摘    要

脑胶质瘤是中枢神经系统中最常见的恶性肿瘤，其复发率和死亡率极高。目前常用的治疗方法包括手术切除、放射治疗和化疗，但由于胶质瘤的侵袭性生长和对传统化疗药物的耐药性，治疗效果有限。此外，由于血脑屏障（Blood-brain barrier，BBB）的存在，对化疗药物剂量要求高、药物的靶向性差，导致化疗效果低且引起全身毒性。在最近研究的许多脑胶质瘤治疗方法中，光动力疗法（Photodynamic therapy，PDT）引起了人们的极大兴趣，并有很大的应用前景。

纳米颗粒给药系统（Nanoparticle drug delivery system，NDDS）因其优越的药物转运能力和可控性质而备受关注。尤其是靶向治疗方面，虽然纳米颗粒可以通过表面修饰特异性配体实现主动靶向到肿瘤组织，但在体内环境中，它们常会受到血清蛋白的屏蔽，从而导致靶向能力显著降低。因此，设计多功能纳米颗粒具有重要意义。一种策略是利用同源细胞膜包裹纳米颗粒，以逃避免疫系统清除并延长其在体内的滞留时间，且细胞膜包覆通过同源粘附作用增强靶向效果。另一种策略是利用血液中的特定蛋白在纳米颗粒表面形成蛋白冠，实现主动靶向。本研究选择了转铁蛋白作为靶向肿瘤组织的策略，因为转铁蛋白与血脑屏障表面的转铁蛋白受体有特异性结合，并且在多种肿瘤中高表达。

因此设计了共载二氢卟酚e6（Chlorin e6，Ce6）和二甲双胍（Metformin，MET）脂质体，表面包覆肿瘤细胞膜，经转铁蛋白配体T₁₀多肽修饰表面形成的转铁蛋白冠介导的细胞膜仿生纳米颗粒。

研究目的：制备出转铁蛋白冠介导细胞膜仿生纳米颗粒(MET/Ce6@Lipo@CM @T₁₀)，并研究其在光照下引起的光动力疗效，以探索其光动力抗肿瘤作用机制。

研究方法：

MET/Ce6@Lipo@CM@T₁₀的制备及表征：合成DSPE-PEG₂₀₀₀-T₁₀及结构鉴定，通过薄膜水化法制备共载MET和Ce6的脂质体，利用挤压法包覆U87肿瘤细胞膜，并经T₁₀多肽修饰，制备成MET/Ce6@Lipo@CM@T₁₀，并表征纳米颗粒的形态、粒径、Zeta电位、紫外吸收光谱、包封率、体外释放和稳定性等理化性质。测定MET/Ce6@Lipo@CM@T₁₀表面膜蛋白情况、转铁蛋白结合能力及空白载体的安全性评价。

MET/Ce6@Lipo@CM@T₁₀体外抗肿瘤评价：以U87为模型细胞，通过激光共聚焦显微镜和流式细胞术定性和定量分析了纳米颗粒的细胞内摄取行为。进一步评估其在体外的抗肿瘤效果，包括ROS产生水平、细胞内缺氧情况、肿瘤细胞内低氧诱导因子-1α（Hypoxia inducible factor-1α，HIF-1α）的表达、线粒体膜电位变化、免疫原性死亡（Immunogenic cell death，ICD）分子释放等。利用CCK-8增殖抑制实验、流式细胞凋亡分析和活细胞染色进一步验证其抑制肿瘤细胞增殖、要到凋亡和杀伤能力。同时，建立体外BBB模型和U87 3D肿瘤球模型，评估MET/Ce6@Lipo@CM@T₁₀跨越血脑屏障的能力及其在肿瘤组织中的渗透性。

MET/Ce6@Lipo@CM@T₁₀的体内抗肿瘤评价：利用裸鼠U87原位脑胶质瘤模型，评估纳米颗粒的体内分布和治疗效果。通过小动物活体成像观察药物的体内分布，采用组织切片染色技术验证其在脑内的分布和靶向效果。MET/Ce6@Lipo@CM@T₁₀尾静脉给药5次后，其抑制胶质瘤生长、诱导肿瘤细胞凋亡的影响、体内安全性等方面进行评价。

研究结果：

成功合成DSPE-PEG₂₀₀₀-T₁₀，¹H-NMR结果显示在浓度为6.74ppm下DSPE-PEG₂₀₀₀-T₁₀中无马来酰亚胺基双键，说明合成功。通过MALDI-TOF-MS质谱分析显示，合成的分子量为T₁₀分子量与DSPE-PEG2000-MAL的分子量之和，进一步证实了分子的成功连接。制备MET/Ce6@Lipo@CM@T₁₀，其平均粒径为（108.9±2.90）nm，Zeta电位为-（30.0±1.95）mV，电镜下观察面呈现球形核壳结构，具有分散性好、分布均匀。紫外吸收光谱显示，MET/Ce6@Lipo@CM@T₁₀成功装载Ce6和MET两种药物，Ce6包封率为83.3%，MET包封率为58.0%。通过体外释放实验表明了纳米颗粒呈缓慢释放状态，在稳定性实验中纳米颗粒在7d内可以保持良好的稳定性和分散性。MET/Ce6@Lipo@CM@T₁₀的SDS-PAGE分析结果，纳米颗粒表面保留了完整的膜蛋白成分，经WB检测纳米颗粒在与体内的血液循环中Tf形成转铁蛋白冠能力较好。最后空白载体安全性实验中，载体材料对U87细胞的安全性较高，对细胞的增殖影响较低，不同浓度载体材料细胞存活率均在90%以上。

在体外抗肿瘤评价中，通过CLSM和流式细胞术的细胞摄取实验结果显示，Ce6@Lipo /DiO@CM@T₁₀的摄取能力和摄取效率最高。体外ROS检测表明MET/Ce6@Lipo@CM@T₁₀在光照下产生高浓度的ROS，并导致线粒体损伤，表明了纳米颗粒具有良好的PDT效应。通过免疫荧光法和WB法检测HIF-1α观察细胞内缺氧情况，结果显示MET/Ce6@Lipo@CM @T₁₀可以缓解PDT疗效引起的细胞内缺氧情况并进一步增强PDT疗效。通过CCK-8、细胞凋亡和Calcein AM活细胞染色证实了，MET/Ce6@Lipo@CM@T₁₀通过PDT疗效，有效抑制U87细胞增殖和诱导U87细胞的凋亡。通过建立体外BBB模型和体外3D肿瘤球培养实验观察，MET/Ce6@Lipo@CM@T₁₀有效跨越BBB到达肿瘤组织蓄积后，并能深入渗透到肿瘤组织中。

