Stability and biocompatibility of a library of polyester dendrimers in comparison to polyamidoamine dendrimers.

Dendrimers can be designed for several biomedical applications due to their well-defined structure, functionality and dimensions. The present study focused on the in vitro biocompatibility evaluation of a library of aliphatic polyester dendrimers based on 2,2-bis(methylol)propionic acid (bis-MPA) with an overall diameter of 0.5-2 nm. In addition, dendrimers with two different chemical surfaces (neutral with hydroxyl end group and anionic with carboxylic end group) and dendrons corresponding to the structural fragments of the dendrimers were evaluated. Commercial polyamidoamine dendrimers (PAMAM) with cationic (amine) or neutral (hydroxyl) end group were also included for comparison. Cell viability studies were conducted in human cervical cancer (HeLa) and acute monocytic leukemia cells (THP.1) differentiated into macrophage-like cells as well as in primary human monocyte-derived macrophages. Excellent biocompatibility was observed for the entire hydroxyl functional bis-MPA dendrimer library, whereas the cationic, but not the neutral PAMAM exerted dose-dependent cytotoxicity in cell lines and primary macrophages. Studies to evaluate material stability as a function of pH, temperature, and time, demonstrated that the stability of the 4th generation hydroxyl functional bis-MPA dendrimer increased at acidic pH. Taken together, bis-MPA dendrimers are degradable and non-cytotoxic to human cell lines and primary cells.

[1]  Jian Qin,et al.  The importance of an endotoxin-free environment during the production of nanoparticles used in medical applications. , 2006, Nano letters.

[2]  Mingwu Shen,et al.  Encapsulation of 2-methoxyestradiol within multifunctional poly(amidoamine) dendrimers for targeted cancer therapy. , 2011, Biomaterials.

[3]  Bengt Fadeel,et al.  Efficient internalization of mesoporous silica particles of different sizes by primary human macrophages without impairment of macrophage clearance of apoptotic or antibody-opsonized target cells. , 2009, Toxicology and applied pharmacology.

[4]  Tongwen Xu,et al.  Design of biocompatible dendrimers for cancer diagnosis and therapy: current status and future perspectives. , 2011, Chemical Society reviews.

[5]  Robert Sinclair,et al.  The Fate and Toxicity of Raman-Active Silica-Gold Nanoparticles in Mice , 2011, Science Translational Medicine.

[6]  Anders Hult,et al.  New methodologies in the construction of dendritic materials. , 2009, Chemical Society reviews.

[7]  J. G. Cory,et al.  Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. , 1991, Cancer communications.

[8]  Hugh J Byrne,et al.  In vitro mammalian cytotoxicological study of PAMAM dendrimers - towards quantitative structure activity relationships. , 2010, Toxicology in vitro : an international journal published in association with BIBRA.

[9]  Hamidreza Ghandehari,et al.  Transport of Poly(Amidoamine) Dendrimers across Caco-2 Cell Monolayers: Influence of Size, Charge and Fluorescent Labeling , 2006, Pharmaceutical Research.

[10]  T. Kissel,et al.  Nanoparticles for paclitaxel delivery: a comparative study of different types of dendritic polyesters and their degradation behavior. , 2011, International journal of pharmaceutics.

[11]  F. Szoka,et al.  Polyester dendritic systems for drug delivery applications: design, synthesis, and characterization. , 2002, Bioconjugate chemistry.

[12]  Hugh J Byrne,et al.  Reactive oxygen species (ROS) induced cytokine production and cytotoxicity of PAMAM dendrimers in J774A.1 cells. , 2010, Toxicology and applied pharmacology.

[13]  Francis C Szoka,et al.  Polyester dendritic systems for drug delivery applications: in vitro and in vivo evaluation. , 2002, Bioconjugate chemistry.

[14]  Marina A Dobrovolskaia,et al.  Ambiguities in applying traditional Limulus amebocyte lysate tests to quantify endotoxin in nanoparticle formulations. , 2010, Nanomedicine.

[15]  N. McKeown,et al.  The influence of surface modification on the cytotoxicity of PAMAM dendrimers. , 2003, International journal of pharmaceutics.

[16]  H. Parekh,et al.  Low‐generation asymmetric dendrimers exhibit minimal toxicity and effectively complex DNA , 2011, Journal of peptide science : an official publication of the European Peptide Society.

[17]  N. Demaurex.  pH Homeostasis of cellular organelles. , 2002, News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society.

[18]  Y. Lim,et al.  Comparative studies on the genotoxicity and cytotoxicity of polymeric gene carriers polyethylenimine (PEI) and polyamidoamine (PAMAM) dendrimer in Jurkat T-cells , 2010, Drug and chemical toxicology.

[19]  H. Byrne,et al.  Mechanistic studies of in vitro cytotoxicity of poly(amidoamine) dendrimers in mammalian cells. , 2010, Toxicology and applied pharmacology.

[20]  Iseult Lynch,et al.  Serum heat inactivation affects protein corona composition and nanoparticle uptake. , 2010, Biomaterials.

