparticles (BSA NP), to determine the radioactive count in different organs of rats at different time points after oral administration of 5 FU 125 I sodium alginate BSA NP and to calculate the kinetic parameters of its metabolism. METHODS Emulsion solidification method was used to prepare 5 FU 125 I sodium alginate BSA NP, and to determine its diameter under transmission electronic microscope (TEM). Then the rate of NP and external drug releasing velocity were measured. Radioactive counting in different organs of rats was made after oral administration of the NP by GAMA Counter, and the kinetic parameters of drug metabolism were calculated by handling the data with the two department model. RESULTS The average arithmatic diameter of the NP was 166nm ± 34nm , the rate of 5 FU was 32 8% and the cumulative external releasing ratio amounted to 84 0% within 72 hours. The NP was mainly distributed in the liver, spleen, lungs and kidneys after NP oral administration to rats. The micro radioautographic experiment showed that NP was distributed in the Kupffers cells of liver, liver parenchymal cells and the phagocytes of spleen and lungs. The kinetic parameters of matabolism were: T 1/2 =9 42h, C max =2 45×10 7Bq, T max =2 18h, AUC=148×10 9Bq. CONCLUSION NP is difficult to pass through the blood-cerebral barrier,and 125 I sodium alginate-BSA NP enters the body circulation by gastroin testinal passage.

Paclitaxel and curcumin co-bound albumin nanoparticles having antitumor potential to pancreatic cancer

Albumin nanoparticles are considered to be an effective way to load water-insoluble anticancer drugs and target tumors via the gp60-mediated pathway. Herein, we fabricated an albumin nanoparticle formulation for co-loading paclitaxel(PTX) and curcumin(CCM), both of which have prominent anticancer efficacy, via nanoparticle albumin-bound(NabTM) technology using high-pressure homogenization. The PTX/CCM co-bound albumin nanoparticles(PTX/CCM Alb-NPs) had a slightly greater particle size of ~250 nm than that of plain PTX AlbNPs and CCM Alb-NPs(~234 and ~134 nm, respectively), with spherical surface morphology and stable size maintenance. However, the zeta potential of PTX/CCM Alb-NPs(ca.-30 mV)was not significantly different from that of PTX or CCM Alb-NPs. The loaded PTX and CCM were released gradually from the PTX/CCM Alb-NPs over ~24 h(97.7 ± 1.7% and 76.2 ± 0.5%,respectively). Furthermore, PTX/CCM Alb-NPs appeared to be efficiently internalized into Mia Paca-2 cells and exhibited a 71% increased IC50 versus PTX Alb-NPs in terms of cytotoxicity to Mia Paca-2 cells. These results suggest that PTX/CCM Alb-NPs are a new potential anticancer agent for combination therapy.

Synthesis of Zinc Oxide Nanoparticles with Good Photocatalytic Activities under Stabilization of Bovine Serum Albumin

Zinc oxide nanoparticles were synthesized using bovine serum albumin as stabilizers through a facile one-pot strategy in aqueous media. The morphology and crystal phase of the zinc oxide nanoparticles were determined by transmission electron microscopy, X-ray diffractograms, and Fourier transform infrared spectroscopy. The synthesized ZnO nanoparticles exhibited strong absorption and photoluminescence properties in the visible wavelength region based on the fluorescence and UV-visible spectroscopy. Based on the results, the zinc oxide nanoparticles could effectively degrade the organic dyes through the mediation of the hydroxyl radical under visible light irradiation. Furthermore, the zinc oxide nanoparticles show good recycling stability during the photocatalytic experiments. These results suggested that the as-prepared zinc oxide nanoparticles might be used as a potential photocatalyst to efficiently treat the organic pollutants.