成功建立裸鼠原位脑胶质瘤模型。纳米颗粒的体内分布和肿瘤靶向性实验，证实了MET/Ce6@Lipo@CM@T₁₀在肿瘤组织中的分布信号最强，滞留时间长，表明了肿瘤细胞膜包覆增强了同源靶向性，T₁₀修饰增强了其主动靶向性。Ce6@Lipo@CM@T₁₀在转铁蛋白冠的介导下能有效靶向肿瘤组织。肿瘤冰冻切片实验也证实了，Ce6@Lipo@CM@T₁₀可以在同源被动靶向性和T₁₀修饰后的主动靶向性，更强地分布至肿瘤组织，并在具有渗透到肿瘤深层组织的能力。体内抗肿瘤药效学结果显示，MET/Ce6@Lipo@CM@T₁₀在PDT作用下能明显抑制肿瘤组织的生长，促进肿瘤细胞坏死和凋亡。最后对MET/Ce6@Lipo@CM@T₁₀的安全性进行了研究，药物在治疗期间没有引起小鼠体重明显下降，血清生化指标无异常，并且心肝脾肺肾等脏器病理切片也证实仿生纳米药物具有良好的体内安全性和生物相容性。

综上所述，本研究成功制备了转铁蛋白冠介导的细胞膜仿生纳米颗粒MET/Ce6@Lipo@CM@T₁₀，并展示了其在靶向递送和光动力治疗中的潜力，为脑胶质瘤的治疗提供了新的思路和方法。

研究结论：

成功制备MET/Ce6@Lipo@CM@T₁₀，具有良好的生物安全性和生物相容性的光动力治疗纳米颗粒；

MET/Ce6@Lipo@CM@T₁₀经U87肿瘤细胞膜包覆具有同源靶向性，进一步经转铁蛋白配体T₁₀多肽修饰后提高了脂质体的主动靶向性；

转铁蛋白冠和细胞膜的双重靶向作用下，增强脑胶质瘤的光动力治疗，显示了优异的临床应用价值。

关键词：转铁蛋白冠；细胞膜仿生纳米颗粒；光动力；脑胶质瘤

Abstract

Glioblastoma is the most common malignant tumor in the central nervous system, with extremely high recurrence and mortality rates. Current treatment methods include surgical resection, radiotherapy, and chemotherapy. However, due to the invasive growth of glioblastomas and their resistance to traditional chemotherapy drugs, treatment efficacy is limited. Furthermore, the presence of the blood-brain barrier (BBB) necessitates high doses of chemotherapy drugs, which lack sufficient targeting ability, leading to low effectiveness and systemic toxicity. Among recent studies on glioblastoma treatment methods, photodynamic therapy (PDT) has garnered significant interest and shown promising applications.

Nanoparticle drug delivery systems have attracted attention for their superior drug transport capabilities and controllability. Particularly in targeted therapy, although nanoparticles can achieve active targeting to tumor tissues through surface modification with specific ligands, they are often shielded by serum proteins in the in vivo environment, significantly reducing their targeting efficiency. Therefore, designing multifunctional nanoparticles is crucial. One strategy involves using nanoparticles cloaked with homologous cell membranes to evade immune system clearance, prolonging their retention in vivo, and enhancing targeting efficacy through homologous adhesion. Another strategy involves forming a protein corona on nanoparticle surfaces using specific blood proteins to achieve active targeting. This study chose transferrin as a strategy for targeting tumor tissues, as transferrin receptors on the blood-brain barrier surface specifically bind to transferrin, which is overexpressed in various tumors.

Thus, we designed multifunctional nanoparticles co-loaded with Ce6 and metformin (MET) liposomes, surface-coated with tumor cell membranes, and modified with T₁₀ peptide ligands for transferrin-mediated biomimetic nanoparticles (MET/Ce6@Lipo@CM@T₁₀).

Research Objective: To prepare transferrin-mediated biomimetic nanoparticles (MET/Ce6@Lipo@CM@T₁₀) and study their photodynamic therapy (PDT) effects under light exposure, exploring their mechanisms of photodynamic anti-tumor action.

Research Methods: 

1. Preparation and characterization of MET/Ce6@Lipo@CM@T₁₀: Synthesis and identification of DSPE-PEG₂₀₀₀-T₁₀, preparation of liposomes co-loaded with MET and Ce6 using thin-film hydration method, coating with U87 tumor cell membranes via extrusion, and surface modification with T₁₀ peptide to prepare MET/Ce6@Lipo@CM@T₁₀. Characterization of nanoparticles' morphology, size, zeta potential, UV absorption spectrum, encapsulation efficiency, in vitro release, and stability. Evaluation of membrane protein status on MET/Ce6@Lipo@CM@T₁₀, transferrin binding capacity, and safety assessment of blank carriers.

2. In vitro anti-tumor evaluation of MET/Ce6@Lipo@CM@T₁₀: Using U87 cells as a model, cellular uptake behavior of nanocarriers was qualitatively and quantitatively analyzed via laser confocal microscopy and flow cytometry. Further evaluation of its anti-tumor effects in vitro included ROS production levels, intracellular hypoxia, expression of Hypoxia Inducible Factor-1α (HIF-1α) in tumor cells, changes in mitochondrial membrane potential, and release of molecules related to Immunogenic Cell Death (ICD). CCK-8 proliferation inhibition assays, flow cytometric apoptosis analysis, and live cell staining were employed to verify its ability to inhibit tumor cell proliferation, induce apoptosis, and exert cytotoxic effects. Additionally, a Transwell in vitro BBB model and U87 3D tumor spheroid model were established to assess the ability of MET/Ce6@Lipo@CM@T₁₀ to cross the blood-brain barrier and penetrate tumor tissues.