[21]  F Philipp Seib,et al.  Comparison of the endocytic properties of linear and branched PEIs, and cationic PAMAM dendrimers in B16f10 melanoma cells. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[22]  E. W. Meijer,et al.  Dendrimers: relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[23]  S. Kannan,et al.  The effect of surface functionality on cellular trafficking of dendrimers. , 2008, Biomaterials.

[24]  Bin He,et al.  Gadolinium-labeled peptide dendrimers with controlled structures as potential magnetic resonance imaging contrast agents. , 2011, Biomaterials.

[25]  Kenneth A. Dawson,et al.  Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts , 2008, Proceedings of the National Academy of Sciences.

[26]  Parag Aggarwal,et al.  Preclinical studies to understand nanoparticle interaction with the immune system and its potential effects on nanoparticle biodistribution. , 2008, Molecular pharmaceutics.

[27]  Bengt Fadeel,et al.  Better safe than sorry: Understanding the toxicological properties of inorganic nanoparticles manufactured for biomedical applications. , 2010, Advanced drug delivery reviews.

[28]  Fabio Beltram,et al.  Dendrimer internalization and intracellular trafficking in living cells. , 2010, Molecular pharmaceutics.

[29]  Bradford G. Orr,et al.  Nanoparticle Interaction with Biological Membranes: Does Nanotechnology Present a Janus Face? , 2007 .

[30]  Bengt Fadeel,et al.  Efficient internalization of silica-coated iron oxide nanoparticles of different sizes by primary human macrophages and dendritic cells. , 2011, Toxicology and applied pharmacology.

[31]  Anil K Patri,et al.  Nanoparticle size and surface charge determine effects of PAMAM dendrimers on human platelets in vitro. , 2012, Molecular pharmaceutics.

[32]  Francis C Szoka,et al.  Designing dendrimers for biological applications , 2005, Nature Biotechnology.

[33]  Brian D. Athey,et al.  Structural Molecular Dynamics Studies on Polyamidoamine Dendrimers for a Therapeutic Application: Effects of pH and Generation , 2002 .

[34]  J. Lemon,et al.  Synthesis, radiolabeling, and bio-imaging of high-generation polyester dendrimers. , 2009, Journal of the American Chemical Society.

[35]  Bengt Fadeel,et al.  Toxicology of engineered nanomaterials: focus on biocompatibility, biodistribution and biodegradation. , 2011, Biochimica et biophysica acta.

[36]  Samuel Achilefu,et al.  Monitoring the biodegradation of dendritic near-infrared nanoprobes by in vivo fluorescence imaging. , 2008, Molecular pharmaceutics.

[37]  Mark W Grinstaff,et al.  Biomedical applications of dendrimers: a tutorial. , 2011, Chemical Society reviews.

[38]  M. Dobrovolskaia,et al.  Immunological properties of engineered nanomaterials , 2007, Nature Nanotechnology.

[39]  R. Haag,et al.  Structure-biocompatibility relationship of dendritic polyglycerol derivatives. , 2010, Biomaterials.

[40]  S. Kawakami,et al.  Designing Dendrimers for Drug Delivery and Imaging: Pharmacokinetic Considerations , 2011, Pharmaceutical Research.

[41]  R. Duncan,et al.  Dendrimer biocompatibility and toxicity. , 2005, Advanced drug delivery reviews.

[42]  Anders Hult,et al.  Synthesis, Characterization, and 1H NMR Self-Diffusion Studies of Dendritic Aliphatic Polyesters Based on 2,2-Bis(hydroxymethyl)propionic Acid and 1,1,1-Tris(hydroxyphenyl)ethane , 1996 .

[43]  Monica Shokeen,et al.  Biodegradable dendritic positron-emitting nanoprobes for the noninvasive imaging of angiogenesis , 2009, Proceedings of the National Academy of Sciences.

[44]  W. Goddard,et al.  Dendritic chelating agents. 1. Cu(II) binding to ethylene diamine core poly(amidoamine) dendrimers in aqueous solutions. , 2004, Langmuir : the ACS journal of surfaces and colloids.

[45]  Zhuxian Zhou,et al.  Degradable dual pH- and temperature-responsive photoluminescent dendrimers. , 2011, Chemistry.

[46]  Andreas M. Nyström,et al.  Linear-Dendritic Polymeric Amphiphiles as Carriers of Doxorubicin-In Vitro Evaluation of Biocompatibility and Drug Delivery , 2012 .

[47]  F. Szoka,et al.  A single dose of doxorubicin-functionalized bow-tie dendrimer cures mice bearing C-26 colon carcinomas , 2006, Proceedings of the National Academy of Sciences.

[48]  N. K. Jain,et al.  The treatment of Glioblastoma Xenografts by surfactant conjugated dendritic nanoconjugates. , 2011, Biomaterials.

[49]  Julianna Kardos,et al.  Assessing toxicity of polyamidoamine dendrimers by neuronal signaling functions , 2012, Nanotoxicology.

[50]  R. Romero,et al.  Inhibition of bacterial growth and intramniotic infection in a guinea pig model of chorioamnionitis using PAMAM dendrimers. , 2010, International journal of pharmaceutics.