Dendritic macromolecules as nano-scale drug carriers: Phase solubility, in vitro drug release, hemolysis and cytotoxicity study

Patel, Pravinkumar M.; Patel, Rinkesh M.; Wadia, Devang; Patel, R. M.

doi:10.1016/j.ajps.2015.04.002

Cited by 12 publications

(7 citation statements)

References 27 publications

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“…Figure S6 shows that PAMC has almost no cytotoxicity at concentrations up to 62.5 μM, indicating that PAMC is rather biocompatible, consistent with previous reports. 24,32,33 PAMP1−3 also shows nontoxicity to the cells, whereas PAMP4 at 2.5 μM presents a cell survival decrease of about 6% (Figure S7), suggesting a weak toxicity to the SH-SY5Y cells. By contrast, Aβ 42 aggregates are toxic to the cells, causing about 39% cell death and PAMC does not affect the toxicity of Aβ 42 aggregates (Figure 4A).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…However, the studies of acidulated BSA and HSA on Aβ aggregation are yet insufficient to support the HyBER hypothesis because of the heterogeneous distribution of negatively and positively charged residues, and hydrophobic patches on the surface of BSA/HSA make it difficult to verify their contribution in the inhibition of Aβ aggregation. Therefore, toward a better understanding and further application of the HyBER hypothesis, we propose to use generation 5 (G5) carboxyl-terminated polyamidoamine (PAMC), a biocompatible dendrimer with only carboxyl groups on its surface, − as a base material to create a neat surface with only negative charges and hydrophobic patches. As illustrated in Scheme S1, G5 PAMC owns a highly branched 3D globular nanostructure with 128 carboxyl groups on the surface and empty hydrophobic cavities inside. , Thus, by surface modification with phenethylamine (PEA) to introduce phenyl groups, the synthesized phenyl-derivatized PAMC (PAMP) surface is distributed with only carboxyl groups and phenyl groups (Scheme ) and the negatively charged hydrophobic surface is expected to function as an amyloid inhibitor via the HyBER hypothesis, if the hypothesis is true.…”

Section: Introductionmentioning

confidence: 99%

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Hydrophobic Modification of Carboxyl-Terminated Polyamidoamine Dendrimer Surface Creates a Potent Inhibitor of Amyloid-β Fibrillation

2018

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Amyloid β-peptide (Aβ) fibrillogenesis is a major hallmark of Alzheimer's disease (AD); inhibition of Aβ fibrillation is thus considered as a promising strategy for AD prevention and treatment. Our group has previously proposed the hydrophobic binding-electrostatic repulsion (HyBER) hypothesis, which provides guidance for the design of new amyloid inhibitors. Inspired by the HyBER hypothesis, we have herein proposed to synthesize hydrophobic-modified generation 5 carboxyl-terminated polyamidoamine dendrimer, denoted as PAMP, to create a potent inhibitor with a negatively charged hydrophobic surface. Results indicate that the PAMP with a proper degree of phenyl substitution (30−42%) alters the conformation of Aβ 42 through both hydrophobic binding and electrostatic repulsive forces on its surface. With these well-balanced interactions, the inhibitor can even completely inhibit the formation of β-sheet structure of the peptide, accompanied by changes at the level of the fibrillary architecture. Moreover, the results also indicate that changes of Aβ 42 aggregation pathway influenced by the PAMP occur at the very early stage, so the PAMP can significantly avoid the formation of toxic intermediates of Aβ 42 aggregation.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hydrophobic Modification of Carboxyl-Terminated Polyamidoamine Dendrimer Surface Creates a Potent Inhibitor of Amyloid-β Fibrillation

2018

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“…A complete hemolytic sample, which was used as a control, was prepared by sonicating blood for 3 min. The percentage of hemolysis was calculated as (OD test – OD formulation ) /OD control × 100% 36 .…”