3. In vivo anti-tumor evaluation of MET/Ce6@Lipo@CM@T₁₀: The distribution and therapeutic effects of nanocarriers were evaluated using an orthotopic U87 glioma model in nude mice. The in vivo distribution of the drug was observed through small animal live imaging, and the distribution and targeting effects in the brain were verified using tissue section staining techniques. After five intravenous tail injections of MET/Ce6@Lipo@CM@T₁₀, its effects on inhibiting glioma growth, inducing tumor cell apoptosis, and evaluating its in vivo safety were assessed.

Research Results:

DSPE-PEG₂₀₀₀-T₁₀ was successfully synthesized. ¹H-NMR results showed no maleimide double bonds at 6.74 ppm concentration, indicating successful synthesis. MALDI-TOF-MS analysis confirmed the molecular weight of DSPE-PEG₂₀₀₀-T₁₀ as the sum of T₁₀ and DSPE-PEG₂₀₀₀-MAL molecular weights, further confirming successful linkage. MET/Ce6@Lipo@CM@T₁₀ was prepared with an average particle size of (108.9±2.90) nm and a Zeta potential of -(30.0±1.95) mV. Electron microscopy revealed a spherical core-shell structure with good dispersity and uniform distribution. UV absorption spectra confirmed successful loading of Ce6 and MET drugs in MET/Ce6@Lipo@CM@T₁₀, with encapsulation efficiencies of 83.3% for Ce6 and 58.0% for MET. In vitro release experiments indicated slow release kinetics, and stability tests showed the nanoparticles maintained good stability and dispersity over 7 days. SDS-PAGE analysis of MET/Ce6@Lipo@CM@T₁₀ showed preserved membrane protein components on the nanoparticle surface. Western blotting confirmed the nanoparticles' ability to form transferrin coronas in circulation. Safety evaluation of blank carriers showed high biocompatibility with U87 cells, with cell viability above 90% across different concentrations.

In vitro anti-tumor evaluation demonstrated that Ce6@Lipo/DiO@CM@T₁₀ exhibited the highest cellular uptake efficiency in CLSM and flow cytometry experiments. ROS detection under light exposure showed MET/Ce6@Lipo@CM@T₁₀ generated high levels of ROS and caused mitochondrial damage, indicating effective PDT effects. Immunofluorescence and Western blotting for HIF-1α revealed MET/Ce6@Lipo@CM@T₁₀ alleviated intracellular hypoxia induced by PDT and enhanced PDT efficacy. CCK-8, apoptosis assays, and Calcein AM staining confirmed MET/Ce6@Lipo@CM@T₁₀ effectively inhibited U87 cell proliferation and induced apoptosis through PDT. Establishment of an in vitro BBB model and 3D tumor spheroid culture experiments demonstrated MET/Ce6@Lipo@CM@T₁₀ effectively crossed the BBB and accumulated deeply within tumor tissues.

A nude mouse orthotopic U87 glioma model was successfully established. In vivo distribution and tumor-targeting experiments confirmed MET/Ce6@Lipo@CM@T₁₀ exhibited the strongest signal in tumor tissues with prolonged retention time, indicating enhanced homologous targeting due to tumor cell membrane encapsulation and active targeting enhanced by T₁₀ modification. Ce6@Lipo@CM@T₁₀ effectively targeted tumor tissues mediated by transferrin coronas and significantly inhibited tumor growth. Frozen tumor sections confirmed Ce6@Lipo@CM@T₁₀ exhibited stronger distribution in tumor tissues due to enhanced homologous passive targeting and active targeting after T₁₀ modification, with the ability to penetrate deep into tumor tissues. Pharmacokinetic results in vivo demonstrated MET/Ce6@Lipo@CM@T₁₀ significantly inhibited tumor tissue growth under PDT, promoting tumor cell necrosis and apoptosis. Safety studies confirmed MET/Ce6@Lipo@CM@T₁₀ caused no significant weight loss in mice during treatment, showed normal serum biochemical indices, and exhibited good in vivo safety and biocompatibility in histopathological sections of heart, liver, spleen, lung, and kidney.

In conclusion, this study successfully prepared transferrin-mediated biomimetic nanoparticles MET/Ce6@Lipo@CM@T₁₀ and demonstrated their potential in targeted delivery and photodynamic therapy, providing new insights and methods for glioblastoma treatment.

Research Conclusions:

1. MET/Ce6@Lipo@CM@T₁₀ was successfully prepared as a photodynamic therapy nanocarrier with excellent biocompatibility and biological safety.

2. Encapsulation of MET/Ce6@Lipo@CM@T₁₀ with U87 tumor cell membranes provided homologous targeting, further enhanced by transferrin ligand T₁₀ peptide modification, improving active targeting of liposomes.

3. Enhanced photodynamic therapy of glioblastoma under dual targeting by transferrin corona and cell membrane demonstrates outstanding clinical application potential.

Key words :Transferrin protein corona; cell membrane biomimetic nanoparticles;  photodynamic therapy; glioblastoma

 

