Molecular Mechanisms of Intracellular Delivery of Nanoparticles Monitored by an Enzyme‑Induced Proximity Labeling

Achieving increasingly finely targeted drug delivery to organs,tissues,cells,and even to intracellular biomacromolecules is one of the core goals of nanomedicines.As the delivery destination is refined to cellular and subcellular targets,it is essential to explore the delivery of nanomedicines at the molecular level.However,due to the lack of technical methods,the molecular mechanism of the intracellular delivery of nanomedicines remains unclear to date.Here,we develop an enzyme-induced proximity labeling technology in nanoparticles(nano-EPL)for the real-time monitoring of proteins that interact with intracellular nanomedicines.Poly(lactic-co-glycolic acid)nanoparticles coupled with horseradish peroxidase(HRP)were fabricated as a model(HRP(+)-PNPs)to evaluate the molecular mechanism of nano delivery in macrophages.By adding the labeling probe biotin-phenol and the catalytic substrate H_(2)O_(2)at different time points in cellular delivery,nano-EPL technology was validated for the real-time in situ labeling of proteins interacting with nanoparticles.Nano-EPL achieves the dynamic molecular profiling of 740 proteins to map the intracellular delivery of HRP(+)-PNPs in macrophages over time.Based on dynamic clustering analysis of these proteins,we further discovered that different organelles,including endosomes,lysosomes,the endoplasmic reticulum,and the Golgi apparatus,are involved in delivery with distinct participation timelines.More importantly,the engagement of these organelles differentially affects the drug delivery efficiency,reflecting the spatial–temporal heterogeneity of nano delivery in cells.In summary,these findings highlight a significant methodological advance toward understanding the molecular mechanisms involved in the intracellular delivery of nanomedicines.

Current optimization-based control of dual three-phase PMSM for low-frequency temperature swing reduction

In this paper,a control scheme based on current optimization is proposed for dual three-phase permanent-magnet synchronous motor(DTP-PMSM)drive to reduce the low-frequency temperature swing.The reduction of temperature swing can be equivalent to reducing maximum instantaneous phase copper loss in this paper.First,a two-level optimization aiming at minimizing maximum instantaneous phase copper loss at each electrical angle is proposed.Then,the optimization is transformed to a singlelevel optimization by introducing the auxiliary variable for easy solving.Considering that singleobjective optimization trades a great total copper loss for a small reduction of maximum phase copper loss,the optimization considering both instantaneous total copper loss and maximum phase copper loss is proposed,which has the same performance of temperature swing reduction but with lower total loss.In this way,the proposed control scheme can reduce maximum junction temperature by 11%.Both simulation and experimental results are presented to prove the effectiveness and superiority of the proposed control scheme for low-frequency temperature swing reduction.

Intelligent Road Safety System Based on Multi-Function Warning Device

A warming device for car driving is proposed in this paper,which includes support rods and warning plates.In this device,several display screens are insalled on one side of the warning panel.Indicator lights are set on the display screen.A waning board is mounted on the top box.Several radar detectors are mounted on one side of the top box,and the radar detectors orrespond to the display screens.Several waming lights are installed on the top box,and the waning lights orespond to sevenl radar detectors.The sliding side of the support rod cleans the unit.The change of positions of the indicator lights based on the radar detectors will be rellected on the display screens,which allows drivers to understand the situation of the road.Therefore,they can prepare for changing lanes and overtaking,and understand the position and speed of all vehicles in this road section in advance.

Reducing oxidative stress and hepatoprotective effect of water extracts from Pu-erh tea on rats with high-fat diet