Section: Methodsmentioning

confidence: 99%

Programmed Hydrolysis in Designing Paclitaxel Prodrug for Nanocarrier Assembly

Wang

et al. 2015

Sci Rep

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Nanocarriers delivering prodrugs are a way of improving in vivo effectiveness and efficiency. For therapeutic efficacy, the prodrug must hydrolyze to its parent drug after administration. Based on the fact that the hydrolysis is impeded by steric hindrance and improved by sufficient polarity, in this study, we proposed the PTX-S-S-VE, the conjugation of paclitaxel (PTX) to vitamin E (VE) through a disulfide bridge. This conjugate possessed the following advantages: first, it can be encapsulated in the VE/VE2-PEG2000/water nanoemulsions because of favorable hydrophobic interactions; second, the nanoemulsions had a long blood circulation time; finally, the concentrated glutathione in the tumor microenvironment could cleave the disulfide bond to weaken the steric hindrance and increase the polarity, promoting the hydrolysis to PTX and increasing the anticancer activity. It was demonstrated in vitro that the hydrolysis of PTX-S-S-VE was enhanced and the cytotoxicity was increased. In addition, PTX-S-S-VE had greater anticancer activity against the KB-3-1 cell line tumor xenograft and the tumor size was smaller after the 4th injection. The present result suggests a new way, use of reduction, to improve the in vivo anticancer activity of a prodrug for nanocarrier delivery by unshielding the ester bond and taking off the steric block.

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“…This unique HyBER mechanism provides a new strategy for the design of effective inhibitors on Aβ 42 aggregation and deserves further explorations. Polyamidoamine (PAMAM), one of the most well-known dendrimers, has been widely investigated in biomedical applications, for example, gene therapy, drug delivery, and magnetic resonance imaging. − Carboxyl-terminated polyamidoamine dendrimer (PAMAM) is a kind of biocompatible nanomaterial with only carboxyl groups on its surface, − which offers a perfect base material for the design of Aβ inhibitors based on the HyBER theory. In the previous study, we did this by synthesizing a series of phenyl-derivatized generation 5 carboxyl-terminated PAMAM (G5) to get potent amyloid inhibitors with a negatively charged hydrophobic surface that meets the HyBER theory on inhibiting Aβ fibrillogenesis.…”

Section: Introductionmentioning

confidence: 99%

Mixed Carboxyl and Hydrophobic Dendrimer Surface Inhibits Amyloid-β Fibrillation: New Insight from the Generation Number Effect

2019

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Fibrillation of amyloid-β peptide (Aβ) is closely associated with the progression of Alzheimer’s disease (AD), and so inhibition of Aβ fibrillation has been considered as one of the promising strategies for AD prevention and treatment. Our group has proposed the hydrophobic binding-electrostatic repulsion (HyBER) theory on inhibiting Aβ fibrillation by a surface with mixed negative charges and hydrophobic groups, which provides a new strategy for the design of potent amyloid inhibitors. Carboxyl-terminated polyamidoamine dendrimer (PAMAM) is a kind of biocompatible nanomaterial with only carboxyl groups on its surface, and its architecture and property vary with the generation number, low-generation dendrimers possessing sparse distributions of terminal groups while high-generation dendrimers having compact surface groups, which offer abundant base materials for further study of the HyBER theory. We have designed a potent amyloid inhibitor with generation 5 PAMAM. To provide new insights into the HyBER mechanism, we have herein proposed to synthesize phenyl-modified PAMAM dendrimers of generations 3 to 6 (G3-P to G6-P) and study the effect of the generation number on Aβ fibrillation. Results show that phenyl derivatives of low-generation dendrimers (G3-P and G4-P) do not show any interference with Aβ aggregation, whereas the phenyl derivatives of high-generation dendrimers (G5-P and G6-P) significantly inhibit Aβ42 aggregation and alter the ultrastructure of Aβ42 aggregates. The results indicate that the density and distribution of surface functional groups on a dendrimer is of great importance for the HyBER effect to happen. The new understanding on the HyBER mechanism would benefit in the development of potent amyloid inhibitors based on the theory.

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Dendritic macromolecules as nano-scale drug carriers: Phase solubility, in vitro drug release, hemolysis and cytotoxicity study

Cited by 12 publications

References 27 publications

Hydrophobic Modification of Carboxyl-Terminated Polyamidoamine Dendrimer Surface Creates a Potent Inhibitor of Amyloid-β Fibrillation

Hydrophobic Modification of Carboxyl-Terminated Polyamidoamine Dendrimer Surface Creates a Potent Inhibitor of Amyloid-β Fibrillation

Programmed Hydrolysis in Designing Paclitaxel Prodrug for Nanocarrier Assembly

Mixed Carboxyl and Hydrophobic Dendrimer Surface Inhibits Amyloid-β Fibrillation: New Insight from the Generation Number Effect

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