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      A study on the hemocompatibility of dendronized chitosan derivatives in red blood cells

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          Abstract

          Dendrimers are hyperbranched macromolecules with well-defined topological structures and multivalent functionalization sites, but they may cause cytotoxicity due to the presence of cationic charge. Recently, we have introduced alkyne-terminated poly(amidoamine) (PAMAM) dendrons of different generations (G=2,3) into chitosan to obtain dendronized chitosan derivatives [Cs- g-PAMAM (G=2,3)], which exhibited a better water solubility and enhanced plasmid DNA transfection efficiency. In this study, we attempted to examine the impact of Cs- g-PAMAM (G=2,3) at different concentrations (25 μg/mL, 50 μg/mL, and 100 μg/mL) on the morphology, surface structure, and viability of rat red blood cells (RBCs). The results showed that treatment of RBCs with Cs- g-PAMAM (G=2,3) at 50 μg/mL and 100 μg/mL induced a slightly higher hemolysis than Cs, and Cs- g-PAMAM (G=3) caused a slightly higher hemolysis than Cs- g-PAMAM (G=2), but all values were <5.0%. Optical microscopic and atomic force microscopic examinations indicated that Cs- g-PAMAM (G=2,3) caused slight RBC aggregation and lysis. Treatment of RBCs with 100 μg/mL Cs- g-PAMAM (G=3) induced echinocytic transformation, and RBCs displayed characteristic irregular contour due to the folding of the periphery. Drephanocyte-like RBCs were observed when treated with 100 μg/mL Cs- g-PAMAM (G=3). Erythrocytes underwent similar shape transition upon treatment with Cs- g-PAMAM (G=2) or Cs. The roughness values (Rms) of RBCs incubated with Cs- g-PAMAM (G=2,3) were significantly larger than those for RBCs incubated with physiological saline ( P<0.01), but the Rms showed no difference for Cs and Cs- g-PAMAM (G=2,3) ( P>0.05). Furthermore, Cs- g-PAMAM (G=2,3) exhibited a lower cytotoxicity in human kidney 293T cells. These results indicate that Cs- g-PAMAM (G=2,3) are hemocompatible but may disturb membrane and lipid structures at higher concentrations. Further safety and biocompatibility evaluations are warranted for Cs- g-PAMAM. Our findings prove helpful for a better understanding of the advantages of combining PAMAM dendrimers and chitosan to design and develop new, safe, and effective drug delivery vehicles.

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          Most cited references 75

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          Dendrimer-based drug and imaging conjugates: design considerations for nanomedical applications.

          Dendrimers are members of a versatile, fourth new class of polymer architecture (i.e. dendritic polymers after traditional linear, crosslinked and branched types). Typically, dendrimers are used as well-defined scaffolding or nanocontainers to conjugate, complex or encapsulate therapeutic drugs or imaging moieties. As a delivery vector, the dendrimer conjugate linker or spacer chemistry plays a crucial part in determining optimum drug delivery to disease sites by conserving active drug efficacy while influencing appropriate release patterns. This review focuses on several crucial issues related to those dendrimer features, namely the role of dendrimers as nanoscaffolding and nanocontainers, crucial principles that might be invoked for improving dendrimer cytotoxicity properties, understanding dendrimer cellular transport mechanisms and the exciting role of dendrimers as high-contrast MRI imaging agents. The review concludes with a brief survey of translational efforts from research and development phases to clinical trials that are actively emerging. 2010 Elsevier Ltd. All rights reserved.
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            Emerging concepts in dendrimer-based nanomedicine: from design principles to clinical applications.

            Dendrimers are discrete nanostructures/nanoparticles with 'onion skin-like' branched layers. Beginning with a core, these nanostructures grow in concentric layers to produce stepwise increases in size that are similar to the dimensions of many in vivo globular proteins. These branched tree-like concentric layers are referred to as 'generations'. The outer generation of each dendrimer presents a precise number of functional groups that may act as a monodispersed platform for engineering favourable nanoparticle-drug and nanoparticle-tissue interactions. These features have attracted significant attention in medicine as nanocarriers for traditional small drugs, proteins, DNA/RNA and in some instances as intrinsically active nanoscale drugs. Dendrimer-based drugs, as well as diagnostic and imaging agents, are emerging as promising candidates for many nanomedicine applications. First, we will provide a brief survey of recent nanomedicines that are either approved or in the clinical approval process. This will be followed by an introduction to a new 'nanoperiodic' concept which proposes nanoparticle structure control and the engineering of 'critical nanoscale design parameters' (CNDPs) as a strategy for optimizing pharmocokinetics, pharmocodynamics and site-specific targeting of disease. This paradigm has led to the emergence of CNDP-directed nanoperiodic property patterns relating nanoparticle behaviour to critical in vivo clinical translation issues such as cellular uptake, transport, elimination, biodistribution, accumulation and nanotoxicology. With a focus on dendrimers, these CNDP-directed nanoperiodic patterns are used as a strategy for designing and optimizing nanoparticles for a variety of drug delivery and imaging applications, including a recent dendrimer-based theranostic nanodevice for imaging and treating cancer. Several emerging preclinical dendrimer-based nanotherapy concepts related to inflammation, neuro-inflammatory disorders, oncology and infectious and ocular diseases are reviewed. Finally we will consider challenges and opportunities anticipated for future clinical translation, nanotoxicology and the commercialization of nanomedicine.
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              Shape and Biomechanical Characteristics of Human Red Blood Cells in Health and Disease.

              The biconcave shape and corresponding deformability of the human red blood cell (RBC) is an essential feature of its biological function. This feature of RBCs can be critically affected by genetic or acquired pathological conditions. In this review, we highlight new dynamic in vitro assays that explore various hereditary blood disorders and parasitic infectious diseases that cause disruption of RBC morphology and mechanics. In particular, recent advances in high-throughput microfluidic devices make it possible to sort/identify healthy and pathological human RBCs with different mechanobiological characteristics.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                14 May 2015
                : 9
                : 2635-2645
                Affiliations
                [1 ]Guangdong Medical Universtity, Dongguan, Guangdong, People’s Republic of China
                [2 ]Department of Materials Science and Engineering, Drexel University, Philadelphia, PA, USA
                [3 ]Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
                Author notes
                Correspondence: Xinsheng Peng, Guangdong Medical Universtity, 1 Xincheng Road, Songshan Lake Science and Technology Industry Park, Dongguan, Guangdong 523808, People’s Republic of China, Tel +86 769 2289 6561, Fax +86 769 2289 6560, Email gdmcpxs@ 123456163.com
                Shu-Feng Zhou, Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B Downs Boulevard, Tampa, FL 33612, USA, Tel +1 813 974 6276, Fax +1 813 905 9885, Email szhou@ 123456health.usf.edu

                *These authors contributed equally to this work

                Article
                dddt-9-2635
                10.2147/DDDT.S77105
                4437608
                25999697
                © 2015 Zhou et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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