Reducing oxidative stress and hepatoprotective effect of Pu-erh tea water extracts on rats fed with high-fat diet were researched for explaining health care of Pu-erh tea.Fifty SD rats were divided into five groups.The body weight was measured once a day.The malondialdehyde(MDA)and glucose(Glu)levels and the activities of alanine aminotransferase(ALT),aspartate aminotransferase(AST),nitric oxide synthase(NOS),and pyruvate kinase(PK)in serum were determined.Furthermore,the hepatic glycogen level(HGL)and the activities of hepatic total superoxide dismutase(T-SOD),catalase(CAT),and glutathione peroxidase(GSH-Px)were also measured after continuous administration for 12 weeks.The result demonstrated that Pu-erh extract caused the decreases in body weight,fat index,MDA and NOS levels,and the increases in hepatic T-SOD,CAT and GSH-Px activities,indicating that the extract may be due to inhibiting the increases of body weight and fat index,reducing oxidant stress state and inhibiting lipid peroxidation,thus decreasing the activities of ALT and AST,and protecting the liver in rat.Meanwhile,the extracts could increase the production of hepatic glycogen and the activity of PK,and reduce glucose level,protecting the liver from the diseases associated with type II diabetes.

A biomimetic antitumor nanovaccine based on biocompatible calcium pyrophosphate and tumor cell membrane antigens

Currently,the cancer immunotherapy has made great progress while antitumor vaccine attracts substantial attention.Still,the selection of adjuvants as well as antigens are always the most crucial issues for better vaccination.In this study,we proposed a biomimetic antitumor nanovaccine based on biocompatible nanocarriers and tumor cell membrane antigens.Briefly,endogenous calcium pyrophosphate nanogranules with possible immune potentiating effect are designed and engineered,both as delivery vehicles and adjuvants.Then,these nanocarriers are coated with lipids and B16-OVA tumor cell membranes,so the biomembrane proteins can serve as tumor-specific antigens.It was found that calcium pyrophosphate nanogranules themselves were compatible and possessed adjuvant effect,while membrane proteins including tumor associated antigen were transferred onto the nanocarriers.It was demonstrated that such a biomimetic nanovaccine could be well endocytosed by dendritic cells,promote their maturation and antigen-presentation,facilitate lymph retention,and trigger obvious immune response.It was confirmed that the biomimetic vaccine could induce strong T-cell response,exhibit excellent tumor therapy and prophylactic effects,and simultaneously possess nice biocompatibility.In general,the present investigation might provide insights for the further design and application of antitumor vaccines.

Small GTPases:Structure,biological function and its interaction with nanoparticles

Small GTPase is a kind of GTP-binding protein commonly found in eukaryotic cells.It plays an important role in cytoskeletal reorganization,cell polarity,cell cycle progression,gene expression and many other significant events in cells,such as the interaction with foreign particles.Therefore,it is of great scientific significance to understand the biological properties of small GTPases as well as the GTPase-nano interplay,since more and more nanomedicine are supposed to be used in biomedical field.However,there is no review in this aspect.This review summarizes the small GTPases in terms of the structure,biological function and its interaction with nanoparticles.We briefly introduced the various nanoparticles such as gold/silver nanoparticles,SWCNT,polymeric micelles and other nano delivery systems that interacted with different GTPases.These current nanoparticles exhibited different pharmacological effect modes and various target design concepts in the small GTPases study.This will help to elucidate the conclusion that the therapeutic strategy targeting small GTPases might be a new research direction.It is believed that the in-depth study on the functional mechanism of GTPases can provide insights for the design and study of nanomedicines.

Double weight determination method for experts of complex multi-attribute large-group decision-making in interval-valued intuitionistic fuzzy environment

The systematic clustering analysis based weight determination methods are suitable for the experts of complex multi-attribute large-group decision-making (CMALGDM) in interval-valued intuitionistic fuzzy environment. However, these methods mainly have two shortcomings: they do not consider the consistency of the experts in each aggregation; the aggregation weights are often determined simply by the 'majority principle', and neglect the quantity of information provided by the holistic aggregation, leading to decision biases. Hence, a double weight determination method for experts is proposed to solve these problems. As for the first shortcoming, a mathematical programming model is used to solve for the optimal expert weights within each aggregation, ensuring consistency in the overall preferences of the aggregations. As for the second shortcoming, we propose a modification of the aggregation weights based on the information entropy, which fully considers both the number of experts and the amount of information provided by the holistic aggregation. With the proposed method, the final expert weights are determined more rigorously and objectively. The feasibility of the proposed method is investigated through an illustrative example. ? 1990-2011 Beijing Institute of Aerospace Information.