Characteristics of magnetic Fe_3O_4 nanoparticles encapsulated with human serum albumin

Magnetic nanoparticles （Fe304） were prepared by chemical precipitation method using Fe^2＋ and Fe^3＋ salts with sodium hydroxide in the nitrogen atmosphere. Fe3O4 nanoparticles were coated with human serum albumin（HSA） for magnetic resonance imaging as contrast agent. Characteristics of magnetic particles coated or uncoated were carried out using scanning electron microscopy and X-ray diffraction. Zeta potentials, package effects and distributions of colloid particles were measured to confirm the attachment of HSA on magnetic particles. Effects of Fe3O4 nanoparticles coated with HSA on magnetic resonance imaging were investigated with rats. The experimental results show that the adsorption of HSA on magnetic particles is very favorable to dispersing of magnetic Fe3O4 particles, while the sizes of Fe3O4 particles coated are related to the molar ratio of Fe3O4 to HSA. The diameters of the majority of particles coated are less than 100 nm. Fe3O4 nanoparticle coated with HSA has a good biocompatibility and low toxicity. This new contrast agent has some effects on the nuclear magnetic resonance imaging of liver and the lowest dosage is 20μmol/kg for the demands of diagnosis.

Bovine Serum Albumin-Conjugated Ferrimagnetic Iron Oxide Nanoparticles to Enhance the Biocompatibility and Magnetic Hyperthermia Performance

Magnetic hyperthermia is a fast emerging, non-invasive cancer treatment method which is used synergistically with the existing cancer therapeutics. We have attempted to address the current challenges in clinical magnetic hyperthermia-improved biocompatibility and enhanced heating characteristics, through a single combinatorial approach. Both superparamagnetic iron oxide nanoparticles(SPIONs) of size 10 nm and ferrimagnetic iron oxide nanoparticles(FIONs) of size 30 nm were synthesized by thermal decomposition method for comparison studies. Two different surface modifying agents, viz, Cetyl Trimethyl Ammonium Bromide and 3-Aminopropyltrimethoxysilane, were used to conjugate Bovine Serum Albumin(BSA) over the iron oxide nanoparticles via two different methods—surface charge adsorption and covalent amide bonding, respectively. The preliminary haemolysis and cell viability experiments show that BSA conjugation mitigates the haemolytic effect of the iron oxide nanoparticles on erythrocytes and is non-cytotoxic to the healthy Baby Hamster Kidney cells. It was observed from the results that due to better colloidal stability, the SAR value of the BSA-iron oxide nanoparticles is higher than the iron oxide nanoparticles without BSA, irrespective of the size of the iron oxide nanoparticles and method of conjugation. The BSA-FIONs seem to show improved biocompatibility, as the haemolytic index is less than 2 % and cell viability is up to 120 %, when normalized with the control. The SAR value of BSAFIONs is 2300 Wg^(-1) when compared to 1700 Wg^(-1) of FIONs without BSA conjugation. Thus, we report here that BSA conjugation over FIONs(with a high saturation magnetization of 87 emug^(-1)) provide a single combinatorial approach to improve the biocompatibility and enhance the SAR value for magnetic hyperthermia, thus addressing both the current challenges of the same.

Bovine Serum Albumin Loaded Solid Lipid Nanoparticles Prepared by Double Emulsion Method

Solid lipid nanoparticles loaded with bovine serum albumin（BSA） were prepared by a double emulsion method. As the mass fraction of the model drug BSA increased from 0 to 15%, the particle size gradually increased. The physical stability of the nanoparticles was investigated by zeta potential measurement and they were shown to be quite stable. Fluorescence spectroscopy confirmed that the loaded position of BSA was on the interface between the inner aqueous phase and the solid lipid phase. Both Fourier-transform infrared spectroscopy and circular dichroism spectra indicate that BSA in the nanoparticles was not destroyed, but the secondary structure was disrupted slightly.

