In Vitro and in Vivo Evaluation of Lactoferrin-Conjugated Liposomes as a Novel Carrier to Improve the Brain Delivery

Huang, Feng-Yun J.; Chen, Wan-Jou; Lee, Wan-Yu; Lo, Su-Tang; Lee, Te‐Wei; Lo, Jason

doi:10.3390/ijms14022862

Cited by 69 publications

(29 citation statements)

References 32 publications

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“…Other studies using Lf-bearing drug delivery systems have also reported an increase of the drug delivery to the brain after intravenous injection, however associated with an increase of the amount of drug delivered to non-specific organs. For example, the administration of Lf-bearing PEG-liposomes encapsulating coumarin-6 resulted in a 1.4-fold increase in the brain uptake of the drug compared to that observed with PEG-liposomes, but non-specific uptake in spleen also increased [26]. In another study, Lf -bearing -cyclodextrin nanocarrier increased the brain uptake of the delivery system by 3.5-fold compared to the non-targeted carrier [27].…”

Section: In Vivo Studymentioning

confidence: 96%

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

Somani

Robb

Pickard

et al. 2015

Journal of Controlled Release

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The possibility of using gene therapy for the treatment of brain diseases such as brain cancer, Alzheimer's and Parkinson's diseases, is currently hampered by the lack of gene delivery systems able to cross the blood-brain barrier and deliver DNA to the brain following intravenous administration. On the basis that lactoferrin can effectively reach the brain by using specific receptors for crossing the blood-brain barrier, we propose to investigate if a lactoferrin-bearing generation 3-diaminobutyric polypropylenimine (DAB) dendrimer would allow the transport of plasmid DNA to the brain after intravenous administration.In this work, we demonstrated that the conjugation of lactoferrin to the dendrimer led to an enhanced DNA uptake by 2.1-fold in bEnd.3 murine brain capillary endothelial cells compared to the unmodified dendriplex in vitro. In vivo, the intravenous administration of lactoferrin-bearing DAB dendriplex resulted in a significantly increased gene expression in the brain, by more than 6.4-fold compared to that of DAB dendriplex, while decreasing gene expression in the lung and the kidneys. Gene expression in the brain was significantly higher than in any other major organs of the body. Lactoferrin-bearing generation 3 polypropylenimine dendrimer is therefore a highly promising delivery system for systemic gene delivery to the brain. KEYWORDSBrain delivery; blood-brain barrier; gene expression; dendrimer; lactoferrin 2 1. Introduction Brain diseases, including glioma, Alzheimer's and Parkinson's diseases, currently represent one of the largest and fastest growing area of unmet clinical need. Brain cancer is the leading cause of cancer death in young people and accounts for more than one third of cancer deaths in children aged under 10. Alzheimer's disease is the most common type of dementia, affecting almost 500 000 people in the UK. The symptoms of this disease develop gradually and become more severe over the course of several years. In addition, there is currently no cure for Parkinson's disease, which affects 127 000 people in the UK [1][2][3][4]. Gene therapy has emerged as a promising therapeutic strategy, as the genetic basis for many of these diseases is known. However, the possibility of using genes as medicines to treat brain pathologies is limited by the lack of safe and efficacious delivery systems able to cross the blood-brain barrier (BBB) and to deliver DNA to the brain after intravenous administration, without secondary effects to healthy tissues. In addition, locally administered treatments fail to achieve a widespread gene expression in the target cells throughout the entire brain, which is necessary for a successful treatment of most brain pathologies [2-3, 5]. There is therefore an urgent need to develop safe and efficacious non-viral gene-based nanomedicines able to cross the BBB after intravenous administration, in order to ultimately provide better treatment options for brain diseases than currently available. Despite acting as an entrance gateway to the brain, the BBB does...

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Section: In Vivo Studymentioning

confidence: 96%

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

Somani

Robb

Pickard

et al. 2015

Journal of Controlled Release

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“…Another peptide (tyrosine-3-octreotide) conjugated liposomes were also reported to generate low to moderate tumor uptake (< 2.5 %ID/g) in xenografted mice (76). Also, synthesis of lactoferrin-conjugated PEGylated liposomes loaded with radioisotope complex, 99m Tc-labeled N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine ( 99m Tc-BMEDA) for SPECT-IGDD to brain was reported by Huang et al (77). In vivo SPECT imaging and biodistribution studies revealed that lactoferrin conjugated PEGylated liposome showed two-fold higher brain uptake than control PEGylated liposome.…”