Thermal-physiological Strategies Underlying the Sympatric Occurrence of Three Desert Lizard Species

Sympatric reptiles are the ideal system for investigating temperature-driven coexistence. Understanding thermally physiological responses of sympatric lizards is necessary to reveal the physiological mechanisms that underpin the sympatric occurrence of reptiles. In this study, we used three lizard species, Eremias argus, E. multiocellata, and Phrynocephalus przewalskii, which are sympatric in the Inner Mongolia desert steppe, as a study system. By comparing their resting metabolic rates(RMR) and locomotion at different body temperatures, we aimed to better understand their physiological responses to thermal environments, which may explain the sympatric occurrence of these lizards. Our results showed that E. argus had significantly higher RMR and sprint speed than E. multiocellata, and higher RMR than P. przewalskii. In addition, the optimal temperature that maximized metabolic rates and locomotion for E. argus and E. multiocellata was 36°C, whereas for P. przewalskii it was 39°C. Our study revealed the physiological responses to temperatures that justify the sympatric occurrence of these lizards with different thermal and microhabitat preferences and active body temperatures. Eremias argus and E. multiocellata, which have lower body temperatures than P. przewalskii, depend on higher RMR and locomotion to compensate for their lower body temperatures in field conditions. Our study also highlights the importance of using an integrative approach, combining behavior and physiology, to explore the basis of sympatric occurrence in ectothermic species.

Highway Cost Prediction Based on LSSVM Optimized by Intial Parameters

The cost of highway is affected by many factors.Its composition and calculation are complicated and have great ambiguity.Calculating the cost of highway according to the traditional highway engineering estimation method is a completely tedious task.Constructing a highway cost prediction model can forecast the value promptly and improve the accuracy of highway engineering cost.This work sorts out and collects 60 sets of measured data of highway engineering;establishes an expressway cost index system based on 10 factors,including main route mileage,roadbed width,roadbed earthwork,and number of bridges;and processes the data through principal component analysis(PCA)and hierarchical cluster analysis.Particle swarm optimization(PSO)is used to obtain the optimal parameter combination of the regularization parameter c and the kernel function width coefficientin least squares support vector machine(LSSVM).Results show that the average relative and mean square errors of the PCA-PSO-LSSVM model are 0.79%and 10.01%,respectively.Compared with BP neural networks and unoptimized LSSVM model,the PCA-PSO-LSSVM model has smaller relative errors,better generalization ability,and higher prediction accuracy,thereby providing a new method for highway cost prediction in complex environments.

Synergistic effects of AAGL and anti-PD-1 on hepatocellular carcinoma through lymphocyte recruitment to the liver

Objective:Therapy for hepatocellular carcinoma(HCC)is a major challenge,and targeted therapies provide only a modest benefit in terms of overall survival.Treatment with antibodies to programmed cell death protein 1(PD-1)/PD-L1 can restore the functions of tumor-infiltrating T cells in HCC and has shown clinical efficacy in 20%of patients with advanced HCC.Novel approaches are urgently needed to treat HCC and to augment the efficacy of immunotherapy.Methods:Tumor-bearing mice were treated with Agrocybe aegerita galectin(AAGL)alone or in combination with anti-PD-1,and the tumor sizes and lifespans of mice were determined.Transcriptome analysis,cytokine analysis,flow cytometry analysis of the number and proportion of immune cell subsets in the liver and spleen,and molecular and cellular analyses of tumors were used to define the underlying mechanisms.Results:AAGL significantly inhibited the growth of liver tumors in a dose-dependent manner.Furthermore,AAGL increased the expression of multiple cytokines and chemokines in tumor-bearing mouse livers;this effect was associated with the activation and migration of T cells and macrophages,in agreement with the in vitro results.Importantly,the aggregation of T cells and macrophages induced by AAGL in tumor-bearing mouse livers clearly enhanced the response to PD-1 blockade immunotherapy.Conclusions:The results showed that AAGL induced the activation and migration of lymphocytes to the liver,and that the combination of AAGL and anti-PD-1 may be a promising strategy for HCC treatment.

