Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS

Maeda, Hiroshi; Sawa, Tomohiro; Konno, Toshimitsu

doi:10.1016/s0168-3659(01)00309-1

Cited by 844 publications

(517 citation statements)

References 31 publications

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“…Nanocarriers entered into the tumor are not removed efficiently and are thus preserved in the tumor. This passive phenomenon has been called the "Enhanced Permeability and Retention (EPR) effect," discovered by Matsumura and Maeda (Matsumura and Maeda, 1986;Maeda et al, 2001;Maeda et al, 2009;Danhier et al, 2010). Rapid vascularization in fastgrowing cancerous tissues is known to result in leaky, defective architecture and impaired lymphatic drainage.…”

Section: Passive Targetingmentioning

confidence: 99%

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

Mirakabad

Nejati-Koshki²,

Akbarzadeh³

et al. 2014

Asian Pacific Journal of Cancer Prevention

391

162

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Section: Passive Targetingmentioning

confidence: 99%

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

Mirakabad

Nejati-Koshki²,

Akbarzadeh³

et al. 2014

Asian Pacific Journal of Cancer Prevention

391

162

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“…Vesicles larger than 200 nm accumulate in the spleen since their size does not allow them to pass through the walls of the venous sinuses in splenic red pulp tissue [2,17,18]. This has been clearly demonstrated with the PEG-coated [ 18 F]FDGlabeled liposomes; the vesicles smaller than 100 nm remained in the blood pool and were accumulated in the tumor tissue due to the enhanced permeability and retention effect [19,20]; conversely, liposomes larger then 200 nm accumulated in spleen and the liver [17]. It was also demonstrated that positively-charged liposomes are more likely to aggregate and become serum-bound compared with neutrally or negatively charged liposomes; and in vivo tests revealed that liver and spleen uptake was maximal in positively charged liposomes, while the neutral liposomes had minimal uptake [17].…”

mentioning

confidence: 99%

Long-circulating liposomes radiolabeled with [18F]fluorodipalmitin ([18F]FDP)

Mařı́k

Tartis

Zhang

et al. 2007

Nuclear Medicine and Biology

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Synthesis of a radiolabeled diglyceride 3-[ 18 F]fluorodipalmitoyl-1,2-glycerol ( 18 F-fluorodipalmitin, [ 18 F]FDP) and its potential as a reagent for radiolabeling long-circulating liposomes were investigated. The incorporation of 18 F into the lipid molecule was accomplished by nucleophilic substitution of p-toluenesolfonyl moiety with a decay corrected yield of 43 ± 10% (n = 12). Radiolabeled long-circulating PEG-coated liposomes were prepared using a mixture of DPPC, cholesterol, DSPE-PEG2000 (61:30:9) and [ 18 F]FDP with a decay corrected yield of 70 ± 8% (n = 4). PET imaging and biodistribution studies were performed with free [ 18 Liposomes are vesicles composed of one or more concentric phospholipid bi-layers and such vesicles have been widely investigated as possible drug carriers [1,2]. Prolonged blood circulation of the liposomes is achieved with the addition of a polyethylene glycol (PEG) coating, which efficiently minimizes their removal by macrophages of the reticuloendothelial system [3][4][5][6]. Liposomes with various target-specific ligands attached to their surface are being investigated for targeted drug delivery [1,2,7]. Liposomes labeled with radioisotopes such as 99m Tc, 186 Re, 67 Ga, 111 In, and 18 F were previously employed to study the biodistribution of different types of liposomes in various animal models using scintigraphy, SPECT and PET. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Materials and Methods GeneralThe solvents and chemicals were purchased from Aldrich (Milwaukee, WI). The 1 H and 13 C NMR spectra were recorded using a Bruker Avance 500 spectrometer and the chemical shifts are reported relative to TMS. Analytical reversed-phase HPLC was performed using a Phenomenex Jupiter 5μ C4 300A column ( . The size distribution of liposomes was determined using a particle size analyzer Nanotrac NPA150 purchased from Microtrac Inc. (North Largo, FL). The lipid concentration was determined using a Phospholipids B kit purchased from Wako Chemicals, Inc. (Richmond, VA). Synthesis of 3-tosyl-1,2-dipalmitoyl glycerol (2)The precursor 2 was prepared according to the previously published procedure [32] from 1,2-dipalmitoyl-sn-glycerol (1) and 4-toluenesulfonyl chloride. The crude product was subsequently purified by recrystalization from hexane. 1 mL). The content of the vial was dissolved in anhydrous acetonitrile (0.35 mL) and transferred into a suspension of 2 (5.5 mg) in anhydrous acetonitrile (0.5 mL). The reaction mixture was heated to 100 ºC for 20 minutes and allowed to cool to room temperature for 5 min...

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“…The lead compound contained anti-MsTfRmAb to achieve active extravasation by transcytosis through binding to endothelial TfR of the tumor vessels. Much less uptake into the tumor was noted in the absence of the antibody and was attributed to tumor dependent EPR effect 13 . Fluorescent versions of the nano conjugates containing Alexa Fluor 680 were synthesized for imaging studies.…”

Section: Representative Resultsmentioning

confidence: 99%

“…The nano drug binds to the receptor and enters the tumor by transcytosis. In addition, some degree of access to the tumor is possible through the disordered endothelial layers that participate in tumor dependent enhanced uptake and retention (EPR) 13 . Next, the nanodrug binds to HER2 expressed on the human cancer cells and internalizes into early endosomes.…”

Section: Figurementioning

confidence: 99%

Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?

Ljubimova

Portilla-Arias

Patil

et al. 2014

JoVE

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Tumors with similar grade and morphology often respond differently to the same treatment because of variations in molecular profiling. To account for this diversity, personalized medicine is developed for silencing malignancy associated genes. Nano drugs fit these needs by targeting tumor and delivering antisense oligonucleotides for silencing of genes. As drugs for the treatment are often administered repeatedly, absence of toxicity and negligible immune response are desirable. In the example presented here, a nano medicine is synthesized from the biodegradable, non-toxic and non-immunogenic platform polymalic acid by controlled chemical ligation of antisense oligonucleotides and tumor targeting molecules. The synthesis and treatment is exemplified for human Her2-positive breast cancer using an experimental mouse model. The case can be translated towards synthesis and treatment of other tumors.

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Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS

Cited by 844 publications

References 31 publications

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

Long-circulating liposomes radiolabeled with [18F]fluorodipalmitin ([18F]FDP)

Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?

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