参考文献：
[1] Ruan H, Chai Z, Shen Q, et al. A novel peptide ligand RAP12 of LRP1 for glioma targeted drug delivery. J Control Release, 2018,279: 306-315.
[2] Szopa W, Burley TA, Kramer-Marek G, et al. Diagnostic and Therapeutic Biomarkers in Glioblastoma: Current Status and Future Perspectives. Biomed Res Int, 2017,2017: 8013575.
[3] Digiacomo L, Pozzi D, Palchetti S, et al. Impact of the protein corona on nanomaterial immune response and targeting ability. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2020,12(4): e1615.
[4] Ostrom QT, Gittleman H, Truitt G, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011-2015. Neuro Oncol, 2018,20(suppl_4): iv1-iv86.
[5] Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol, 2016,131(6): 803-820.
[6] Schaff LR, Mellinghoff IK. Glioblastoma and Other Primary Brain Malignancies in Adults: A Review. Jama, 2023,329(7): 574-587.
[7] Rominiyi O, Vanderlinden A, Clenton SJ, et al. Tumour treating fields therapy for glioblastoma: current advances and future directions. Br J Cancer, 2021,124(4): 697-709.
[8] Zhou Y, Peng Z, Seven ES, et al. Crossing the blood-brain barrier with nanoparticles. J Control Release, 2018,270: 290-303.
[9] Tang W, Fan W, Lau J, et al. Emerging blood-brain-barrier-crossing nanotechnology for brain cancer theranostics. Chem Soc Rev, 2019,48(11): 2967-3014.
[10] Zhang W, Mehta A, Tong Z, et al. Development of Polymeric Nanoparticles for Blood-Brain Barrier Transfer-Strategies and Challenges. Adv Sci (Weinh), 2021,8(10): 2003937.
[11] Scheiber IF, Dringen R. Astrocyte functions in the copper homeostasis of the brain. Neurochem Int, 2013,62(5): 556-565.
[12] Hirrlinger J, Dringen R. The cytosolic redox state of astrocytes: Maintenance, regulation and functional implications for metabolite trafficking. Brain Res Rev, 2010,63(1-2): 177-188.
[13] Sandoval KE, Witt KA. Blood-brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis, 2008,32(2): 200-219.
[14] Hwang HH, Lee DY. Protein-Based Drug Delivery in Brain Tumor Therapy. Adv Exp Med Biol, 2020,1249: 203-221.
[15] Wu SK, Tsai CL, Huang Y, et al. Focused Ultrasound and Microbubbles-Mediated Drug Delivery to Brain Tumor. Pharmaceutics, 2020,13(1).
[16] Sun C, Ding Y, Zhou L, et al. Noninvasive nanoparticle strategies for brain tumor targeting. Nanomedicine, 2017,13(8): 2605-2621.
[17] Tsou YH, Zhang XQ, Zhu H, et al. Drug Delivery to the Brain across the Blood-Brain Barrier Using Nanomaterials. Small, 2017,13(43).
[18] Jena L, McErlean E, McCarthy H. Delivery across the blood-brain barrier: nanomedicine for glioblastoma multiforme. Drug Deliv Transl Res, 2020,10(2): 304-318.
[19] Patel MM, Patel BM. Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain. CNS Drugs, 2017,31(2): 109-133.
[20] Kang MH, Park MJ, Yoo HJ, et al. RIPL peptide (IPLVVPLRRRRRRRRC)-conjugated liposomes for enhanced intracellular drug delivery to hepsin-expressing cancer cell. Eur J Pharm Biopharm, 2014,87(3): 489-499.
[21] Tortorella S, Karagiannis TC. Transferrin receptor-mediated endocytosis: a useful target for cancer therapy. J Membr Biol, 2014,247(4): 291-307.
[22] Prabhu S, Goda JS, Mutalik S, et al. A polymeric temozolomide nanocomposite against orthotopic glioblastoma xenograft: tumor-specific homing directed by nestin. Nanoscale, 2017,9(30): 10919-10932.
[23] Hettiarachchi SD, Graham RM, Mintz KJ, et al. Triple conjugated carbon dots as a nano-drug delivery model for glioblastoma brain tumors. Nanoscale, 2019,11(13): 6192-6205.
[24] Chen L, Hong W, Ren W, et al. Recent progress in targeted delivery vectors based on biomimetic nanoparticles. Signal Transduct Target Ther, 2021,6(1): 225.
[25] Niu W, Xiao Q, Wang X, et al. A Biomimetic Drug Delivery System by Integrating Grapefruit Extracellular Vesicles and Doxorubicin-Loaded Heparin-Based Nanoparticles for Glioma Therapy. Nano Lett, 2021,21(3): 1484-1492.
[26] Alghamdi M, Gumbleton M, Newland B. Local delivery to malignant brain tumors: potential biomaterial-based therapeutic/adjuvant strategies. Biomater Sci, 2021,9(18): 6037-6051.
[27] Bastiancich C, Bozzato E, Henley I, et al. Does local drug delivery still hold therapeutic promise for brain cancer? A systematic review. J Control Release, 2021,337: 296-305.
[28] Pashirova TN, Zueva IV, Petrov KA, et al. Mixed cationic liposomes for brain delivery of drugs by the intranasal route: The acetylcholinesterase reactivator 2-PAM as encapsulated drug model. Colloids Surf B Biointerfaces, 2018,171: 358-367.
[29] Singleton WG, Collins AM, Bienemann AS, et al. Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model. Int J Nanomedicine, 2017,12: 1385-1399.
[30] Fan Y, Chen M, Zhang J, et al. Updated Progress of Nanocarrier-Based Intranasal Drug Delivery Systems for Treatment of Brain Diseases. Crit Rev Ther Drug Carrier Syst, 2018,35(5): 433-467.
[31] Miyake MM, Bleier BS. The blood-brain barrier and nasal drug delivery to the central nervous system. Am J Rhinol Allergy, 2015,29(2): 124-127.
[32] Upadhaya PG, Pulakkat S, Patravale VB. Nose-to-brain delivery: exploring newer domains for glioblastoma multiforme management. Drug Deliv Transl Res, 2020,10(4): 1044-1056.
[33] Wu M, Chen W, Chen Y, et al. Focused Ultrasound-Augmented Delivery of Biodegradable Multifunctional Nanoplatforms for Imaging-Guided Brain Tumor Treatment. Adv Sci (Weinh), 2018,5(4): 1700474.