Au-nanocluster-loaded human serum albumin nanoparticles with enhanced cellular uptake for fluorescent imaging

Protein-directed fluorescent Au nanoclusters have been widely studied owing to their potential applications in sensing,imaging,and drug and gene delivery.However,the use of nanoclusters in drug delivery is limited by low cellular uptake.In this study,human serum albumin-directed Au nanoclusters served as building blocks to obtain protein nanoparticles by desolvation.The nanoparticles had a decent quantum yield(QY),high colloidal stability and low cytotoxicity,and they could be readily conjugated with biological molecules.The cellular uptake of the Au nanoclusters and nanocluster-loaded protein nanoparticles were studied by confocal fluorescence microscopy.Agglomeration of the protein-directed Au nanoclusters into 50–150-nm nanoparticles dramatically increased the cellular uptake.

Synthesis and Physicochemical Characterization of Biodegradable Star-Shaped Poly Lactide-Co-Glycolide-<i>β</i>-Cyclodextrin Copolymer Nanoparticles Containing Albumin

The purposes of this research were to synthesize and characterize star-shaped poly lactide-co-glycolide-β-cyclo-dextrin (PLGA-β-CD) copolymer by reacting L-lactide, glycolide and β-cyclodextrin in the presence of stannous octoate as a catalyst. The structure of PLGA-β-CD copolymer was confirmed with 1H-NMR, 13C-NMR and FT-IR spectra. Albumin as a model peptide drug was encapsulated within nanoparticles made of PLGA-β-CD with a modified double emulsion method. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) photomicrographs showed that the nanoparticles have the mean diameter within the range of 80 - 210 nm. Also they were almost spherical in shape. Effects of the experimental parameters, such as copolymer composition, copolymer concentration, and reaction temperature, on particular size and encapsulation efficiency were investigated.

Synthesis of Silver Nanoparticles Using Albumin as a Reducing Agent

The preparation of stable, uniformed silver nanoparticles by the reduction of silver ions using albumin is reported in the present paper. It is a simple process for obtaining silver nanoparticles. The samples have been characterized by X-ray diffraction (XRD) and transmission electron microscopy (TEM), which reveal the nature of the nanoparticles. These studies conclude that the particles are mostly spherical in shape and have an average size of 26 nm. The UV-vis spectra show that an absorption band, occurred because of the Surface Plasmon Resonance, existing at 443 nm;the Thermogravimetric Analysis (TGA) shows that only 2% of the weight is organic matter. The average particle size was measured with a Nanosizer DLS.

Hemocompatibility of Albumin Nanoparticles as a Drug Delivery System—An in Vitro Study

As a major plasma protein, albumin has a distinct advantage compared with other materials for nanoparticle preparation. It is cheap and easily available. The present work aimed to prepare bovine albumin nanoparticles (BAN) with a simple coacervation method and to test their hemocompatibility. The albumin nanoparticles obtained by this method had a range of sizes from 250 - 350 nm at pH = 7.4. In vitro hemocompatibility tests of the prepared (BAN) were conducted after the incubation of BAN with normal blood for 2 h at 37&degC. Hemocompatibility tests showed that the reduction in the hemolysis percentage of erythrocytes was due to exposure to BAN. The other blood parameters such as hemoglobin (HG), mean corpuscle hemoglobin (MCH), and mean corpuscle hemoglobin concentration (MCHC) were in the normal range. The prothrombin time (PT) and erythrocyte sedimentation rate (ESR) decreased as the concentration of BAN increased. The results obtained in this study demonstrated that BAN could be used safely and without abnormal effect when interacted with blood through many biomedical applications.

Label-free colorimetric estimation of proteins using nanoparticles of silver

Metallic nanoparticles have received considerable attention in bioassays and diagnostics due to their unique surface plasmon resonance(SPR) properties.Gold nanoparticles have been employed for the development of SPR-based colorimetric bioassays.In the present report we have described a sensitive colorimetric approach for estimation of proteins,within a detection limit of 10?80 μg/m L,using unmodified silver nanoparticles.Besides the common advantages of colorimetric assay such as simplicity,high sensitivity,and low cost,our method has a label-free design and provides an important and attractive alternative to classical sensing probes and systems.The present work will contribute to the development of nanotechnology-based diagnostic tools.

