Anionic linear-globular dendrimers: biocompatible hybrid materials with potential uses in nanomedicine

Abstract

The use of dendrimers as nano-sized excipients/vectors in biological and pharmaceutical systems is dependent on the investigation of their toxicological profiles in biological media. In this study, a series of mechanistic in vitro structure-associated cell toxicity evaluations was performed on the two generations of an anionic linear-globular dendrimer G1 and G2 (where PEG is the core, and citric acid is the periphery) each of which has a different size, charge, and MW. In vitro cytotoxicity behavior of the dendrimers with the methods like crystal violet staining, methyl thiazolyl tetrazolium (MTT), and lactate dehydrogenase (LDH) assays was analyzed. The cell death mechanisms (apoptosis-necrosis) induced by the dendrimers were also evaluated in HT1080 cell line. The impact of the dendrimers on the release of the pro-inflammatory cytokines like TNF-alpha (tumor necrosis factor alpha) and IL1-beta (interleukin 1 beta) was assessed in THP-1 cell line. Hemolysis assay and coagulation studies such as PT (prothrombin time) and APTT (activated partial thromboplastin time) on human blood samples were conducted to examine the interactions of the dendrimers with such bio-environments. The results of cell cytotoxicity experiments and the amounts of IL1-beta and TNF-alpha secretions from THP-1 cell line were consistent with the hemoglobin release from the erythrocytes and the results gained from the coagulation studies. In fact, no significant harmful effect was observed for the dendrimers up to the concentration of 0.5 mg/ml. Both apoptosis and necrosis were ascribed to cell death. The G1 with more flexibility, less negative charge, and greater poly dispersity in size versus the G2 displayed more toxicity than the G2 at the concentration of 1 mg/ml and above in most of the experiments. As a whole, these results suggest a biocompatible range for these hybrid structures up to the concentration of 0.5 mg/ml. Therefore, the potentiality for these structures to be employed in the different and numerous realms of nanomedicine will be very great.

Novel Nanosized Gd3+-ALGD-G2-C595: In vivo Dual Selective MUC-1 Positive Tumor Molecular MR Imaging and Therapeutic Agent

“…-ALGDG 2 -C595 nano-conjugate Procedures for preparation of Gd 3+ -ALGDG 2 -C595 nanoconjugate was done according to the literature [12][13][14]. Briefly, PEG-600 was chosen as the core and reacted with citric acid in the presence of excess amounts of thionyl chloride and the dialysis bag was used for the purification.…”

“…Dendrimers (nanosized polymers) have been explored for the targeting of hydrophobic pharmaceuticals and or for the delivery of anticancer drugs including MR imaging contrast agents [7][8][9][10][11][12][13][14]. Dendrimerbased gadolinium chelates are a new class of macromolecular MR imaging contrast agents with extremely molecular relaxivities [7,9].…”

“…Dendrimerbased gadolinium chelates are a new class of macromolecular MR imaging contrast agents with extremely molecular relaxivities [7,9]. The chemico-physical characteristics of dendrimers, including their monodispersity, water solubility, drug loading ability, and large number of functionalizable peripheral groups, make these macromolecules appropriate candidates for evaluation as MR tumor imaging or therapeutic vehicles [7][8][9][10][11][12][13][14]. As dendrimer generation increases, the number of terminal branches increases exponentially, while diameter increases linearly by about 1nm/generation.…”

“…As dendrimer generation increases, the number of terminal branches increases exponentially, while diameter increases linearly by about 1nm/generation. This is often possible by means of safe nanocarriers such as anionic linear globular dendrimers [10][11][12][13]. Yet, not all of the dendrimers are suitable in MR imaging; biocompatible properties like log P, biodegradability, non cytotoxicity, and non immunogenicity characteristics must be checked for dendrimers in vitro and in vivo.…”

“…One of the verified dendrimer, one generation of a highly water soluble anionic linear-globular dendrimer G 2 (MW<2000 Da), (poly ethylene glycol core) and citric acid periphery surface, was selected for the synthesis and subsequent MR coupling. This dendrimer has shown good capacity of drug loading in cancer therapy [12,13].…”