On the Mechanism and Dynamics of Uptake and Permeation of Polyether-Copolyester Dendrimers Across an In Vitro Blood–Brain Barrier Model

Dhanikula, Renu Singh; Hammady, Taha; Hildgen, Patrice

doi:10.1002/jps.21669

Cited by 43 publications

(26 citation statements)

References 56 publications

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“…The antitumoral effect of MTX-loaded dendrimers was better than the result obtained with free MTX [242]. Moreover, these dendrimers did not manifest significant cytotoxic effects evaluated by MTT cell proliferation assay, erythrocyte lysis, and bEnd.3 viability experiments, even at high concentrations [243,244]. Study of BBB crossing mechanisms showed relatively rapid transcytosis from 5 to 22 µg in the first hour.…”

Section: Dendrimersmentioning

confidence: 75%

“…A permeation investigation in the presence of the endocytosis inhibitor sodium fluoride (NaF) revealed the inhibition of transport. In addition, the combination of NaF and low temperature (4 o C) at the same time indicated that energy-dependent endocytosis was involved in the process [243]. Thus, the proposed PEG-PEPE dendrimers present a very interesting object for further study.…”

Section: Dendrimersmentioning

confidence: 95%

“…The open nature of the dendritic architecture has led several groups to investigate the possibility of encapsulating drug molecules within the branches of dendrimers (dendrons). In particular, very encouraging data on methotrexate (MTX) delivery in an in vitro model of the BBB for the treatment of gliomas were reported, with polyester-polyether (PEPE) dendrimers having the same butanetetracarboxylic core, PEG spacers, and different branching agents: 3,5-dihydroxybenzoic acid, gallic acid, and 2,2-bis(hydroxymethyl)butyric acid [241,242,243]. The efficient penetration of dendrimers across bEnd.3 culture (a BBB model) and internalization into U87 MG and U343 MG-A tumor cells and their spheroids as paradigms of solid tumor tissue have been observed.…”

Section: Dendrimersmentioning

confidence: 99%

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Drug-Loaded Nanocarriers: Passive Targeting and Crossing of Biological Barriers

Rabanel

Aoun²,

Elkin³

et al. 2012

CMC

160

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Poor bioavailability and poor pharmacokinetic characteristics are some of the leading causes of drug development failure. Therefore, poorly-soluble drugs, fragile proteins or nucleic acid products may benefit from their encapsulation in nanosized vehicles, providing enhanced solubilization, protection against degradation, and increased access to pathological compartments. A key element for the success of drug-loaded nanocarriers is their ability to either cross biological barriers themselves, or allow loaded drugs to traverse them to achieve optimal pharmacological action at pathological sites. Depending on the mode of administration, nanocarriers may have to cross different physiological barriers in their journey towards their target. In this review, the crossing of biological barriers by passive targeting strategies will be presented for intravenous delivery (vascular endothelial lining, particularly for tumor vasculature and blood brain barrier targeting), oral administration (gastrointestinal lining), and upper airway administration (pulmonary epithelium). For each specific barrier, background information will be provided on the structure and biology of the tissues involved as well as available pathways for nano-objects or loaded drugs (diffusion and convection through fenestration, transcytosis, tight junction crossing, etc.). The determinants of passive targeting - size, shape, surface chemistry, surface patterning of nanovectors - will be discussed in light of current results. Perspectives on each mode of administration will be presented. The focus will be on polymeric nanoparticles and dendrimers, although advances in liposome technology will be also reported as they represent the largest body in the drug delivery literature.