[34] Coluccia D, Figueiredo CA, Wu MY, et al. Enhancing glioblastoma treatment using cisplatin-gold-nanoparticle conjugates and targeted delivery with magnetic resonance-guided focused ultrasound. Nanomedicine, 2018,14(4): 1137-1148.
[35] Chan MH, Chen W, Li CH, et al. An Advanced In Situ Magnetic Resonance Imaging and Ultrasonic Theranostics Nanocomposite Platform: Crossing the Blood-Brain Barrier and Improving the Suppression of Glioblastoma Using Iron-Platinum Nanoparticles in Nanobubbles. ACS Appl Mater Interfaces, 2021,13(23): 26759-26769.
[36] Gao W, Zhang L. Coating nanoparticles with cell membranes for targeted drug delivery. J Drug Target, 2015,23(7-8): 619-626.
[37] Kang H, Rho S, Stiles WR, et al. Size-Dependent EPR Effect of Polymeric Nanoparticles on Tumor Targeting. Adv Healthc Mater, 2020,9(1): e1901223.
[38] Bae YH, Park K. Targeted drug delivery to tumors: myths, reality and possibilit. J Control Release, 2011,153(3): 198-205.
[39] Gao H. Perspectives on Dual Targeting Delivery Systems for Brain Tumors. J Neuroimmune Pharmacol, 2017,12(1): 6-16.
[40] Zhu Q, Ling X, Yang Y, et al. Embryonic Stem Cells-Derived Exosomes Endowed with Targeting Properties as Chemotherapeutics Delivery Vehicles for Glioblastoma Therapy. Adv Sci (Weinh), 2019,6(6): 1801899.
[41] Wang B, Lv L, Wang Z, et al. Nanoparticles functionalized with Pep-1 as potential glioma targeting delivery system via interleukin 13 receptor α2-mediated endocytosis. Biomaterials, 2014,35(22): 5897-5907.
[42] Meenu Vasudevan S, Ashwanikumar N, Vinod Kumar GS. Peptide decorated glycolipid nanomicelles for drug delivery across the blood-brain barrier (BBB). Biomater Sci, 2019,7(10): 4017-4021.
[43] Zhong Y, Su T, Shi Q, et al. Co-Administration Of iRGD Enhances Tumor-Targeted Delivery And Anti-Tumor Effects Of Paclitaxel-Loaded PLGA Nanoparticles For Colorectal Cancer Treatment. Int J Nanomedicine, 2019,14: 8543-8560.
[44] Yang J, Zhang Q, Liu Y, et al. Nanoparticle-based co-delivery of siRNA and paclitaxel for dual-targeting of glioblastoma. Nanomedicine (Lond), 2020,15(14): 1391-1409.
[45] Shi X, Ma R, Lu Y, et al. iRGD and TGN co-modified PAMAM for multi-targeted delivery of ATO to gliomas. Biochem Biophys Res Commun, 2020,527(1): 117-123.
[46] Liu YL, Chen D, Shang P, et al. A review of magnet systems for targeted drug delivery. J Control Release, 2019,302: 90-104.
[47] Gandhi H, Sharma AK, Mahant S, et al. Recent advancements in brain tumor targeting using magnetic nanoparticles. Ther Deliv, 2020,11(2): 97-112.
[48] Aghajanzadeh M, Zamani M, Rajabi Kouchi F, et al. Synergic Antitumor Effect of Photodynamic Therapy and Chemotherapy Mediated by Nano Drug Delivery Systems. Pharmaceutics, 2022,14(2).
[49] Bartusik-Aebisher D, Żołyniak A, Barnaś E, et al. The Use of Photodynamic Therapy in the Treatment of Brain Tumors-A Review of the Literature. Molecules, 2022,27(20).
[50] Xu HZ, Li TF, Ma Y, et al. Targeted photodynamic therapy of glioblastoma mediated by platelets with photo-controlled release property. Biomaterials, 2022,290: 121833.
[51] Chilakamarthi U, Giribabu L. Photodynamic Therapy: Past, Present and Future. Chem Rec, 2017,17(8): 775-802.
[52] Ji B, Wei M, Yang B. Recent advances in nanomedicines for photodynamic therapy (PDT)-driven cancer immunotherapy. Theranostics, 2022,12(1): 434-458.
[53] O'Connor AE, Gallagher WM, Byrne AT. Porphyrin and nonporphyrin photosensitizers in oncology: preclinical and clinical advances in photodynamic therapy. Photochem Photobiol, 2009,85(5): 1053-1074.
[54] Mokwena MG, Kruger CA, Ivan MT, et al. A review of nanoparticle photosensitizer drug delivery uptake systems for photodynamic treatment of lung cancer. Photodiagnosis Photodyn Ther, 2018,22: 147-154.
[55] Guyon L, Ascencio M, Collinet P, et al. Photodiagnosis and photodynamic therapy of peritoneal metastasis of ovarian cancer. Photodiagnosis Photodyn Ther, 2012,9(1): 16-31.
[56] Chen KC, Hsieh YS, Tseng YF, et al. Pleural Photodynamic Therapy and Surgery in Lung Cancer and Thymoma Patients with Pleural Spread. PLoS One, 2015,10(7): e0133230.
[57] Simões JCS, Sarpaki S, Papadimitroulas P, et al. Conjugated Photosensitizers for Imaging and PDT in Cancer Research. J Med Chem, 2020,63(23): 14119-14150.
[58] Manoto SL, Sekhejane PR, Houreld NN, et al. Localization and phototoxic effect of zinc sulfophthalocyanine photosensitizer in human colon (DLD-1) and lung (A549) carcinoma cells (in vitro). Photodiagnosis Photodyn Ther, 2012,9(1): 52-59.
[59] Broekgaarden M, de Kroon AI, Gulik TM, et al. Development and in vitro proof-of-concept of interstitially targeted zinc- phthalocyanine liposomes for photodynamic therapy. Curr Med Chem, 2014,21(3): 377-391.
[60] Sutter FK, Kurz-Levin MM, Fleischhauer J, et al. Macular atrophy after combined intravitreal triamcinolone acetonide (IVTA) and photodynamic therapy (PDT) for retinal angiomatous proliferation (RAP). Klin Monbl Augenheilkd, 2006,223(5): 376-378.
[61] Düzgüneş N, Piskorz J, Skupin-Mrugalska P, et al. Photodynamic therapy of cancer with liposomal photosensitizers. Ther Deliv, 2018,9(11): 823-832.
[62] Derycke AS, de Witte PA. Liposomes for photodynamic therapy. Adv Drug Deliv Rev, 2004,56(1): 17-30.
[63] Ohulchanskyy TY, Roy I, Goswami LN, et al. Organically modified silica nanoparticles with covalently incorporated photosensitizer for photodynamic therapy of cancer. Nano Lett, 2007,7(9): 2835-2842.
[64] Brevet D, Gary-Bobo M, Raehm L, et al. Mannose-targeted mesoporous silica nanoparticles for photodynamic therapy. Chem Commun (Camb), 2009, (12): 1475-1477.