Uptake of albumin nanoparticle surface modified with glycyrrhizin by primary cultured rat hepatocytes

AIM: To investigate the uptake difference between bovine serum albumin nanoparticle (BSA-NP) and bovine serum albumin nanoparticles with their surface modified byglycyrrhizin (BSA-NP-GL) and to develop a novel hepatocyte targeting BSA-NP-GL based on active targeting technology mediated by specific binding site of GL on rat cellular membrane. METHODS: Calcein loaded bovine serum albumin nanoparticles (Cal-BSA-NP) were prepared by desolvation process. Glycyrrhizin was conjugated to the surface reactive amino groups (SRAG) of Cal-BSA-NP by sodium periodate oxidization, which resulted in calcein-loaded bovine serum albumin nanoparticles with their surface modified by glycyrrhizin (Cal-BSA-NP-GL). The morphology of the two types of prepared nanoparticles (NP) was observed by transmission electron microscopy. The diameter of NP was measured with a laser particle size analyzer. The interaction between Cal-BSA-NP-GL and primary cultured hepatocytes was studied through cellular uptake experiments. The uptake amount of Cal-BSA-NPGL and Cal-BSA-NP by rat hepatocytes was determinedby fluorospectrophotometry. Uptake characteristics were investigated through experiments of competitive inhibition of specific binding site of GL. RESULTS: Both Cal-BSA-NP-GL and Cal-BSA-NP had regular spherical surfaces. The average diameter of CalBSA-NP-GL and Cal-BSA-NP was 77 and 79 nm respectively. The uptake amount of the two NP by hepatocytes reached its maximum at 2 h after incubation. The uptake amount of Cal-BSA-NP-GL by rat hepatocytes was 4.43-fold higher than that of Cal-BSA-NP. There was a significant difference in the uptake of Cal-BSA-NP-GL and Cal-BSA-NP by hepatocytes (P＜0.01). The uptake of Cal-BSA-NP-GL was inhibited when GL was added previously to isolated rat hepatocytes, and the uptake of Cal-BSA-NP was not affected by GL.CONCLUSION: A binding site of GL is present on the surface of rat hepatocytes, BSA-NP-GL may be internalized via this site by hepatocytes and can be used as a drug carrier for active targeting of delivery drugs to hepatocytes.

Weekly intravenous nanoparticle albumin-bound paclitaxel for elderly patients with stage IV non-small-cell lung cancer:a series of 20 cases

The purpose of this study was to evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel as a rescue regimen in the treatment of patients with advanced non-small-cell lung cancer. We retrospectively reviewed the medical records of 20 patients with stage IV non-small-cell lung cancer. The patients had progressive disease after standard antitumor therapy and subsequently received intravenous albumin-bound paclitaxel at the dose of 100 mg/m2 in weekly schedule. Cumulative findings showed that the overall response rate was 30.0%, the disease control rate amounted to 40%, and the 1 year survival rate was 30%. In addition, the median time to progression and the median survival time reached 5 and 10 months, respectively. Meanwhile, no severe hypersensitivity reactions and grade 4 adverse effects were reported. In summary, weekly-administered albumin-bound paclitaxel seems to be an effective and safe regimen for elderly patients with stage IV non-small-cell lung cancer who were refractory to conventional therapy.