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Section: Dendrimersmentioning

confidence: 75%

Section: Dendrimersmentioning

confidence: 95%

Section: Dendrimersmentioning

confidence: 99%

See 1 more Smart Citation

Drug-Loaded Nanocarriers: Passive Targeting and Crossing of Biological Barriers

Rabanel

Aoun²,

Elkin³

et al. 2012

CMC

160

View full text Add to dashboard Cite

show abstract

“…5). For example, dendrimer transport across the BBB has been reported to occur via clathrin and caveolin mediated endocytosis 30 and via specific receptor-mediated endocytosis pathways driven by brain-targeting ligands conjugated to the dendrimer surface. The (im)permeability of the BBB is reflected in high transendothelial electrical resistance (TEER), approximately three-fold higher than in other tissues.…”

Section: Dendrimer-mediated Transport Across the Blood-brain Barriermentioning

confidence: 99%

Dendrimers for Biomedical Applications

Kaminskas

McLeod

Jones

et al. 2014

Frontiers in Nanobiomedical Research

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Dendrimers are globular polymers with well-defi ned molecular structures and polyfunctional surfaces. The ability to functionalize the surface of dendrimers with a range of chemical species and to tailor physicochemical properties has resulted in the exploration of dendrimers for a wide range of biomedical applications. The clinical application of dendrimers is still in the early stages of development, although data generated thus far have suggested that they have the potential to advance the fi elds of drug delivery, gene therapy, imaging and wound healing. This chapter provides an overview of the current state-of-the-art of research into the biomedical application of dendrimers.

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“…A promising approach to overcome limited drug flux into the CNS is the employment of multifunctional nanoparticles (2). Numerous studies have shown that nanoparticle uptake into brain parenchyma can occur through receptor-mediated endocytosis, absorptive transcytosis, and tight junction opening (3,4). However, many in vivo reports of nanoparticle CNS applications, particularly those of metal-based nanoparticles, showed only indirect evidence of flux across the BBB into brain parenchyma.…”

Section: Introductionmentioning

confidence: 99%

Alternating Magnetic Field-Induced Hyperthermia Increases Iron Oxide Nanoparticle Cell Association/Uptake and Flux in Blood–Brain Barrier Models

Bae

Pittman

et al. 2014

Pharm Res

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Purpose Superparamagnetic iron oxide nanoparticles (IONPs) are being investigated for brain cancer therapy because alternating magnetic field (AMF) activates them to produce hyperthermia. For central nervous system applications, brain entry of diagnostic and therapeutic agents is usually essential. We hypothesized that AMF-induced hyperthermia significantly increases IONP blood–brain barrier (BBB) association/uptake and flux. Methods Cross-linked nanoassemblies loaded with IONPs (CNA-IONPs) and conventional citrate-coated IONPs (citrate-IONPs) were synthesized and characterized in house. CNA-IONP and citrate-IONP BBB cell association/uptake and flux were studied using two BBB Transwell® models (bEnd.3 and MDCKII cells) after conventional and AMF-induced hyperthermia exposure. Results AMF-induced hyperthermia for 0.5 h did not alter CNA-IONP size but accelerated citrate-IONP agglomeration. AMF-induced hyperthermia for 0.5 h enhanced CNA-IONP and citrate-IONP BBB cell association/uptake. It also enhanced the flux of CNA-IONPs across the two in vitro BBB models compared to conventional hyperthermia and normothermia, in the absence of cell death. Citrate-IONP flux was not observed under these conditions. AMF-induced hyperthermia also significantly enhanced paracellular pathway flux. The mechanism appears to involve more than the increased temperature surrounding the CNA-IONPs. Conclusions Hyperthermia induced by AMF activation of CNA-IONPs has potential to increase the BBB permeability of therapeutics for the diagnosis and therapy of various brain diseases.

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On the Mechanism and Dynamics of Uptake and Permeation of Polyether-Copolyester Dendrimers Across an In Vitro Blood–Brain Barrier Model

Cited by 43 publications

References 56 publications

Drug-Loaded Nanocarriers: Passive Targeting and Crossing of Biological Barriers

Drug-Loaded Nanocarriers: Passive Targeting and Crossing of Biological Barriers

Dendrimers for Biomedical Applications

Alternating Magnetic Field-Induced Hyperthermia Increases Iron Oxide Nanoparticle Cell Association/Uptake and Flux in Blood–Brain Barrier Models

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