Section: Carriers For Spect-igddmentioning

confidence: 99%

Image-Guided Drug Delivery with Single-Photon Emission Computed Tomography: A Review of Literature

Chakravarty

Hong²,

Cai³

2015

CDT

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Tremendous resources are being invested all over the world for prevention, diagnosis, and treatment of various types of cancer. Successful cancer management depends on accurate diagnosis of the disease along with precise therapeutic protocol. The conventional systemic drug delivery approaches generally cannot completely remove the competent cancer cells without surpassing the toxicity limits to normal tissues. Therefore, development of efficient drug delivery systems holds prime importance in medicine and healthcare. Also, molecular imaging can play an increasingly important and revolutionizing role in disease management. Synergistic use of molecular imaging and targeted drug delivery approaches provides unique opportunities in a relatively new area called `image-guided drug delivery' (IGDD). Single-photon emission computed tomography (SPECT) is the most widely used nuclear imaging modality in clinical context and is increasingly being used to guide targeted therapeutics. The innovations in material science have fueled the development of efficient drug carriers based on, polymers, liposomes, micelles, dendrimers, microparticles, nanoparticles, etc. Efficient utilization of these drug carriers along with SPECT imaging technology have the potential to transform patient care by personalizing therapy to the individual patient, lessening the invasiveness of conventional treatment procedures and rapidly monitoring the therapeutic efficacy. SPECT-IGDD is not only effective for treatment of cancer but might also find utility in management of several other diseases. Herein, we provide a concise overview of the latest advances in SPECT-IGDD procedures and discuss the challenges and opportunities for advancement of the field.

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“…Conjugation with antibodies makes liposomes more recognizable by ECs. 98 To deliver PEG-treated liposomes to the brain, the liposomes undergo an additional modification involving conjugation of monoclonal antibodies to glia, transferrin receptors (OX-26), lactoferrin receptors, 99 low-density lipoprotein (LDL) receptors, 100 or insulin receptors. 101 Evidence suggests that conjugation of a liposome with diphtheria toxin receptor (Heparin binding [HB]-EGF) also represents a promising method for drug delivery across the BBB.…”

Section: Liposomesmentioning

confidence: 99%

Nanoscale drug delivery systems and the blood–brain barrier

Alyautdin¹,

Khalin²,

Nafeeza³

et al. 2014

IJN

121

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The protective properties of the blood–brain barrier (BBB) are conferred by the intricate architecture of its endothelium coupled with multiple specific transport systems expressed on the surface of endothelial cells (ECs) in the brain’s vasculature. When the stringent control of the BBB is disrupted, such as following EC damage, substances that are safe for peripheral tissues but toxic to neurons have easier access to the central nervous system (CNS). As a consequence, CNS disorders, including degenerative diseases, can occur independently of an individual’s age. Although the BBB is crucial in regulating the biochemical environment that is essential for maintaining neuronal integrity, it limits drug delivery to the CNS. This makes it difficult to deliver beneficial drugs across the BBB while preventing the passage of potential neurotoxins. Available options include transport of drugs across the ECs through traversing occludins and claudins in the tight junctions or by attaching drugs to one of the existing transport systems. Either way, access must specifically allow only the passage of a particular drug. In general, the BBB allows small molecules to enter the CNS; however, most drugs with the potential to treat neurological disorders other than infections have large structures. Several mechanisms, such as modifications of the built-in pumping-out system of drugs and utilization of nanocarriers and liposomes, are among the drug-delivery systems that have been tested; however, each has its limitations and constraints. This review comprehensively discusses the functional morphology of the BBB and the challenges that must be overcome by drug-delivery systems and elaborates on the potential targets, mechanisms, and formulations to improve drug delivery to the CNS.

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In Vitro and in Vivo Evaluation of Lactoferrin-Conjugated Liposomes as a Novel Carrier to Improve the Brain Delivery

Cited by 69 publications

References 32 publications

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

Image-Guided Drug Delivery with Single-Photon Emission Computed Tomography: A Review of Literature

Nanoscale drug delivery systems and the blood–brain barrier

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In Vitro and in Vivo Evaluation of Lactoferrin-Conjugated Liposomes as a Novel Carrier to Improve the Brain Delivery

Cited by 69 publications

References 32 publications

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

Image-Guided Drug Delivery with Single-Photon Emission Computed Tomography: A Review of Literature

Nanoscale drug delivery systems and the blood&ndash;brain barrier

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Nanoscale drug delivery systems and the blood–brain barrier