Biophysical interactions between silver nanoparticle-albumin interface and curcumin

Active targeted drug delivery methods facilitate effective uptake of functionalized nanoparticles through receptor-mediated transcytosis.In recent years,albumin-nanoparticle interaction has been critically examined so that this functionalized nanoparticle can be efficiently loaded with drugs.The present investigation aims at understanding the adsorption of Bovine Serum Albumin(BSA)on Silver Nano-particle(SNP)surface,preparation of soft conjugates(SC)and hard conjugates(HC)of BSA-functionalized SNP(SNP-BSA),and their interaction with curcumin(CUR).HC contains tightly bound BSA whereas SC involves tightly and loosely bound BSA.Increase in the hydrodynamic radii of conjugates was observed upon SNP incubation with increased concentration of BSA.Three different SNP-BSA conjugate ratios were selected to study their interaction with CUR.Fluorescence spectroscopy showed a strong association between CUR and SNP:BSA conjugates.However,binding varied with a change in the conjugate ratio.Circular Dichroism(CD)/Fourier Transform Infrared(FTIR)spectroscopy revealed the alterations in the secondary structure of BSA upon CUR binding to the conjugates.Zeta potential data indicated stable conjugate formation.CUR in SNP:BSA conjugate was found to have a higher half-life as compared to the control.We believe that this is the first biophysical characterization report of conjugates that can be effectively extrapolated for targeted drug delivery.

A stability-indicating high performance liquid chromatography method to determine apocynin in nanoparticles

In this study, we developed and validated a fast, specific, sensitive, precise and stability-indicating high performance liquid chromatography（HPLC） method to determine the drug apocynin in bovine serum albumin（BSA） nanoparticles. Chromatographic analyses were performed on an RP C18 column and using a photodiode array detector at a wavelength of 276 nm. Mobile phase consisted of a mixture of acetonitrile and 1% acetic acid（60：40, v/v）, and it was eluted isocratically at a flow rate of 0.8 mL/min. The retention time of apocynin chromatographic peak was 1.65 min. The method was linear, precise, accurate and specific in the range of 5–100 μg/mL. The intra-and inter-day precisions presented relative standard deviation（RSD） values lower than 2%. The method was robust regarding changes in mobile phase proportion, but not for flow rate. Limits of detection and quantitation were 78 ng/mL and 238 ng/mL, respectively. Apocynin was exposed to acid and alkali hydrolysis, oxidation and visible light. The drug suffered mild degradation under acid and oxidation conditions and great degradation under alkali conditions. Light exposure did not degrade the drug. The method was successfully applied to determine the encapsulation efficiency of apocynin in BSA nanoparticles.

Biomedical Applications of Single Protein Nanoparticles

The drug carrier function of single protein nanoparticles, i.e., each individual protein molecule covered by a very thin, porous and few nanometer thick polymer layer, has been investigated. This layer around protein molecule is very thin, about 3-5 nm thick and highly porous, thus it does not reduce seriously the enzymatic function of protein molecule. The spatial structure of encapsulated protein molecule, which is essential in its function, can be stabilized by this polymer layer. Bovine serum albumin was used as protein drug molecule and it was encapsulated with acrylamide-bisarylamide random copolymer. The polymerization, starting from the modified sites of the surface of bovine serum albumin molecules was initiated by TEMED （tetramethylethylenediamine）. These single albumin nanoparticles were painted with fluorescein isothiocyanate. This material was then injected into the inferior vena cava of rats. The treated rats were decapitated after 1 to 10 minutes and its brain was investigated by fluorescent microscopy. It was proved that bovine serum albumin molecules as drugs encapsulated in polymer nano-layer with a reduced size （about 10 nm） can pass through the blood brain barrier. The results suggest that this method is capable of transformation of biomacromolecules to access the brain tissue via the blood.