[65] Ricci-Júnior E, Marchetti JM. Zinc(II) phthalocyanine loaded PLGA nanoparticles for photodynamic therapy use. Int J Pharm, 2006,310(1-2): 187-195.
[66] Rojnik M, Kocbek P, Moret F, et al. In vitro and in vivo characterization of temoporfin-loaded PEGylated PLGA nanoparticles for use in photodynamic therapy. Nanomedicine (Lond), 2012,7(5): 663-677.
[67] Feng X, Zhang S, Lou X. Controlling silica coating thickness on TiO2 nanoparticles for effective photodynamic therapy. Colloids Surf B Biointerfaces, 2013,107: 220-226.
[68] Pan X, Xie J, Li Z, et al. Enhancement of the photokilling effect of aluminum phthalocyanine in photodynamic therapy by conjugating with nitrogen-doped TiO2 nanoparticles. Colloids Surf B Biointerfaces, 2015,130: 292-298.
[69] Cheng Y, Chang Y, Feng Y, et al. Simulated Sunlight-Mediated Photodynamic Therapy for Melanoma Skin Cancer by Titanium-Dioxide-Nanoparticle-Gold-Nanocluster-Graphene Heterogeneous Nanocomposites. Small, 2017,13(20).
[70] Koo H, Lee H, Lee S, et al. In vivo tumor diagnosis and photodynamic therapy via tumoral pH-responsive polymeric micelles. Chem Commun (Camb), 2010,46(31): 5668-5670.
[71] Ichikawa K, Hikita T, Maeda N, et al. PEGylation of liposome decreases the susceptibility of liposomal drug in cancer photodynamic therapy. Biol Pharm Bull, 2004,27(3): 443-444.
[72] Sadzuka Y, Tokutomi K, Iwasaki F, et al. The phototoxicity of photofrin was enhanced by PEGylated liposome in vitro. Cancer Lett, 2006,241(1): 42-48.
[73] Shemesh CS, Hardy CW, Yu DS, et al. Indocyanine green loaded liposome nanocarriers for photodynamic therapy using human triple negative breast cancer cells. Photodiagnosis Photodyn Ther, 2014,11(2): 193-203.
[74] Huang X, Mu N, Ding Y, et al. Tumor microenvironment targeting for glioblastoma multiforme treatment via hybrid cell membrane coating supramolecular micelle. J Control Release, 2024,366: 194-203.
[75] Ge J, Zuo M, Wang Q, et al. Near-infrared light triggered in situ release of CO for enhanced therapy of glioblastoma. J Nanobiotechnology, 2023,21(1): 48.
[76] Liu Z, Xie Z, Li W, et al. Photodynamic immunotherapy of cancers based on nanotechnology: recent advances and future challenges. J Nanobiotechnology, 2021,19(1): 160.
[77] Wei X, Song M, Jiang G, et al. Progress in advanced nanotherapeutics for enhanced photodynamic immunotherapy of tumor. Theranostics, 2022,12(12): 5272-5298.
[78] Zhang M, Qin X, Xu W, et al. Engineering of a dual-modal phototherapeutic nanoplatform for single NIR laser-triggered tumor therapy. J Colloid Interface Sci, 2021,594: 493-501.
[79] Qin X, Zhang M, Hu X, et al. Nanoengineering of a newly designed chlorin e6 derivative for amplified photodynamic therapy via regulating lactate metabolism. Nanoscale, 2021,13(27): 11953-11962.
[80] Tian Y, Liu Z, Wang J, et al. Nanomedicine for Combination Urologic Cancer Immunotherapy. Pharmaceutics, 2023,15(2).
[81] Schcolnik-Cabrera A, Oldak B, Juárez M, et al. Calreticulin in phagocytosis and cancer: opposite roles in immune response outcomes. Apoptosis, 2019,24(3-4): 245-255.
[82] Srivastava P. Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol, 2002,2(3): 185-194.
[83] Kim D, Lee S, Na K. Immune Stimulating Antibody-Photosensitizer Conjugates via Fc-Mediated Dendritic Cell Phagocytosis and Phototriggered Immunogenic Cell Death for KRAS-Mutated Pancreatic Cancer Treatment. Small, 2021,17(10): e2006650.
[84] Min Y, Roche KC, Tian S, et al. Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nat Nanotechnol, 2017,12(9): 877-882.
[85] Korbelik M. Induction of tumor immunity by photodynamic therapy. J Clin Laser Med Surg, 1996,14(5): 329-334.
[86] Duan X, Chan C, Lin W. Nanoparticle-Mediated Immunogenic Cell Death Enables and Potentiates Cancer Immunotherapy. Angew Chem Int Ed Engl, 2019,58(3): 670-680.
[87] Galluzzi L, Buqué A, Kepp O, et al. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol, 2017,17(2): 97-111.
[88] Galluzzi L, Vitale I, Warren S, et al. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J Immunother Cancer, 2020,8(1).
[89] Bloy N, Garcia P, Laumont CM, et al. Immunogenic stress and death of cancer cells: Contribution of antigenicity vs adjuvanticity to immunosurveillance. Immunol Rev, 2017,280(1): 165-174.
[90] Matzinger P. The danger model: a renewed sense of self. Science, 2002,296(5566): 301-305.
[91] Krysko DV, Agostinis P, Krysko O, et al. Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol, 2011,32(4): 157-164.
[92] De Munck J, Binks A, McNeish IA, et al. Oncolytic virus-induced cell death and immunity: a match made in heaven?. J Leukoc Biol, 2017,102(3): 631-643.
[93] Vénéreau E, Ceriotti C, Bianchi ME. DAMPs from Cell Death to New Life. Front Immunol, 2015,6: 422.
[94] Patel S. Danger-Associated Molecular Patterns (DAMPs): the Derivatives and Triggers of Inflammation. Curr Allergy Asthma Rep, 2018,18(11): 63.
[95] Krysko O, Løve Aaes T, Bachert C, et al. Many faces of DAMPs in cancer therapy. Cell Death Dis, 2013,4(5): e631.
[96] Fucikova J, Becht E, Iribarren K, et al. Calreticulin Expression in Human Non-Small Cell Lung Cancers Correlates with Increased Accumulation of Antitumor Immune Cells and Favorable Prognosis. Cancer Res, 2016,76(7): 1746-1756.
[97] Garg AD, Galluzzi L, Apetoh L, et al. Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death. Front Immunol, 2015,6: 588.
