Microautoradiographic study on the tissue localization of liposome-entrapped or unentrapped 3H-labeled .BETA.-galactosidase injected into rats.

Onodera, Hidetoshi; Takada, Goro; Tada, Keiya; Desnick, Robert J.

doi:10.1620/tjem.140.1

Cited by 16 publications

(7 citation statements)

References 9 publications

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“…2 and 3), which confirms the earlier observation of Onodera et al (1983). The blood concentration of the ␤-galactosidaseTfRmAb is 5-to 10-fold higher than the corresponding blood concentration of unconjugated ␤-galactosidase at 1 to 4 h after injection (Table 2).…”

Section: Discussionsupporting

confidence: 88%

Delivery of β-Galactosidase to Mouse Brain via the Blood-Brain Barrier Transferrin Receptor

Zhang

Pardridge²

2005

J Pharmacol Exp Ther

106

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Enzyme replacement therapy of lysosomal storage disorders is complicated by the lack of enzyme transport across the bloodbrain barrier (BBB). The present studies evaluate the delivery of a model enzyme across the BBB following enzyme conjugation to a BBB receptor-specific monoclonal antibody (mAb). Bacterial ␤-galactosidase (116 kDa) was conjugated to the rat 8D3 mAb to the rat transferrin receptor (TfR) via a streptavidin-biotin linkage. The unconjugated ␤-galactosidase or the ␤-galactosidase-8D3 conjugate was injected intravenously in adult mice, and enzyme activity was measured at 1 and 4 h in brain and peripheral organs (liver, spleen, kidney, and heart). Unconjugated ␤-galactosidase was rapidly removed from the blood compartment owing to avid uptake by liver and spleen. There was minimal uptake of the unconjugated ␤-galactosidase by brain. Following conjugation of the enzyme to the 8D3 TfRmAb, there was a 10-fold increase in brain uptake of the enzyme based on measurement of enzyme activity. Histochemistry of brain showed localization of the enzyme in the intraendothelial compartment of brain following intravenous injection of the enzyme-mAb conjugate. The capillary depletion technique showed that more than 90% of the enzyme-8D3 conjugate that entered into the endothelial compartment of brain passed through the BBB to enter brain parenchyma. In conclusion, high molecular weight enzymes, such as bacterial ␤-galactosidase, can be conjugated to BBB targeting antibodies for effective delivery across the BBB in vivo. Fusion proteins comprised of BBB targeting antibodies and recombinant enzymes could be therapeutic in the treatment of the brain in human lysosomal storage disorders.Lysosomal storage disorders are treated with recombinant enzyme replacement therapy. The majority of lysosomal storage disorders affect the brain (Cheng and Smith, 2003). A major limitation in the enzyme replacement therapy of lysosomal storage disorders is the lack of transport of the therapeutic enzyme across the brain capillary wall, which forms the blood-brain barrier (BBB). The involvement of the central nervous system is generally severe in lysosomal storage disorders (Cheng and Smith, 2003), and it is important to develop BBB drug delivery strategies for therapeutic enzymes. Recombinant proteins as large as 40,000 Da have been delivered across the BBB in vivo with molecular Trojan horses that access endogenous BBB receptor-mediated transport systems (Pardridge, 2001). A peptidomimetic monoclonal antibody (mAb) to the BBB transferrin receptor (TfR) mediated the delivery of several peptides and recombinant proteins across the BBB with in vivo central nervous system pharmacological effects following intravenous administration (Pardridge, 2002). The recombinant protein is attached to the TfRmAb via avidin-biotin technology. In this approach, the nontransportable protein drug is monobiotinylated in parallel with the production of a TfRmAb-streptavidin (SA) conjugate. Owing to the very high affinity of SA binding of biotin, the...