One-pot preparation of nanodispersion with readily available components for localized tumor photothermal and photodynamic therapy

Photothermal(PTT) and photodynamic(PDT) combined therapy has been hindered to clinical translation, due to the lack of available biomaterials, difficult designs of functions,and complex chemical synthetic or preparation procedures. To actualize a high-efficiency combination therapy for cancer via a feasible approach, three readily available materials are simply associated together in one-pot, namely the single-walled carbon nanohorns(SWCNH), zinc phthalocyanine(ZnPc), and surfactant TPGS. The established nanodispersion is recorded as PCT. The association of SWCNH/ZnPc/TPGS was confirmed by energy dispersive spectrum, Raman spectrum and thermogravimetric analysis. Under lighting, PCT induced a temperature rising up to about 60 ℃ due to the presence of SWCNH, production a 7-folds of singlet oxygen level elevation because of ZnPc, which destroyed almost all4T1 tumor cells in vitro. The photothermal effect of PCT depended on both laser intensity and nanodispersion concentration in a linear and nonlinear manner, respectively. After a single peritumoral injection in mice and laser treatment, PCT exhibited the highest tumor temperature rise(to 65 ℃) among all test groups, completely destroyed primary tumor without obvious toxicity, and inhibited distant site tumor. Generally, this study demonstrated the high potential of PCT nanodispersion in tumor combined therapy.

Optimize the combination regimen of Trastuzumab and Nab-paclitaxel in HER2-positive tumors via modulating Caveolin-1 expression by lovastatin

The combination regimen of trastuzumab(Tras)plus Nab-paclitaxel(Nab)is recommended to treat HER2-positive(HER2+)cancers.However,they exert effects in different mechanisms:Tras need to stay on cell membranes,while Nab need to be endocytosed,therefore the concurrent combination regimen may not be the best one in HER2+tumors treatment.Caveolin-1(Cav-1)is a key player in mediating their endocytosis and is associated with their efficacy,but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy.Herein,we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+Cav-1 High tumor treatment.In the regimen,lovastatin(Lova)was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression,increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+Cav-1 High cells but not in HER2+Cav-1 Low cells.Therefore,by exchanging the dosing sequence of Nab and Tras,and by adding Lova at appropriate time points,the precise three-drug-sequential regimen(PTDS,Nab(D1)-Lova(D2)-Lova&Tras(D2+12 h))was established.Compared with the concurrent regimen,the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+Cav-1 High tumors,which might be a promising combination regimen for these patients in clinics.

Boosting synergism of chemo- and immunotherapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs.It is critical to inspire new potential to remodel the value of this classical therapeutic strategy.Here,we fabricate bisphosphonate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic drugs.Alendronate in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle core.The synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic mechanism.Differing from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate metabolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes theaccumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy.Therefore,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

An enzyme-responsive and transformable PD-L1 blocking peptide-photosensitizer conjugate enables efficient photothermal

Mild photothermal therapy combined with immune checkpoint blockade has received increasing attention for the treatment of advanced or metastatic cancers due to its good therapeutic efficacy.However,it remains a challenge to facilely integrate the two therapies and make it potential for clinical translation.This work designed a peptide-photosensitizer conjugate(PPC),which consisted of a PD-L1 antagonist peptide(CVRARTR),an MMP-2 specific cleavable sequence,a self-assembling motif,and the photosensitizer Purpurin 18.The single-component PPC can self-assemble into nanospheres which is suitable for intravenous injection.The PPC nanosphere is cleaved by MMP-2 when it accumulates in tumor sites,thereby initiating the cancer-specific release of the antagonist peptide.Simultaneously,the nanospheres gradually transform into co-assembled nanofibers,which promotes the retention of the remaining parts within the tumor.In vivo studies demonstrated that PPC nanospheres under laser irradiation promote the infiltration of cytotoxic T lymphocytes and maturation of DCs,which sensitize 4T1 tumor cells to immune checkpoint blockade therapy.Therefore,PPC nanospheres inhibit tumor growth efficiently both in situ and distally and blocked the formation of lung metastases.The present study provides a simple and efficient integrated strategy for breast cancer photoimmunotherapy.