[98] Alzeibak R, Mishchenko TA, Shilyagina NY, et al. Targeting immunogenic cancer cell death by photodynamic therapy: past, present and future. J Immunother Cancer, 2021,9(1).
[99] Oudin MJ, Weaver VM. Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis. Cold Spring Harb Symp Quant Biol, 2016,81: 189-205.
[100] Taylor CT, Colgan SP. Regulation of immunity and inflammation by hypoxia in immunological niches. Nat Rev Immunol, 2017,17(12): 774-785.
[101] Doedens AL, Stockmann C, Rubinstein MP, et al. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res, 2010,70(19): 7465-7475.
[102] Corzo CA, Condamine T, Lu L, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med, 2010,207(11): 2439-2453.
[103] Barsoum IB, Smallwood CA, Siemens DR, et al. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res, 2014,74(3): 665-674.
[104] Zhou Y, Miao J, Wu H, et al. PD-1 and PD-L1 expression in 132 recurrent nasopharyngeal carcinoma: the correlation with anemia and outcomes. Oncotarget, 2017,8(31): 51210-51223.
[105] Ruf M, Moch H, Schraml P. PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma. Int J Cancer, 2016,139(2): 396-403.
[106] Silva VL, Al-Jamal WT. Exploiting the cancer niche: Tumor-associated macrophages and hypoxia as promising synergistic targets for nano-based therapy. J Control Release, 2017,253: 82-96.
[107] Li M, Shao Y, Kim JH, et al. Unimolecular Photodynamic O(2)-Economizer To Overcome Hypoxia Resistance in Phototherapeutics. J Am Chem Soc, 2020,142(11): 5380-5388.
[108] Lan Y, Zhu X, Tang M, et al. Construction of a near-infrared responsive upconversion nanoplatform against hypoxic tumors via NO-enhanced photodynamic therapy. Nanoscale, 2020,12(14): 7875-7887.
[109] Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 2009,324(5930): 1029-1033.
[110] Fu LH, Qi C, Hu YR, et al. Glucose Oxidase-Instructed Multimodal Synergistic Cancer Therapy. Adv Mater, 2019,31(21): e1808325.
[111] Moreno-Sánchez R, Rodríguez-Enríquez S, Saavedra E, et al. The bioenergetics of cancer: is glycolysis the main ATP supplier in all tumor cells?. Biofactors, 2009,35(2): 209-225.
[112] Moreno-Sánchez R, Marín-Hernández A, Saavedra E, et al. Who controls the ATP supply in cancer cells? Biochemistry lessons to understand cancer energy metabolism. Int J Biochem Cell Biol, 2014,50: 10-23.
[113] Secomb TW, Hsu R, Ong ET, et al. Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors. Acta Oncol, 1995,34(3): 313-316.
[114] Pavlova NN, Zhu J, Thompson CB. The hallmarks of cancer metabolism: Still emerging. Cell Metab, 2022,34(3): 355-377.
[115] Shiva S, Brookes PS, Patel RP, et al. Nitric oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase. Proc Natl Acad Sci U S A, 2001,98(13): 7212-7217.
[116] Mai X, Zhang Y, Fan H, et al. Integration of immunogenic activation and immunosuppressive reversion using mitochondrial-respiration-inhibited platelet-mimicking nanoparticles. Biomaterials, 2020,232: 119699.
[117] Wheaton WW, Weinberg SE, Hamanaka RB, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife, 2014,3: e02242.
[118] Zhao M, Yang X, Fu H, et al. Immune/Hypoxic Tumor Microenvironment Regulation-Enhanced Photodynamic Treatment Realized by pH-Responsive Phase Transition-Targeting Nanobubbles. ACS Appl Mater Interfaces, 2021,13(28): 32763-32779.
[119] Meng X, Song J, Lei Y, et al. A metformin-based nanoreactor alleviates hypoxia and reduces ATP for cancer synergistic therapy. Biomater Sci, 2021,9(22): 7456-7470.
[120] Yang Z, Chen Q, Chen J, et al. Tumor-pH-Responsive Dissociable Albumin-Tamoxifen Nanocomplexes Enabling Efficient Tumor Penetration and Hypoxia Relief for Enhanced Cancer Photodynamic Therapy. Small, 2018,14(49): e1803262.
[121] Fang RH, Gao W, Zhang L. Targeting drugs to tumours using cell membrane-coated nanoparticles. Nat Rev Clin Oncol, 2023,20(1): 33-48.
[122] Dash P, Piras AM, Dash M. Cell membrane coated nanocarriers - an efficient biomimetic platform for targeted therapy. J Control Release, 2020,327: 546-570.
[123] Lopes J, Lopes D, Pereira-Silva M, et al. Macrophage Cell Membrane-Cloaked Nanoplatforms for Biomedical Applications. Small Methods, 2022,6(8): e2200289.
[124] Fang RH, Hu CM, Luk BT, et al. Cancer cell membrane-coated nanoparticles for anticancer vaccination and drug delivery. Nano Lett, 2014,14(4): 2181-2188.
[125] Chen Z, Zhao P, Luo Z, et al. Cancer Cell Membrane-Biomimetic Nanoparticles for Homologous-Targeting Dual-Modal Imaging and Photothermal Therapy. ACS Nano, 2016,10(11): 10049-10057.
[126] Chen Y, Zhi S, Ou J, et al. Cancer Cell Membrane-Coated Nanoparticle Co-loaded with Photosensitizer and Toll-like Receptor 7 Agonist for the Enhancement of Combined Tumor Immunotherapy. ACS Nano, 2023,17(17): 16620-16632.
[127] Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med, 2017,23(9): 1018-1027.
[128] Terstappen GC, Meyer AH, Bell RD, et al. Strategies for delivering therapeutics across the blood-brain barrier. Nat Rev Drug Discov, 2021,20(5): 362-383.
[129] Cedervall T, Lynch I, Lindman S, et al. Understanding the nanoparticle-protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proc Natl Acad Sci U S A, 2007,104(7): 2050-2055.
[130] Akhter MH, Khalilullah H, Gupta M, et al. Impact of Protein Corona on the Biological Identity of Nanomedicine: Understanding the Fate of Nanomaterials in the Biological Milieu. Biomedicines, 2021,9(10).
