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Is active targeting of brain metastases of breast cancer superior to passive targeting?

Journal of Cancer Metastasis and Treatment 2019年第2期4卷 51-64页

作者： Nermeen H.KamaI Fatema EI-Amrawy Heba AbduIIah AIi Ivan Edafiogho Mohamed IsmaiI Nounou Department of Pharmaceutics College of pharmacyArab Academy for ScienceTechnology and Maritime Transport(AASTMT)Alexandria 1029Egypt Biomedical Informatics and Medical Statistics Department Medical Research Institute(MRI)Alexandria UniversityAlexandria 21561Egypt Department of Pharmaceutics and Industrial Pharmacy College of Pharmacy for GirlsAl Azhar UniversityCairo 11651Egypt Department of Pharmaceutical Sciences(DPS) School of Pharmacy and Physician Assistant Studies(SOPPAS)University of Saint Joseph(USJ)HartfordCT 06103USA

Brain metastasis is a major cause of death in patients with solid cancers. Breast cancer cells have high tendency to migrate towards brain. Cancer cells within brain are characterized by severe aggressiveness and inaccessibility. Currently, breast cancer and its metastasis are the second leading cause of death among women. Tumor microenvironment and blood brain barrier (BBB) represent great obstacles in targeting breast cancer and its metastasis. Chemotherapy is a safer treatment modality for brain metastasis compared with risky surgical resection and brain radiotherapy. Unfortunately, conventional chemotherapy lack penetration of BBB and suffer from multiple resistance mechanisms. Current treatment technologies for brain metastases of breast cancer have limited long-term success and numerous side effects, illustrating the urgent need for novel smart strategies. Various novel drug entities and nanosystems have been employed to improve diagnosis and targeted treatment of breast cancer and its metastasis. Immunotherapy agents and small tyrosine kinase inhibitors have been shown to reduce tumor size and increase survival in patients with breast cancer, but still poorly penetrate BBB. Tailored sized nanoparticles to some extent crossed brain tumor barrier and enhanced drug accumulation in tumors by taking advantage of enhanced permeability and retention. Furthermore, various active targeting strategies have been adopted to improve accessibility to brain malignancies. Therefore, to achieve enhanced antitumor therapy against ;breast cancer and its brain metastasis, multi-talented delivery systems are urgently needed for optimal treatment. This review focuses on the various active and passive targeting technologies for the treatment of breast cancer brain metastases in the past decade. A comprehensive summary and examples along with pros and cons of each system will be discussed. Different treatment modalities and nanotechnology facilities will be demonstrated to aid in de

关键词： Active targeting passive targeting brain metastasis breast cancer

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targeting orthotopic gliomas with renal-clearable luminescent gold nanoparticles

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Nano Research 2017年第4期10卷 1366-1376页

作者： Chuanqi Peng Xiaofei Gao Jing Xu Bujie Du Xuhui Ning Shaoheng Tang Robert M. Bachoo Mengxiao Yu Woo-Ping Ge Jie Zheng Department of Chemistry and Biochemistry The University of Texas at Dallas Richardson TX 75080 USA Children's Research Institute Department of Pediatrics Department of Neuroscience Harold C. Simmons Comprehensive Cancer Center UT Southwestem Medical Center Dallas TX 75390 USA Simmons Cancer Center Annette G. Strauss Center for Neuro-Oncology Department of Internal Medicine Department of Neurology and Neurotherapeutics UT Southwestern Medical Center Dallas TX 75390 USA

A major clinical translational challenge in nanomedicine is the potential of toxicity associated with the uptake and long-term retention of non-degradable nanoparticles （NPs） in major organs. The development of inorganic NPs that undergo renal clearance could potentially resolve this significant biosafety concern. However, it remains unclear whether inorganic NPs that can be excreted by the kidneys remain capable of targeting tumors with poor permeability. Glioblastoma multiforme, the most malignant orthotopic brain tumor, presents a unique challenge for NP delivery because of the blood-brain barrier and robust blood-tumor barrier of reactive microglia and macroglia in the tumor microenvironment. Herein, we used an orthotopic murine glioma model to investigate the passive targeting of glutathione-coated gold nanoparticles （AuNPs） of 3 nm in diameter that undergo renal clearance and 18-nm AuNPs that fail to undergo renal clearance. Remarkably, we report that 3-nm AuNPs were able to target intracranial tumor tissues with higher efficiency （2.3× relative to surrounding non-tumor normal brain tissues） and greater specificity （3.0×） than did the larger AuNPs. Pharmacokinetics studies suggested that the higher glioma targeting ability of the 3-nm AuNPs may be attributed to the longer retention time in circulation. The total accumulation of the 3-nm AuNPs in major organs was significantly less （8.4×） than that of the 18-nm AuNPs. Microscopic imaging of blood vessels and renal-clearable AuNPs showed extravasation of NPs from the leaky blood-tumor barrier into the tumor interstitium. Taken together, our results suggest that the 3-nm AuNPs, characterized by enhanced permeability and retention, are able to target brain tumors and undergo renal clearance.

