Influence of PAMAM dendrimers on human red blood cells

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Abstract

Polyamidoamine (PAMAM) dendrimers with different concentrations (1 nM–1 mM) (generations 2, 3, and 4) impact on human red blood cell morphology, and membrane integrity is studied. Erythrocyte shape changes from biconcave to echinocytic in dendrimers. Cell aggregation occurs. Polymers cause also concentration- and generation-dependent haemolysis.

Introduction

Dendrimers have attracted much interest since their synthesis in the mid-1980s [1] due to their unique nanoscopic architecture. There are attempts to use them in biomedical applications [2], [3]. Functional groups presented on the surface have been utilized for the conjugation of drugs. In addition, a dendrimer interior has been shown to be capable of encapsulating various molecules. More information about dendrimer toxicity and biological properties is needed to continue studies on dendrimers in therapeutic applications.

The circulatory system seems to be the most convenient way of drug administration because an active compound within a relatively short time is able to reach distant tissues, which are unavailable directly. However, blood constituents can be the first and unwanted targets of drug action. Binding to plasma proteins, erythrocytes, leukocytes, platelets, and blood vessel walls may lead to serious problems, or at least dramatically lower the amount of drug available for therapy.

In this study, polyamidoamine (PAMAM) dendrimers impact on red blood cell morphology and haemolysis is checked. PAMAM dendrimers are synthesised from an ethylenediamine core by a successive addition of methyl acrylate and ethylenediamine. The number of terminal amino groups doubles after each cycle and the dendrimer is of higher generation. Here we have examined the haematotoxicity of three PAMAM dendrimer generations: second (G2), third (G3), and fourth (G4). The short characterisation of used dendrimers is presented in Table 1.

Section snippets

Experimental

Polyamidoamine dendrimers (generation 2, 3, and 4) were purchased from Aldrich (UK). Blood from healthy donors was obtained from the Central Blood Bank (Lodz). Blood was anticoagulated with 3% sodium citrate. Erythrocytes were separated from blood plasma and leukocytes by centrifugation (5000×g, 5 min) at 4 °C and washed three times with phosphate-buffered saline (PBS; 150 mM NaCl; 1.9 mM NaH2PO4; 8.1 mM Na2HPO4, pH 7.4) and suspended in PBS. Erythrocytes were used immediately after isolation.

Results and discussion

The present work was aimed to investigate whether PAMAM dendrimers influence red blood cell morphology. In the circulation, erythrocytes have the shape of a biconcave disc—hence the name ‘discocyte.’ Discocytes in physiological conditions are highly deformable. It is essential for their survival in the microcirculation. Under the influence of intrinsic or extrinsic factors, discocytes can transform to echinocytes (crenated cells) or stomatocytes (cup-shaped cells) [5].

Changes in the red blood

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