负载EPZ6438牛血清白蛋白-壳聚糖纳米粒抑制骨肉瘤的效应

背景:骨肉瘤肿瘤干细胞激活最显著的转录因子是EZH2,据报道沉默EZH2可以抑制骨肉瘤细胞生长。研究证实,牛血清白蛋白-壳聚糖纳米粒是一种具有优异生物相容性和生物降解性的药物传递载体,且白蛋白载体可提供靶向肿瘤的药物递送功能。目的:探讨负载EPZ6438(EZH2抑制剂)血清白蛋白-壳聚糖纳米粒抑制骨肉瘤的效应及机制。方法:①制备未负载与负载EPZ6438的血清白蛋白-壳聚糖纳米粒,检测载EPZ6438血清白蛋白-壳聚糖纳米粒的药物包载率及药物释放率。②将MG-63细胞分4组培养,分别加入PBS(对照组)、血清白蛋白-壳聚糖纳米粒浸提液(空白纳米粒组)、EPZ6438溶液(游离药物组)及负载EPZ6438的血清白蛋白-壳聚糖纳米粒浸提液(载药纳米粒组),培养3 d后,利用流式细胞仪检测细胞凋亡、RT-PCR法检测细胞caspase3 mRNA的表达。③取12只裸鼠,通过腋下注射MG-63细胞悬液建立皮下荷瘤小鼠模型,造模成功后随机分4组干预,分别向肿瘤组织内注射生理盐水(对照组)、血清白蛋白-壳聚糖纳米粒溶液(空白纳米粒组)、EPZ6438溶液(游离药物组)及负载EPZ6438的血清白蛋白-壳聚糖纳米粒溶液(载药纳米粒组),每组3只。注射7 d后,观察肿瘤体积及肿瘤组织冰冻切片TUNEL染色。结果与结论:①载药纳米粒的药物包载率约为8.8%,该纳米粒在纯水中具有良好的药物释放效果,24 h药物释放量为(34.72±1.93)μg,72 h为(48.58±1.10)μg,120 h为(49.18±1.24)μg,168 h(50.25±1.13)μg,药物释放在120 h到达平台期,释放率约为97.9%;②与MG-63细胞培养3 d后,对照组、空白纳米粒组细胞凋亡率低于游离药物组、载药纳米粒组(P<0.001),caspase3 mRNA的表达低于游离药物组、载药纳米粒组(P<0.0001);③注射7 d后,载药纳米粒组裸鼠肿瘤体积小其他3组(P<0.05),肿瘤组织TUNEL染色阳性细胞比率高于其他3组(P<0.0001);④结果显示,负载EPZ6438的血清白蛋白-壳聚糖纳米粒可通过诱导肿瘤细胞的凋亡来抑制骨肉瘤生长。

基于真实世界数据的注射用紫杉醇(白蛋白结合型)药学监护路径研究

目的:建立注射用紫杉醇(白蛋白结合型)(nab-PTX)药学监护路径,为临床合理用药提供参考。方法:对2020年1月至2023年6月该院使用过nab-PTX的患者资料进行回顾性分析,评价用药合理性。以nab-PTX的药品说明书为基础,以循证医学为依据,结合该院nab-PTX使用的真实世界数据等,建立nab-PTX在肿瘤患者真实世界人群中合理用药的药学监护路径。结果:本研究纳入279例使用过nab-PTX的患者数据。分析结果显示,42例转移性乳腺癌患者符合nab-PTX的药品说明书适应证;超说明书适应证用药的共237例(占84.9%),其中有循证医学证据的超说明书适应证用药有209例(包括宫颈癌、胰腺癌、胃癌、非小细胞肺癌、鼻咽癌、卵巢癌或输卵管癌、食管癌、子宫内膜癌、胆管癌),评价为用药合理,而部分超说明书用药(口腔癌、纵隔恶性肿瘤、骨肿瘤、软组织恶性肿瘤、前列腺癌、十二指肠恶性肿瘤等)循证医学证据不足,评价为不合理用药。患者使用nab-PTX最常见的不良反应为骨髓抑制和周围神经病变,与药品说明书相符。在此基础上,从化疗前、化疗中、化疗后及随访等多方面建立了nab-PTX药学监护路径。结论:nab-PTX超说明书用药普遍存在,应加强对nab-PTX应用的管理,通过制定住院患者nab-PTX药学监护路径,可以提高药师的工作效率,保障肿瘤患者合理用药。