International Journal of Pharmaceutics 464 (2014) 152–167 Contents lists available at ScienceDirect International Journal of Pharmaceutics j ourna l h om epa ge: www.elsevier.com/locate/ijpharm Pharmaceutical Nanotechnology Can metabolic impairments in experimental diabetes be cured with poly(amido)amine (PAMAM) G4 dendrimers? – In the search for minimizing of the adverse effects of PAMAM administration Magdalena Labieniec-Watala a,∗ , Tomasz Przygodzki b , Katarina Sebekova c , Cezary Watala b a University of Lodz, Faculty of Biology and Environmental Protection, Department of Thermobiology, Pomorska 141/143, 90-236 Lodz, Poland b Department of Haemostasis and Haemostatic Disorders, Medical University of Lodz, University Clinical Hospital No. 2, Zeromskiego 113, 90-549 Lodz, Poland c Institute of Molecular BioMedicine, Comenius University, 811 08 Bratislava, Slovakia a r t i c l e i n f o Article history: Received 14 October 2013 Received in revised form 4 January 2014 Accepted 7 January 2014 Available online 21 January 2014 Keywords: PAMAM dendrimers Streptozotocin-diabetes Survival Diabetic hyperglycaemia markers Sprague-Dawley rats In vivo study a b s t r a c t Poly(amido)amine (PAMAM) G4 dendrimers, given intraperitoneally to diabetic rats, have been reported to scavenge excessive blood glucose and minimize the effects of hyperglycaemia, however, at the cost of reduced survival. This paper is the first to compare the effectiveness of three different routes of PAMAM G4 administration with regard to minimizing the adverse effects of hyperglycaemia in rats. Hence, the aim of the study is to identify the most effective and the least harmful method of dendrimer administration. Control and streptozotocin-diabetic Sprague-Dawley rats were exposed to PAMAM G4 (0.5 mol/kg b.w.) for 60 days, administered intraperitoneally, intragastrically or subcutaneously. Intraperitoneal and subcutaneous administration of PAMAM G4 was found to be most effective in suppressing the long-term markers of hyperglycaemia, while the intragastric route appeared the least effective. Otherwise, the greatest incidence of adverse effects was associated with intraperitoneal and the lowest with subcutaneous delivery. Harmful effects of intragastrical administration were much lower compared to intraperitoneal route, but at the cost of reduced hypoglycaemizing potential. Otherwise, subcutaneous injection represents the best compromise of moderate PAMAM dendrimer toxicity and effective reduction in the markers of long-term severe hyperglycaemia in chronic experimental diabetes. © 2014 Elsevier B.V. All rights reserved. Abbreviations: CMG, control animals given methanol (vehicle) intragastri- cally; CMI, control animals given methanol (vehicle) intraperitoneally; CPG, control animals given PAMAM intragastrically; CPI, control animals given PAMAM intraperi- toneally; DMG, diabetic animals given methanol intragastrically; DMI, diabetic animals given methanol intraperitoneally; DMS, diabetic animals given methanol subcutaneously; DPG, diabetic animals given PAMAM intragastrically; DPI, diabetic animals given PAMAM intraperitoneally; DPS, diabetic animals given PAMAM sub- cutaneously; GRAN, granulocytes; Hb, haemoglobin; LYMPH, lymphocytes; MCV, mean corpuscular volume; MCH, mean cell haemoglobin; MCHC, mean corpuscu- lar haemoglobin concentration; MID, minimum inhibitory dilution a measure of rare cells and a number of precursor white cells; MPV, mean platelet volume; PCT, plateletcrit; PLT, platelet count; STZ, streptozotocin; WBC, white blood cells. ∗ Corresponding author at: University of Lodz, Department of Thermobiology, Pomorska 141/143, 90-236 Lodz, Poland. Tel.: +48 42 635 44 81; fax: +48 42 635 44 73. E-mail addresses: magdalab@biol.uni.lodz.pl (M. Labieniec-Watala), tomasz.przygodzki@umed.lodz.pl (T. Przygodzki), katarina.sebekova@szu.sk (K. Sebekova), cezary.watala@umed.lodz.pl (C. Watala). 1. Introduction The potential application of poly(amido)amine (PAMAM) den- drimers seems very promising, however, both the in vitro and in vivo toxicity profiles of these agents is nowadays considered a major concern. In general, dendrimers are hemolytic and cytotoxic, and these disadvantageous characteristics depend on both the molec- ular weight (generation) and on the number and type of terminal groups on their surface (Domanski et al., 2004; Mukherjee et al., 2010; Prieto et al., 2011). Reports dealing with toxicity of PAMAM dendrimers are largely inconsistent or even contradictory in claiming either considerable, slight or even no adverse side-effects. The majority of studies on PAMAM dendrimers have been performed under in vitro condi- tions, using such standardized systems and assays as transepithelial toxicity or cellular transport and few in vivo reports have been pub- lished of their bioavailability and biocompatibility. Some recent studies, employing mice as animal models, have focused mainly on establishing the maximum tolerated doses for PAMAM dendrimers 0378-5173/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ijpharm.2014.01.011