Evaluation of Biotinylated PAMAM Dendrimer Toxicity in Models of the Blood Brain Barrier: A Biophysical and Cellular Approach

Bullen, Heather A.; Hemmer, Ruth M.; Haskamp, Anthony; Cason, Chevelle A.; Wall, Stephen L. De; Spaulding, Robert; Rossow, Brett; Hester, Michael; Caroway, Megan; Haik, Kristi L.

doi:10.4236/jbnb.2011.225059

Cited by 15 publications

(11 citation statements)

References 41 publications

(46 reference statements)

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“…Mukherjee et al suggest this difference can be explained by different intrinsic antioxidant levels of both cell lines, as estimated by intracellular reactive oxygen species assays. 44 Higher cytotoxicity also was observed for biotinylated compared with nonbiotinylated G4 PAMAM dendrimers by a lactate dehydrogenase release assay performed with the bEnd.3 immortalized murine brain capillary endothelial cell line, but not with normal keratinocytes, by Bullen et al 45 The authors investigated the permeability of the blood-brain barrier for the delivery of therapeutic drugs to the brain by means of biotinylated PAMAM dendrimers, as biotin has been shown to cross the barrier through carrier-mediated endocytosis. The blood-brain barrier creates a permeability barrier caused by tight junctions of specialized brain capillary endothelial cells building brain capillary walls.…”

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confidence: 99%

In vitro cytotoxicity of the ternary PAMAM G3–pyridoxal–biotin bioconjugate

Uram

Szuster

Gargasz

et al. 2013

IJN

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A third-generation polyamidoamine dendrimer (PAMAM G3) was used as a macromolecular carrier for pyridoxal and biotin. The binary covalent bioconjugate of G3, with nine molecules of biotin per one molecule of G3 (G3 9B ), and the ternary covalent bioconjugate of G3, with nine biotin and ten pyridoxal molecules (G3 9B10P ), were synthesized. The biotin and pyridoxal residues of the bioconjugate were available for carboxylase and transaminase enzymes, as demonstrated in the conversion of pyruvate to oxaloacetate and alanine to pyruvate, respectively, by in vitro monitoring of the reactions, using 1 H nuclear magnetic resonance spectroscopy. The toxicity of the ternary bioconjugate (BC-PAMAM) was studied in vitro on BJ human normal skin fibroblasts and human squamous cell carcinoma (SCC-15) cell cultures in comparison with PAMAM G3, using three cytotoxicity assays (XTT, neutral red, and crystal violet) and an estimation of apoptosis by confocal microscopy detection. The tests have shown that BC-PAMAM has significantly lower cytotoxicity compared with PAMAM. Nonconjugated PAMAM was not cytotoxic at concentrations up to 5 μM (NR) and 10 μM (XTT), and BC-PAMAM was not cytotoxic up to 50 μM (both assays) for both cell lines. It has been also found that normal fibroblasts were more sensitive than SCC to both PAMAM and BC-PAMAM. The effect of PAMAM and BC-PAMAM on the initiation of apoptosis (PAMAM in fibroblasts at 5 μM and BC-PAMAM at 10 μM in both cell lines) corresponded with cytotoxicity assays for both cell lines. We concluded that normal fibroblasts are more sensitive to the cytotoxic effects of the PAMAM G3 dendrimer and that modification of its surface cationic groups by substitution with biologically active molecules significantly decreases that effect, confirming that PAMAM G3 is a useful candidate as a carrier for active biocompound delivery.

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confidence: 99%

In vitro cytotoxicity of the ternary PAMAM G3–pyridoxal–biotin bioconjugate

Uram

Szuster

Gargasz

et al. 2013

IJN

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“…This work reports the first analysis of PAMAM dendrimers using this combined approach. The results provide important insights into strategies for developing nanoparticle systems for brain drug delivery 38 .…”

Section: Dendrimers In Cns Drug Deliverymentioning

confidence: 96%

Potential Application of Dendrimers in Drug Delivery: A Concise Review and Update

Parajapati

Maurya

Das

et al. 2016

J. Drug Delivery Ther.

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“…For example, PAMAM dendrimers have been shown to be haemolytic and cytotoxic [98]. Some research results also showed that biotinylated PAMAM dendrimers may prove to be more toxic compared to PAMAM dendrimers alone [99]. The versatility of nanoemulsions is based on the different types of oils and surface modifiers that can be used [101].…”

Section: Dendrimersmentioning

confidence: 99%

Nano carriers for drug transport across the blood–brain barrier

Tsibouklis

Weng³

et al. 2016

Journal of Drug Targeting

206

124

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Effective therapy lies in achieving a therapeutic amount of drug to the proper site in the body and then maintaining the desired drug concentration for a sufficient time interval to be clinically effective for treatment. The blood-brain barrier (BBB) hinders most drugs from entering the central nervous system (CNS) from the blood stream, leading to the difficulty of delivering drugs to the brain via the circulatory system for the treatment, diagnosis and prevention of brain diseases. Several brain drug delivery approaches have been developed, such as intracerebral and intracerebroventricular administration, intranasal delivery and blood-to-brain delivery, as a result of transient BBB disruption induced by biological, chemical or physical stimuli such as zonula occludens toxin, mannitol, magnetic heating and ultrasound, but these approaches showed disadvantages of being dangerous, high cost and unsuitability for most brain diseases and drugs. The strategy of vector-mediated blood-to-brain delivery, which involves improving BBB permeability of the drug-carrier conjugate, can minimize side effects, such as being submicrometre objects that behave as a whole unit in terms of their transport and properties, nanomaterials, are promising carrier vehicles for direct drug transport across the intact BBB as a result of their potential to enter the brain capillary endothelial cells by means of normal endocytosis and transcytosis due to their small size, as well as their possibility of being functionalized with multiple copies of the drug molecule of interest. This review provids a concise discussion of nano carriers for drug transport across the intact BBB, various forms of nanomaterials including inorganic/solid lipid/polymeric nanoparticles, nanoemulsions, quantum dots, nanogels, liposomes, micelles, dendrimers, polymersomes and exosomes are critically evaluated, their mechanisms for drug transport across the BBB are reviewed, and the future directions of this area are fully discussed.

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Evaluation of Biotinylated PAMAM Dendrimer Toxicity in Models of the Blood Brain Barrier: A Biophysical and Cellular Approach

Cited by 15 publications

References 41 publications

In vitro cytotoxicity of the ternary PAMAM G3–pyridoxal–biotin bioconjugate

In vitro cytotoxicity of the ternary PAMAM G3–pyridoxal–biotin bioconjugate

Potential Application of Dendrimers in Drug Delivery: A Concise Review and Update

Nano carriers for drug transport across the blood–brain barrier

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Evaluation of Biotinylated PAMAM Dendrimer Toxicity in Models of the Blood Brain Barrier: A Biophysical and Cellular Approach

Cited by 15 publications

References 41 publications

In vitro cytotoxicity of the ternary PAMAM G3&ndash;pyridoxal&ndash;biotin bioconjugate

In vitro cytotoxicity of the ternary PAMAM G3&ndash;pyridoxal&ndash;biotin bioconjugate

Potential Application of Dendrimers in Drug Delivery: A Concise Review and Update

Nano carriers for drug transport across the blood–brain barrier

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Product

Resources

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In vitro cytotoxicity of the ternary PAMAM G3–pyridoxal–biotin bioconjugate

In vitro cytotoxicity of the ternary PAMAM G3–pyridoxal–biotin bioconjugate