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Section: Discussionsupporting

confidence: 88%

Delivery of β-Galactosidase to Mouse Brain via the Blood-Brain Barrier Transferrin Receptor

Zhang

Pardridge²

2005

J Pharmacol Exp Ther

106

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“…As described by Tiwri and Amuji (2006), liposomes have generally proven successful as a delivery system for transport drugs across the BBB (although their use is hampered by efficiency and several contradictory reports exist: Tokes et al (1980); Schackert et al (1989). Relative to larger delivery systems, liposomes have been reported to reduce the rate of clearance from blood of molecules that include b-galactosidase (Onodera et al 1983), thyrotropin-releasing hormone (Postmes et al 1980), g-amino butyric acid (GABA) (Loeb et al 1982), or phenytoin (Mori et al 1995). In the case of the GABA and phenytoin, the enhanced delivery across the BBB was confirmed with behavioral analysis including a measurable reduction in chemically induced epilepsy.…”

Section: Nanoparticles and Liposomes For Cns Deliverymentioning

confidence: 99%

Targeted nanoparticle-based drug delivery and diagnosis

Emerich

Thanos

2007

Journal of Drug Targeting

204

101

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Nanotechnology, or systems/device manufacture at sizes generally ranging between 1 and 100 nm, is a multidisciplinary scientific field undergoing explosive development. The genesis of nanotechnology can be traced to advances in medicine, communications, genomics and robotics. One of the greatest values of nanotechnology will be in the development of new and effective medical treatments (i.e. nanomedicine). This review focuses on the potential of nanomedicine as it relates to the development of nanoparticles for enabling and improving the targeted delivery of therapeutic and diagnostic agents. We highlight the use of nanoparticles for specific intra-compartmental analysis using the examples of delivery to malignant cancers, to the central nervous system, and across the gastrointestinal barriers.

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“…For example, it was reported that when liposomes containing β -galactosidase were injected into rat tail vein, they penetrated the blood-brain barrier and reached the lysosomes in the central nervous system tissue more effectively than the free enzyme itself [32]. Also, when liposome entrapped γ−amino butyric acid (GABA) was administered intraperitoneally to Sprague-Dawley rats with penicillin induced epileptic activity, the formulation decreased or prevented the epileptic activity, whereas no significant changes were seen when free GABA was administered [33].…”

Section: Liposomesmentioning

confidence: 99%

A Review of Nanocarrier-Based CNS Delivery Systems

Tiwari¹,

Amiji²

2006

CDD

180

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Drug delivery to the central nervous system (CNS) is one of the most challenging fields of research and development for pharmaceutical and biotechnology products. A number of hydrophilic therapeutic agents, such as antibiotics, anticancer agents, or newly developed neuropeptides do not cross the blood brain barrier (BBB) after systemic administration. The BBB is formed by the tight junctions at the brain capillary endothelial cells, which strictly control drug transfer from blood to brain. Drug modification, osmotic opening of cerebral capillary endothelium, and alternative routes for administration (e.g., intracerebral delivery) have been successfully used to enhance drug transport to the CNS. The use of nanocarriers, such as liposomes and solid polymeric or lipid nanoparticles may be advantageous over the current strategies. These nanocarriers can not only mask the BBB limiting characteristics of the therapeutic drug molecule, but may also protect the drug from chemical/enzymatic degradation, and additionally provide the opportunity for sustained release characteristics. Reduction of toxicity to peripheral organs can also be achieved with these nanocarriers. This review article discusses the various barriers for drug delivery to the CNS and reviews the current state of nanocarriers for enhancing drug transport into the CNS.

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Microautoradiographic study on the tissue localization of liposome-entrapped or unentrapped 3H-labeled .BETA.-galactosidase injected into rats.

Cited by 16 publications

References 9 publications

Delivery of β-Galactosidase to Mouse Brain via the Blood-Brain Barrier Transferrin Receptor

Delivery of β-Galactosidase to Mouse Brain via the Blood-Brain Barrier Transferrin Receptor

Targeted nanoparticle-based drug delivery and diagnosis

A Review of Nanocarrier-Based CNS Delivery Systems

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