European Polymer Congress, EPF 2019
Heraklion Crete, June 9-14, 2019
Characterization data of water-soluble hydrophilic and amphiphilic dendrimers
prodrugs for delivering bioactive chemical entities otherwise non soluble
Silvana Alfei,
*Andrea Spallarossa, Silvia Catena, Federica Turrini, Guendalina Zuccari, Anna Pittaluga, Raffaella Boggia
Dipartimento di Farmacia, Università di Genova, Viale Cembrano 4, I-16148 Genova, Italy
E-mail: alfei@difar.unige.it
ABSTRACT
More than 40% of bioactive chemical entities (BCEs) developed in pharmaceutical industry are almost water-insoluble, poorly orally bioavailable and/or not via parenteral administrable, and this strongly limits their clinical applications. Drug Delivery (DD) is an engineered technology dealing with the development of delivery systems (DDSs) able to solubilize, transport, target release and maintain therapeutic drugs concentration where needed for long periods. DD frequently makes use of nanosized carriers, often positive charged, including dendrimer such as commercially available and strongly cationic PAMAM and PEI. Nowadays, uncharged dendrimer scaffolds modified with amino acids-modified in their cationic form, are preferred because a more controlled number of nitrogen atoms causes less damage to cells. Then, two hydrophilic (1, 2) [1] (Fig. 1) and three amphiphilic (3-5) [2] (Fig. 2) water-soluble dendrimers were prepared and completely characterized.
O O O O O O O O O O O O O O O O O O O O O O O O ArgO O ArgO ArgO O O O ArgO O O O LysO O O O O O O O O O O O O O O O O O O O O O O OArg O OLys O OLys O O O OLys O O O O O O O O O O OO O O O O O O O O OO O O O O ArgO O O O OArg ArgO O O O O ArgO O N O O N O O N O O N O O N O O N OO N O O N O ON O O N CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH 3CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OO H2N HNNH H2N O O H 2N H2N O O HN CH3 OO H N CH3 O ONH H3C LysO OLys O O N H H3C O O HN CH3 O O H2N H2N O O NH2 H2N O O H2N H2N O O NH2 NH2 O O NH2 NH2 O O NH2 H 2N O O NH2 NH2 O O NH2 H2N O O NH 2 NH HNNH2 O O NH 2 H N NH NH2 O O NH2 HNNH NH2 OArg O O H2N N H HN H2N O O NH2 NH HN H2N O O NH2 NH HN NH2 O O NH2 NH HN H2N 81 HCl 1 O O O O O O O O O O O O O O O O O O O O O O O O ArgO O ArgO ArgO O O O ArgO O O O LysO O O O O O O O O O O O O O O O O O O O O O O OArg O OLys O OLys O O O LysO O O O O O O O O O O OO O O O O O O O O OO O O O O ArgO O O O OArg ArgO O O O O ArgO O NH OO N O O N O O N O O N O O NH OO N O O N O ON O O NH CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH 3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH O O NH2 NH2 O O NH CH3 OO NHCH3 O ONH CH3 OLys OLys O O NH CH3 O O NH CH3 O O NH2 NH2 O O NH2 NH2 O O NH2 NH2 O O NH 2 NH2 O O NH2 NH 2 O O NH2 NH 2 O O NH 2 NH2 O O NH2 NH2 O O NH 2 NH NH NH2 O O NH2 NH NH NH2 OArg O O NH2 NH NH NH2 O O NH2 NH NH NH2 O O NH2 NH NH NH2 O O NH2 NH NH NH2 O O NH2 NH2 79 HCl 2 O O O O O O O O O H3C(H2C)16 O NH2 NH HN NH2 OH OH O NH2 NH HN NH2 O O O O O H2N HN NH H2N HO O 8 HCl 3 O O O O H2N HN NH NH2 HO O O O O(CH2)16CH3 O O O O OO O O O O LO LO O AO AO O O O O LO O O LOAO O OO O OA OS O O OL O O O O O SO O AO HO O O O O OOS O OL OA O O O O OL O OS OA O O O O N O N O O N O O N O N 5 37 HCl O O O O O O O O O O (CH2)16CH3 O H2N HN NH H2N O O H2N HN NH H2N O O NH2 H N NH H2N O H2N HNNH H2N O O O O O NH2 NH HN NH2 O O H2N H N HN NH2 O 16 HCl 4 O O O O NH2 NH HN NH2 O O H2N N H NH NH2
Fig. 1: Hydrophilic dendrimers 1, 2 Fig. 2: Amphiphilic dendrimers 3-5
Once established through proper routine investigations, that these materials could work well as DDSs, they have been used to physically entrap two completely insoluble BCEs i.e. the thiocarbamate (O-TC) 6 [3] and Ellagic Acid (EA) 7 (Fig. 3) with the aim at improving their solubility and in parallel at protecting them from early degradation, at promoting their fast cellular up-take and thus reducing eventual systemic toxicity. Without resorting to toxic excipients and harmful solubilizing agents often used despite the resulting unpleasant side effects, five structurally different nanodispersions (DPXs) loaded with 6 [4] and two with 7 [5] were achieved and completely characterized to confirm their structure and to evaluate their potentiality in biomedical applications.
Firstly, FT-IR and NMR analysis were performed
then, in relation to the loaded BCE, water and/or
alcohol-solubility, drug loading capacity, mean size of particles and Z-potential, cytotoxicity or antioxidant power, buffer capacity etc, were taken into account and explored. In the present work an overview of the obtained results organized in tables, graphs and spectra has been provided.
REFERENCES:
1. S. Alfei & S. Catena, Polym. Advan. Technol., 29, 2735 (2018). 2. S. Alfei & S. Catena, Polym. Int., 67, 1572 (2018). 3. A. Spallarossa et al., Eur. J. Med. Chem., 44, 2190 (2009). 4. S. Alfei et al., Eur. J. Pharm. Sci., 124, 153 (2018). 5. S. Alfei et al., New J. Chem., 2019, DOI: 10.1039/c8nj05657a.
6 7