[131] Wang X, Zhang W. The Janus of Protein Corona on nanoparticles for tumor targeting, immunotherapy and diagnosis [J]. J Control Release, 2022,345: 832-850.
[132] Fasoli E. Protein corona: Dr. Jekyll and Mr. Hyde of nanomedicine. Biotechnol Appl Biochem, 2021,68(6): 1139-1152.
[133] Xiao W, Gao H. The impact of protein corona on the behavior and targeting capability of nanoparticle-based delivery system. Int J Pharm, 2018,552(1-2): 328-339.
[134] Xiao Q, Zoulikha M, Qiu M, et al. The effects of protein corona on in vivo fate of nanocarriers. Adv Drug Deliv Rev, 2022,186: 114356.
[135] Jiang Z, Chu Y, Zhan C. Protein corona: challenges and opportunities for targeted delivery of nanomedicines. Expert Opin Drug Deliv, 2022,19(7): 833-846.
[136] Neagu M, Piperigkou Z, Karamanou K, et al. Protein bio-corona: critical issue in immune nanotoxicology. Arch Toxicol, 2017,91(3): 1031-1048.
[137] Pinals RL, Chio L, Ledesma F, et al. Engineering at the nano-bio interface: harnessing the protein corona towards nanoparticle design and function. Analyst, 2020,145(15): 5090-5112.
[138] Piella J, Bastús NG, Puntes V. Size-Dependent Protein-Nanoparticle Interactions in Citrate-Stabilized Gold Nanoparticles: The Emergence of the Protein Corona. Bioconjug Chem, 2017,28(1): 88-97.
[139] Kong H, Xia K, Ren N, et al. Serum protein corona-responsive autophagy tuning in cells. Nanoscale, 2018,10(37): 18055-18063.
[140] Hata K, Higashisaka K, Nagano K, et al. Evaluation of silica nanoparticle binding to major human blood proteins. Nanoscale Res Lett, 2014,9(1): 2493.
[141] Saha K, Rahimi M, Yazdani M, et al. Regulation of Macrophage Recognition through the Interplay of Nanoparticle Surface Functionality and Protein Corona. ACS Nano, 2016,10(4): 4421-4430.
[142] Solorio-Rodríguez A, Escamilla-Rivera V, Uribe-Ramírez M, et al. A comparison of the human and mouse protein corona profiles of functionalized SiO(2) nanocarriers. Nanoscale, 2017,9(36): 13651-13660.
[143] Yallapu MM, Chauhan N, Othman SF, et al. Implications of protein corona on physico-chemical and biological properties of magnetic nanoparticles. Biomaterials, 2015,46: 1-12.
[144] Albanese A, Walkey CD, Olsen JB, et al. Secreted biomolecules alter the biological identity and cellular interactions of nanoparticles. ACS Nano, 2014,8(6): 5515-5526.
[145] Hadjidemetriou M, Al-Ahmady Z, Mazza M, et al. In Vivo Biomolecule Corona around Blood-Circulating, Clinically Used and Antibody-Targeted Lipid Bilayer Nanoscale Vesicles. ACS Nano, 2015,9(8): 8142-8156.
[146] Vilanova O, Mittag JJ, Kelly PM, et al. Understanding the Kinetics of Protein-Nanoparticle Corona Formation. ACS Nano, 2016,10(12): 10842-10850.
[147] Zhang Z, Wang C, Zha Y, et al. Corona-directed nucleic acid delivery into hepatic stellate cells for liver fibrosis therapy. ACS Nano, 2015,9(3): 2405-2419.
[148] Tenzer S, Docter D, Kuharev J, et al. Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology. Nat Nanotechnol, 2013,8(10): 772-781.
[149] Reyes-López M, Piña-Vázquez C, Serrano-Luna J. Transferrin: Endocytosis and Cell Signaling in Parasitic Protozoa. Biomed Res Int, 2015,2015: 641392.
[150] Daniels TR, Delgado T, Rodriguez JA, et al. The transferrin receptor part I: Biology and targeting with cytotoxic antibodies for the treatment of cancer [J]. Clin Immunol, 2006,121(2): 144-158.
[151] Daniels TR, Delgado T, Helguera G, et al. The transferrin receptor part II: targeted delivery of therapeutic agents into cancer cells [J]. Clin Immunol, 2006,121(2): 159-176.
[152] Santi M, Maccari G, Mereghetti P, et al. Rational Design of a Transferrin-Binding Peptide Sequence Tailored to Targeted Nanoparticle Internalization [J]. Bioconjug Chem, 2017,28(2): 471-480.
[153] Kang T, Jiang M, Jiang D, et al. Enhancing Glioblastoma-Specific Penetration by Functionalization of Nanoparticles with an Iron-Mimic Peptide Targeting Transferrin/Transferrin Receptor Complex [J]. Mol Pharm, 2015,12(8): 2947-2961.
[154] Zhang W, Wang J, Li P, et al. Transferrin-navigation Nano Artificial Antibody Fluorescence Recognition of Circulating Tumor Cells [J]. Sci Rep, 2017,7(1): 10142.
[155] Huo T, Yang Y, Qian M, et al. Versatile hollow COF nanospheres via manipulating transferrin corona for precise glioma-targeted drug delivery [J]. Biomaterials, 2020,260: 120305.
[156] Srinivasan B, Kolli AR, Esch MB, et al. TEER measurement techniques for in vitro barrier model systems [J]. J Lab Autom, 2015,20(2): 107-126.
[157] Franke H, Galla H, Beuckmann CT. Primary cultures of brain microvessel endothelial cells: a valid and flexible model to study drug transport through the blood-brain barrier in vitro [J]. Brain Res Brain Res Protoc, 2000,5(3): 248-256.
[158] de Wilde S, de Jong MGH, Le Brun PPH, et al. Unlicensed pharmaceutical preparations for clinical patient care: Ensuring safety [J]. Pharmacoepidemiol Drug Saf, 2018,27(1): 3-8.
[159] Yan Y, Li XQ, Duan JL, et al. Nanosized functional miRNA liposomes and application in the treatment of TNBC by silencing Slug gene [J]. Int J Nanomedicine, 2019,14: 3645-3667.
[160] Hu C, Zhuang W, Yu T, et al. Multi-stimuli responsive polymeric prodrug micelles for combined chemotherapy and photodynamic therapy [J]. J Mater Chem B, 2020,8(24): 5267-5279.
[161] Peng N, Yu H, Yu W, et al. Sequential-targeting nanocarriers with pH-controlled charge reversal for enhanced mitochondria-located photodynamic-immunotherapy of cancer [J]. Acta Biomater, 2020,105: 223-238.