Brain drug delivery of small molecules using immunoliposomes

Huwyler, Jörg; Wu, Di; Pardridge, William M.

doi:10.1073/pnas.93.24.14164

Cited by 599 publications

(399 citation statements)

References 30 publications

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“…Targeting ligands are peptidomimetic monoclonal antibodies, i.e., able to trigger the activation of receptors (transferrin or insulin receptors) that are highly expressed on the brain capillary endothelium. 134,136,137 These antibodies directed against external receptor epitopes do not interfere with the natural ligand binding sites, thus avoiding competition. Colloidal carriers should have diameter less than 100 nm to fit the loading capacity of these transport systems.…”

Section: Drug Loadingmentioning

confidence: 99%

“…Such a method was successfully applied to the preparation of brain-targeted immunoliposomes. 134 In a recent work, we used the same procedure to design brain-targeted pegylated immunonanoparticles. 142 Maleimidefunctionalized pegylated nanoparticles were prepared with maleimide-PEG 3500 -PLA 40000 and mPEG 2600 -PLA 40000 (according to a 1:40 molar ratio) using the [(water-in-oil) in water] solvent evaporation technique.…”

Section: Drug Loadingmentioning

confidence: 99%

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Drug transport to brain with targeted nanoparticles

2005

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Summary: Nanoparticle drug carriers consist of solid biodegradable particles in size ranging from 10 to 1000 nm (50 -300 nm generally). They cannot freely diffuse through the bloodbrain barrier (BBB) and require receptor-mediated transport through brain capillary endothelium to deliver their content into the brain parenchyma. Polysorbate 80-coated polybutylcyanoacrylate nanoparticles can deliver drugs to the brain by a still debated mechanism. Despite interesting results these nanoparticles have limitations, discussed in this review, that may preclude, or at least limit, their potential clinical applications. Long-circulating nanoparticles made of methoxypoly(ethylene glycol)-polylactide or poly(lactide-co-glycolide) (mPEG-PLA/ PLGA) have a good safety profiles and provide drug-sustained release. The availability of functionalized PEG-PLA permits to prepare target-specific nanoparticles by conjugation of cell surface ligand. Using peptidomimetic antibodies to BBB transcytosis receptor, brain-targeted pegylated immunonanoparticles can now be synthesized that should make possible the delivery of entrapped actives into the brain parenchyma without inducing BBB permeability alteration. This review presents their general properties (structure, loading capacity, pharmacokinetics) and currently available methods for immunonanoparticle preparation.

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Section: Drug Loadingmentioning

confidence: 99%

Section: Drug Loadingmentioning

confidence: 99%

Drug transport to brain with targeted nanoparticles

2005

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“…Extended circulation time can be accomplished with smallsized liposomes (< 10 nm) composed of neutral, saturated phospholipids and cholesterol. Furthermore, many modern studies use liposomes with a surface modified with polyethylene glycol (PEG) [162][163][164]. Such modification ("PEGylation") reduces opsonisation of liposomes in plasma and decreases its recognition and removal by the MP system in liver and spleen.…”

Section: Liposomesmentioning

confidence: 99%

“…Overall, encapsulation of a drug into liposomes may prolong drug circulation time in blood stream, reduce drug side effects, and enhance drug therapeutic effects in CNS. Indeed, liposomes were evaluated for CNS drug delivery in a number of publications [162,[167][168][169][170][171][172][173][174][175][176][177][178][179].…”

Section: Liposomesmentioning

confidence: 99%

“…In addition considerable work was reported on antibodies to transferrin receptor, OX26, that were linked to the surface of PEGylated liposomes via PEG spacers. Such immunoliposome constructs were used to deliver small drugs, Daunomycin [162], and Digoxin [182] as well as plasmid DNA [169] to the brain. Notably, OX26-conjugated liposomes selectively distributed to BMVEC but avoided choroid plexus epithelium, neurons, and glia [177].…”

Section: Liposomesmentioning

confidence: 99%

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Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

Kabanov

Gendelman

2007

Progress in Polymer Science

235

138

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Neurodegenerative and infectious disorders including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and stroke are rapidly increasing as population's age. Alzheimer's disease alone currently affects 4.5 million Americans, and more than $100 billion is spent per year on medical and institutional care for affected people. Such numbers will double in the ensuing decades. Currently disease diagnosis for all disorders is made, in large measure, on clinical grounds as laboratory and neuroimaging tests confirm what is seen by more routine examination. Achieving early diagnosis would enable improved disease outcomes. Drugs, vaccines or regenerative proteins present "real" possibilities for positively affecting disease outcomes, but are limited in that their entry into the brain is commonly restricted across the blood-brain barrier. This review highlights how these obstacles can be overcome by polymer science and nanotechnology. Such approaches may improve diagnostic and therapeutic outcomes. New developments in polymer science coupled with cell-based delivery strategies support the notion that diseases that now have limited therapeutic options can show improved outcomes by advances in nanomedicine.

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GD2-mediated melanoma cell targeting and cytotoxicity of liposome-entrapped fenretinide

et al. 1999

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Melanoma is a highly malignant and increasingly common neoplasm. Because metastatic melanoma remains incurable, new treatment approaches are needed. Immunoliposomes have been previously shown to enhance the selective localization of immunoliposome-entrapped drugs to solid tumors with improvements in the therapeutic index of the drugs. Previously, we reported that the synthetic retinoid fenretinide (HPR) is an inducer of apoptosis in neuroblastoma (NB) cells, sharing the neuroectodermal origin with melanoma cells. HPR is a strong inducer of apoptosis also in melanoma cells, although at doses 10-fold higher than those achievable clinically. Thus, our purpose was to investigate the in vitro potentiation of its cytotoxic effect on melanoma cells in combination with long-circulating GD2-targeted immunoliposomes. GD2 is a disialoganglioside extensively expressed on tumors of neuroectodermal origin, including melanoma. Murine anti-GD2 antibody (Ab) 14.G2a and its human/mouse chimeric variant ch14.18 have been ligated to sterically stabilized liposomes by covalent coupling of Ab to the polyethylene glycol (PEG) terminus. Ab-bearing liposomes showed specific, competitive binding to and uptake by various melanoma cell lines compared with liposomes bearing nonspecific isotype-matched Abs or Ab-free liposomes. Cytotoxicity was evaluated after 2 hr treatment, followed by extensive washing and 72 hr incubation. This treatment protocol was designed to minimize non-specific adsorption of liposomes to the cells, while allowing for maximum Ab-mediated binding. When melanoma cells were incubated with 30 M HPR entrapped in anti-GD2 liposomes, a significant reduction in cellular growth was observed compared to free HPR, entrapped HPR in Ab-free liposomes or empty liposomes. Cytotoxicity was not evident in tumor cell lines of other origins that did not express GD2. Growth of NB cells was also inhibited by immunoliposomes with entrapped HPR.

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Brain drug delivery of small molecules using immunoliposomes

Abstract: Immunoliposomes (antibody-directed liposomes) were used in the present study for delivery of the antineoplastic agent daunomycin to the rat brain.

Cited by 599 publications

References 30 publications

Drug transport to brain with targeted nanoparticles

Drug transport to brain with targeted nanoparticles

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

GD2-mediated melanoma cell targeting and cytotoxicity of liposome-entrapped fenretinide

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