Effect of Blood-Brain Barrier and Blood-Tumor Barrier Modification on Central Nervous System Liposomal Uptake

Gennuso, Rosemaria; Spigelman, Melvin; Chinol, Marco; Zappulla, Rosario A.; Nieves, Julia; Vallabhajosula, Shankar; Paciucci, Paolo Alberto; Goldsmith, Stanley J.; Holland, James F.

doi:10.3109/07357909309024829

Cited by 30 publications

(15 citation statements)

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“…The phospholipid bilayer membrane of the liposomal BPD can be responsible for the rapid tumor delivery [34]. However, the applicability of liposomal drug carriers to the brain and brain tumors may be different than to systemic tumors due to the unique properties of the blood-brain barrier [35]. Our results indicate that brain tumor uptake at 5 h was at maximum for both the subcutaneous and the intracerebral glioma model.…”

Section: Discussionsupporting

confidence: 48%

Preclinical Evaluation of Benzoporphyrin Derivative Combined with a Light-Emitting Diode Array for Photodynamic Therapy of Brain Tumors

et al. 1999

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Objective: The aim of this study was to investigate the second-generation photosensitizer benzoporphyrin derivative (BPD) and a novel light source applicator based on light-emitting diode (LED) technology for photodynamic therapy (PDT) of brain tumors. Methods: We used a canine model to investigate normal brain stem toxicity. Twenty-one canines underwent posterior fossa craniectomies followed by PDT with BPD. These animals were compared to light only and BPD control. In addition, we investigated the ability of BPD and LED to cause inhibition of cell growth in canine glioma and human glioma cell lines, in vitro. The biodistribution of BPD labeled with ¹¹¹In-BPD in mice with subcutaneous and intracerebral gliomas and canines with brain tumors was studied. Results: The in vivo canine study resulted in a maximal tolerated dose of 0.75 mg/kg of BPD and 100 J/cm² of LED light for normal brain tissue. The in vitro study demonstrated 50% growth inhibition for canine and human glioma cell lines of 10 and 4 ng/ml, respectively. The mucine study using ¹¹¹In-BPD showed a tumor to normal tissue ratio of 12:1 for intracerebral tumors and 3.3:1 for subcutaneous tumors. Nuclear scans of canines with brain tumors showed uptake into tumors to be maximal from 3 to 5 h. Conclusion: Our study supports that BPD and LED light sources when used at appropriate drug and light doses limit normal brain tissue toxicity at doses that can cause significant glioma cell toxicity in vitro. In addition, there is higher BPD uptake in brain tumors as compared to normal brain in a mouse glioma model. These findings make BPD a potential new-generation photosensitizer for the treatment of childhood posterior fossa tumors as well as other malignant cerebral pathology.

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Section: Discussionsupporting

confidence: 48%

Preclinical Evaluation of Benzoporphyrin Derivative Combined with a Light-Emitting Diode Array for Photodynamic Therapy of Brain Tumors

et al. 1999

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“…This opening of the BBB with osmotic treatment has been attributed to the shrinkage of the endothelial cells and the separation of the tight junctions. Similarly, pharmacological disruption with etoposide enhanced the brain uptake of liposomes [65]. Use of angiotensin II [64], peptidase inhibitors [66] and bradykinin [67] has been reported to induce transient opening of the BBB and improved uptake of liposomal contents.…”

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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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“…Conventional liposomes are not delivered to brain in vivo (14)(15)(16), because these agents are not transported through the brain capillary endothelial wall, which makes up the bloodbrain barrier (BBB) in vivo. However, certain receptor specific monoclonal antibodies (mAbs) undergo receptor-mediated transcytosis through the BBB (17), and mAb-gold conjugates are transcytosed through the BBB (18) in vivo.…”

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confidence: 99%