关键词： enhanced permeability and retention brain tumor passive targeting gold nanoparticles renal clearance

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Biomimetic nanomedicines for precise atherosclerosis theranostics

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4442-4460页

作者： Ying Tao Xinmiao Lan Yang Zhang Chenxing Fu Lu Liu Feng Cao Weisheng Guo Department of Minimally Invasive Interventional Radiology Key Laboratory of Molecular Target&Clinical PharmacologySchool of Biomedical Engineering&the Second Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510260China School of Pharmaceutical Sciences Capital Medical UniversityBeijing 100069China Department of Cardiology the Second Medical Center&National Clinical Research Center for Geriatric DiseasesChinese PLA General HospitalBeijing 100853China Department of Cardiology and Laboratory of Heart Center Zhujiang HospitalSouthern Medical UniversityGuangzhou 510280China Department of Pharmacology and Pharmacy Li Ka Shing Faculty of Medicinethe University of Hong KongHong Kong SAR 999077China

Atherosclerosis(AS)is a leading cause of the life-threatening cardiovascular disease(CVD),creating an urgent need for efficient,biocompatible therapeutics for diagnosis and *** nanomedicines(b NMs)are moving closer to fulfilling this need,pushing back the frontier of nano-based drug delivery systems *** review seeks to outline how these nanomedicines(NMs)might work to diagnose and treat atherosclerosis,to trace the trajectory of their development to date and in the coming years,and to provide a foundation for further discussion about atherosclerotic theranostics.

关键词： Nanotheranostics Atherosclerosis Biomimetic nanomedicines Drug delivery passive targeting Active targeting Plaques Diagnosis and treatment

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EPR Effect of Amphiphilic Copolymer Micelles Observed by Fluorescent Imaging

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Chemical Research in Chinese Universities 2011年第4期27卷 628-634页

作者： LIU Tong-jun LIU Shi HU Xiu-li SHENG Shi-hou HUANG Yu-bin JING Xia-bin Department of Colorectal and Anal Surgery China-Japan Union Hospital of Jilin University Changehun 130033 P. R. China State Key Laboratory of Polymer Physics and Chemistry Changchun Institue of Applied Chemistry Chinese Academy of Sciences Changchun 130022 P.R. China

Enhanced permeation and retention（EPR） targeting effect of rhodamine B labeled PEG-b-P（LA-co-DHP） [PEG：poly（ethylene glycol）;LA：L-lactide;DHP：2,2-dihydroxylmethyl-propylene carbonate] micelles（RhB-micelles） was observed in H22 liver cancer bearing *** RhB-micelles were prepared by conjugating rhodamine B with the DHP units of amphiphilic block copolymer PEG-b-P（LA-co-DHP） followed by subsequent self-assembling of the *** parent copolymer PEG-b-P（LA-co-DHP） was synthesized by ring-opening copolymerization of LA and DHP with PEG as macroinitiator and diethyl zinc（ZnEt2） as *** micelles have a spherical shape and the average diameter is ca.50 nm by TEM（transmission electron microscope） or 80 nm by DLS（dynamic light scattering）.Their in vitro cell uptake experiment by CLSM（confocal laser scanning microscopy） and flow cytometry showed preferential internalization of micelles by MCF-7 human breast cancer cells to free *** in vivo tests by live animal imaging and ex vivo excised organ imaging showed that after vena tail injection,free RhB molecules were distributed in the whole body through the circulation system and then gradually metabolized and excreted and there was no preferential partition in tumor bed from the beginning to the *** the RhB-micelles were preferentially distributed to the tumor bed so that their concentration（fluorescent intensity） in tumor bed got the level of the liver at a certain time point between 1 and 6 h and reached a maximum relative intensity at around 12 h,indicating an obvious EPR effect of RhB-micelles in H22 liver cancer.

关键词： Enhanced permeability and retention(EPR) effect Fluorescent imaging Micelle passive targeting

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Conventional treatments and non-PEGylated liposome encapsulated doxorubicin for visceral leishmaniasis:A scoping review

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Asian Pacific Journal of Tropical Medicine 2022年第7期15卷 293-307页

作者： Soumya Ranjan Satapathy Rudra Narayan Sahoo School of Pharmaceutical Sciences Siksha‘O’Anusandhan(Deemed to be University)BhubaneswarIndia School of Pharmacy and Life Sciences Centurion University of Technology and ManagementOdishaIndia