NIGT1 represses plant growth and mitigates phosphate starvation signaling to balance the growth response tradeoff in rice

Inorganic phosphate(Pi)availability is an important factor which affects the growth and yield of crops,thus an appropriate and effective response to Pi fluctuation is critical.However,how crops orchestrate Pi signaling and growth under Pi starvation conditions to optimize the growth defense tradeoff remains unclear.Here we show that a Pi starvationinduced transcription factor NIGT1(NITRATE-INDUCIBLE GARP-TYPE TRANSCRIPTIONAL REPRESSOR 1)controls plant growth and prevents a hyper-response to Pi starvation by directly repressing the expression of growth-related and Pisignaling genes to achieve a balance between growth and response under a varying Pi environment.NIGT1 directly binds to the promoters of Pi starvation signaling marker genes,like IPS1,mi R827,and SPX2,under Pi-deficient conditions to mitigate the Pi-starvation responsive(PSR).It also directly represses the expression of vacuolar Pi efflux transporter genes VPE1/2 to regulate plant Pi homeostasis.We further demonstrate that NIGT1 constrains shoot growth by repressing the expression of growth-related regulatory genes,including brassinolide signal transduction master regulator BZR1,cell division regulator CYCB1;1,and DNA replication regulator PSF3.Our findings reveal the function of NIGT1 in orchestrating plant growth and Pi starvation signaling,and also provide evidence that NIGT1 acts as a safeguard to avoid hyper-response during Pi starvation stress in rice.

无机-有机杂化材料用于胶体类悬浮物的絮凝脱除

胶体类悬浮物一直以来均是废水处理的难点,不仅消耗大量的絮凝剂,且常需多种药剂组合使用,造成水处理成本高、固体废渣产生量大、工艺流程冗长等一系列问题。为了克服物理共混法导致无机与有机材料复合不均匀的弊端,借助有机单体在无机组分中的原位聚合反应,成功研制出无机-有机杂化材料聚(硅酸氯化铝-丙烯酰胺)[P(SAC-AM)]。选择煤气化废水作为研究对象,并与常用市售絮凝剂聚合硅酸氯化铝,聚丙烯酰胺以及聚二甲基二烯丙基氯化铵进行对比,考察了P(SACAM)对胶体类悬浮物的絮凝性能。结果表明,P(SAC-AM)可充分发挥电中和与吸附架桥的协同作用,在低投加量条件下,获得比市售絮凝剂单独或组合使用时均较优的絮凝效果,并可形成粒径较大且密实的絮体,有利于悬浮物后续的沉降与分离。此外,P(SAC-AM)可同时实现废水中COD,Ca^(2+),Mg^(2+)等的少量去除。

Effects of potassium channel blockage on inverse stochastic resonance in Hodgkin-Huxley neural systems

Inverse stochastic resonance(ISR)is a phenomenon in which the firing activity of a neuron is inhibited at a certain noise level.In this paper,the effects of potassium channel blockage on ISR in single Hodgkin-Huxley neurons and in small-world networks were investigated.For the single neuron,the ion channel noise-induced ISR phenomenon can occur only in a certain small range of potassium channel blockage ratio.Bifurcation analysis showed that this small range is the bistable region regulated by the external bias current.For small-world networks,the effect of non-homogeneous network blockage on ISR was investigated.The network blockage ratio was used to represent the proportion of potassium-channel-blocked neurons to total network neurons.It is found that an increase in network blockage ratio at small coupling strengths results in shorter ISR duration.When the coupling strength is increased,the ISR is more significant in the case of a large network blockage ratio.The ISR phenomenon is determined by the network blockage ratio,the coupling strength,and the ion channel noise.Our results will provide new perspectives on the observation of ISR in neuroscience experiments.