Visceral leishmaniasis(VL),also known as Kala-azar,is caused by Leishmania(L.)donovani complex,which includes *** and *** and is associated with a high death rate as compared to the cutaneous and subcutaneous *** of VL includes chemotherapeutic agents which are associated with some major hurdles like toxicities,parenteral administration,high cost,parasite resistance and ***,there is an urgent requirement to develop novel chemotherapeutic agents or repurposing of existing drugs against *** formulation of new chemical entity for the treatment of VL is laborious,time consuming and associated with huge financial ***,screening of existing chemotherapeutic agents is a good alternative to avail cost-effective treatment option for ***-PEGylated liposome encapsulated doxorubicin(Myocet®)is proposed as an alternative treatment option for VL in this review ***,we covered the fundamental aspects of VL,loophole associated with available current treatment strategies and non-PEGylated liposome encapsulated doxorubicin as a novel alternative formulation for treating VL,as this liposomal delivery system of doxorubicin might passively target the intra-cellular regions of macrophage.

关键词： Visceral leishmaniasis Doxorubicin passive targeting Repositioning Non-PEGylated liposome encapsulated doxorubicin Resistance

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Optical tweezer and TIRF microscopy for single molecule manipulation of RNA/DNA nanostructures including their rubbery property and single molecule counting

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Biophysics Reports 2021年第6期7卷 449-474页

作者： Chiran Ghimire Peixuan Guo Center for RNA Nanobiotechnology and Nanomedicine College of Pharmacy 3. Dorothy M. Davis Heart and Lung Research Institute 4. College of Medicine 5. James Compréhensive Cancer Center The Ohio State University

Life science is often focused on the microscopic level. Single-molecule technology has been used to observe components at the micro-or nanoscale. Single-molecule imaging provides unprecedented information about the behavior of individual molecules in contrast to the information from ensemble methods that average the information of many molecules in various states. A typical feature of living systems is motion. The lack of synchronicity of motion biomachines in living systems makes it challenging to image the motion process with high resolution. Thus, single-molecule technology is especially useful for real-time study on motion mechanism of biomachines, such as viral DNA packaging motor, or other ATPases. The most common optical instrumentations in single-molecule studies are optical tweezers and single molecule total internal refection fluorescence microscopy(sm TIRF). Optical tweezers are the force-based technique. The analysis of RNA using optical tweezer has led to the discovery of the rubbery or amoeba property of RNA nanoparticles for compelling vessel extravasation to enhance tumor targeting and fast renal excretion. The rubbery property of RNA lends mechanistic evidence for RNAs use as an ideal reagent in cancer treatment with undetectable toxicity. Single molecule photobleaching allows for the direct counting of biomolecules. This technique was invented for single molecule counting of RNA in the phi29 DNA packaging motor to resolve the debate between five and six copies of RNA in the motor. The technology has subsequently extended to counting components in biological machines composed of protein, DNA, and other macromolecules. In combination with statistical analysis, it reveals biomolecular mechanisms in detail and leads to the development of ultra-sensitive sensors in diagnosis and forensics. This review focuses on the applications of optical tweezers and fluorescence-based techniques as single-molecule technologies to resolve mechanistic questions related

关键词： Stoichiometry passive targeting Photobleaching Renal excretion Cancer imaging pRNA Bacteriophage Phi29 DNA packaging motor Portal vertex Organ accumulation Single layer patterned arrays

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Preparation of lomustine loaded liposomes and studies of its pharmacokinetics and tissue distribution properties

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Journal of Chinese Pharmaceutical Sciences 2010年第5期19卷 353-362页

作者：王金萍祝侠丽席延伟王德凤黄桂华山东大学药学院山东济南250012

Liposomes are used as carriers for targeted drug delivery by the intravenous route. The aim of our study was to prepare lomustine loaded liposomes （CCNU-Lips） and evaluate its physicochemical properties and the tissue targeting after intravenous （i.v.） injection. CCNU-Lips were prepared by film dispersion method. In vitro drug release was investigated in phosphate-buffered saline （pH 6.8） at 37℃. The concentrations of CCNU in selected organs were determined using reversed-phase high-performance liquid chromatography （HPLC） following i.v. administration of CCNU-Lips and inclusion complex solution of CCNU with hydroxypropyl-β-cyclodextrin （CCNU-Sol）. CCNU-Lips had an average diameter of （189.8±28.5） nm with a zeta potential of （-19.13±0.12） mV and the in vitro drug release was monitored for up to 3 d, and the release behavior was in accordance with Weibull-equation. The CCNU-Lips exhibited a longer elimination half life （t1/2β） in vivo compared with CCNU-Sol after i.v. injection to New Zealand rabbits. The encapsulation of lomustine in liposomes also changed its biodistribution in mice. CCNU-Lips showed significant brain targeting with AUC, Te and Re of the brain all showing obvious elevation. These results indicated that CCNU-Lips were promising passive targeting formulation to the brain.

关键词： Liposomes Lomustine (CCNU) passive targeting Pharmacokinetics Sustained release system Tissue distribution

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