过表达tRNA基因tL(CAA)K提高酿酒酵母乙酸耐受性

乙酸是木质纤维素类生物质水解液中的常见毒性抑制物,选育乙酸耐受性好的酿酒酵母菌株,有利于高效利用木质纤维素类生物质,发酵生产生物燃料和生物基化学品。目前对酿酒酵母抗逆性的研究多集中在转录水平,但对转运RNA(Transfer RNA,tRNA)在耐受性中的作用研究较少。在对酿酒酵母抗逆性研究过程中发现,一些转运RNA基因在耐受性好的酿酒酵母菌株中转录明显上调。本文深入分析了精氨酸tRNA基因tR(ACG)D和亮氨酸tRNA基因tL(CAA)K过表达对酿酒酵母耐受木质纤维素水解液的影响。结果表明,在4.2 g/L乙酸胁迫条件下进行乙醇发酵时,过表达tL(CAA)K的菌株生长和发酵性能均优于对照酵母菌株,乙醇生产强度比对照菌株提高了29.41%,但过表达tR(ACG)D基因的菌株生长和代谢能力较对照菌株明显降低,体现了不同tRNA的不同调控作用。进一步分析发现,过表达tL(CAA)K的重组酵母菌株乙酸耐受性调控相关基因HAA1、MSN2和MSN4等胁迫耐受性相关转录因子编码基因的转录水平上调。本文的研究为选育高效利用木质纤维素资源进行生物炼制的酵母菌株提供了新的改造策略,也为进一步揭示酿酒酵母tRNA基因表达调控对抗逆性的影响提供了基础。

通过针对纳米粒诱导细胞响应的蛋白质组学分析揭示纳米粒跨上皮细胞转运机制

药物在口服药物递送的应用可以有效地促进药物在肠上皮细胞的吸收和转运。然而,缺乏有效性和安全性的机制研究限制了它们在人体的最终转化。虽然囊泡转运已被证实为纳米药物转运的一般特征,但其更深层次的分子机制尚不清楚。此外,纳米药物的细胞转运是一个由不同细胞器和组分参与的动态过程。然而,现有的研究大多只关注纳米药物的静态定位,而忽视了纳米药物对细胞的动态生物学效应。在此,我们制备了金纳米粒作为模型,并培养上皮细胞单层,在分子水平上探索纳米-生物相互作用。传统的药物抑制策略和亚细胞成像技术阐明了巨胞饮/内吞体/多囊泡体/溶酶体的转运路径。基于质谱的蛋白质组策略被用来识别和定量分析参与纳米药物胞内转运的蛋白质。研究表明,与亚细胞结构、信号转导、能量转化和代谢调节相关的多种蛋白都受到纳米粒转运的调控。这些蛋白表达的改变阐明了细胞内蛋白的作用,并验证了传统的发现。更重要的是,揭示了细胞对纳米粒转运的反馈机制。我们相信,这些新的调控机制将为纳米药物通过上皮屏障的有效转运提供新的策略。

cRGD-DOX自组装纳米粒与贝伐珠单抗联合治疗乳腺癌（英文）

肿瘤微环境中不同细胞群之间的相互作用能够促进肿瘤生长,靶向不同细胞群可以提高肿瘤的治疗效果。整合素高表达于多种肿瘤细胞表面,血管内皮生长因子(VEGF)对肿瘤新生血管生长具有强烈的促进作用。因此,本研究针对肿瘤细胞和新生血管制备了一种靶向于整合素的阿霉素偶联药物(cRGD-DOX)纳米粒,并将其与抗VEGF抗体贝伐珠单抗联合应用,在整合素高表达的MDA-MB-231肿瘤模型上考察其抗肿瘤效果。细胞水平研究结果表明,c RGD-DOX纳米粒可以被MDA-MB-231细胞摄取,其摄取与整合素表达相关;与游离阿霉素相比,c RGD-DOX纳米粒的细胞毒下降;贝伐珠单抗在1mg/mL以下无明显的细胞毒。体内研究结果表明,贝伐珠单抗可以降低肿瘤间质液压;与单制剂组相比,cRGD-DOX纳米粒和贝伐珠单抗联用后药效增强。总之,联合应用靶向新生血管的抗体药物和靶向整合素的细胞毒药物纳米粒是一个有效的抗肿瘤治疗方案。